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Screened Disorders

Screened disorders are listed alphabetically by group on this page.

Most of the disorders on the newborn screening panel are genetic.  A genetic counselor is trained to provide support and information to families impacted by a genetic disorder.  To learn more about genetic counseling, please visit the Genetic Counseling page.

2,4-Dienoyl-CoA reductase (2,4-Di) deficiency

Definition:

2,4-Di deficiency is caused by mutations in the DECR1 gene. Individuals with this disorder are unable to convert certain fats to energy.

Diagnosis:

Diagnostic testing may include quantification of plasma acylcarnitines.

How it is inherited:

2,4-Di deficiency is inherited in an autosomal recessive pattern. Normally a person has two functional DECR1 genes. In people with 2,4 Di deficiency, both genes have a mutation and there is a deficiency of the critical enzyme activity. Each parent of a newborn with 2,4-Di deficiency typically has one functional and one mutated gene and is considered a carrier. When both parents are carriers, the chance of a newborn inheriting two mutated genes is 25%.

Newborn screening:

  • Incidence: 2,4-Di deficiency is extremely rare. The overall incidence is unknown. As of June 2013, only one patient has been identified with 2,4-Di deficiency through newborn screening in New York State.
  • New York State Method of Screening (First Tier): Screening for 2,4-Di deficiency is accomplished by measuring an acylcarnitine (C10:2) by tandem mass spectrometry (MS/MS).
  • Second Tier Screening: None
  • Testing can be affected by: None known due to lack of information available about this disorder.
  • Interpretation/reporting of data: Results are reported as screen negative, borderline or as a referral. A repeat specimen should be collected for a borderline result. Prompt consultation with a specialist is required for a referral.
  • Referral to Specialty Care Center: Patients with an abnormal newborn screen for 2,4-Di deficiency are referred to an Inherited Metabolic Disorder Specialty Care Center for evaluation by a biochemical geneticist trained in the diagnosis and treatment of 2,4-Di deficiency.

Prognosis:

Prognosis is unknown. Outcome was poor in the single patient reported.

Symptoms:

The single baby reported in the literature with 2,4-Di deficiency died at 4 months of age and had low muscle tone and respiratory failure.

Symptoms in carriers:

There has only been one report of a patient with 2,4-Di deficiency. It is unknown if carriers would have any symptoms.

Treatment:

Dietary therapy was initiated in the single patient with this disorder, but did not impact prognosis.

Educational materials:

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2-methyl-3-hydroxybutyryl-CoA dehydrogenase deficiency (MHBD)

Also known as:

2M3HBA

Definition:

2-methyl-3-hydroxybutyryl-CoA dehydrogenase (MHBD) deficiency is an organic acid disorder (inherited metabolic disorder) because abnormal levels of organic acids build-up in the bodies of those affected.

A component of protein (isoleucine) and branched-chain fatty acids are broken down as part of normal metabolism. The HADH2 gene provides instructions for an important enzyme in this process. If there is a mutation in HADH2, the enzyme does not function and isoleucine and the branched-chain fatty acids are not broken down. Toxic metabolites accumulate and cause neurological symptoms.

Diagnosis:

Diagnostic testing may include urine organic acid analysis, HADH2 gene sequencing and MHBD enzyme activity analysis.

How it is inherited:

MHBD deficiency is caused by a mutation in the HADH2 gene on the X chromosome. Because females have two X chromosomes, they have two HADH2 genes. Because males have one X chromosome, they have one HADH2 gene. Males with a nonfunctioning HADH2 gene have MHBD deficiency and females with one HADH2 gene mutation will be carriers. When a mother is a carrier of MHBD deficiency, each son has a 50% chance of inheriting the disorder.

Newborn screening:

  • Incidence: MHBD deficiency is very rare. There are only a few patients reported in the literature.
  • New York State Method of Screening (First Tier): Screening for MHBD deficiency is accomplished by measuring the acylcarnitine C5:1 by tandem mass spectrometry (MS/MS).
  • Second Tier Screening: None
  • Testing can be affected by: Newborn screening cannot distinguish between MHBD deficienct and mitochondrial acetoacetyl-CoA thiolase deficiency (beta-ketothiolase (BKT) deficiency).
  • Interpretation/reporting of data: Results are reported as screen negative, borderline or as a referral. A repeat specimen should be collected for a borderline result. Prompt consultation with a specialist is required for a referral.
  • Referral to Specialty Care Center: Patients with an abnormal newborn screen for MHBD deficiency are referred to an Inherited Metabolic Disorder Specialty Care Center for evaluation by a biochemical geneticist trained in the diagnosis and treatment of MHBD deficiency.

Prognosis:

Prognosis is not well known.  In some patients, neurological symptoms were improved after starting treatment.

Symptoms:

Males with MHBD deficiency have a progressive neurological disorder. Symptoms include rigidity, unusual movements, cortical blindness, seizures and brain abnormalities (atrophy, basal ganglia and periventricular white matter changes).

Symptoms in carriers:

Carriers of MHBD deficiency may have symptoms including developmental delay.

Treatment:

Treatment may include an isoleucine restricted diet.

Educational materials:

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2-Methylbutyryl-CoA dehydrogenase (2-MBCD) deficiency

Also known as:

2-MBAD, short/branched chain acyl-CoA dehydrogenase deficiency, SBCAD deficiency, 2-MBG, 2-methylbutyrylglycinuria

Definition:

2-methylbutyryl-CoA dehydrogenase (2-MBCD) deficiency is a disorder of organic acid metabolism (inherited metabolic disorder).

A component of protein (isoleucine) is broken down as part of normal metabolism. The 2-MBAD gene provides instructions for an important enzyme in this process. If there is a mutation in 2-MBAD gene, the enzyme does not function and isoleucine is not broken down. Toxic metabolites accumulate and may cause neurological damage.

Diagnosis:

Diagnostic testing may include urine organic acid analysis, plasma amino acid analysis and 2-MBAD gene sequencing.

How it is inherited:

2-MBCD deficiency is inherited in an autosomal recessive pattern. Normally a person has two functional genes. In people with 2-MBCD deficiency, both genes have a mutation and there is a deficiency of the critical enzyme activity. Each parent of a newborn with 2-MBCD deficiency typically has one functional and one mutated gene and is considered a carrier. When both parents are carriers, the chance of a newborn inheriting two mutated genes is 25%.

Newborn screening:

  • Incidence: 2-MBCD deficiency is very rare. There are less than 50 patients reported in the literature. There are reports that 2-MBCD deficiency is more common, but likely milder, in people of Hmong descent.
  • New York State Method of Screening (First Tier): Screening for 2-MBCD deficiency is accomplished by measuring C5 (isovalerylcarnitine) by tandem mass spectrometry (MS/MS).
  • Second Tier Screening: None
  • Testing can be affected by: Newborn screening cannot distinguish between 2-MBCD deficiency and isovaleric acidemia (IVA). Pivalic acid, common in many medications (including some antibiotics), can produce an elevated C5 and thus a false positive newborn screen.
  • Interpretation/reporting of data: Results are reported as screen negative, borderline or as a referral. A repeat specimen must be collected for a borderline result. Prompt consultation with a specialist is required for a referral.
  • Referral to Specialty Care Center: Patients with an abnormal newborn screen for 2-MBCD deficiency are referred to an Inherited Metabolic Disorder Specialty Care Center for evaluation by a biochemical geneticist trained in the diagnosis and treatment of 2-MBCD.

Prognosis:

Many patients remain asymptomatic.

Symptoms:

The symptoms of 2-MBCD deficiency are variable from one individual to the next. Many patients diagnosed through newborn screening have remained asymptomatic. There are reports of patients with developmental delay, seizures, low muscle tone and failure to thrive.

Symptoms in carriers:

None known

Treatment:

Treatment may include an isoleucine restricted diet and carnitine supplementation.

Educational materials:

More information:

3-hydroxy-3-methylglutaryl-CoA lyase (HMG-CoA lyase) deficiency

Also known as:

3HMG, 3-hydroxy-3-methylglutaryl coenzyme A lyase deficiency, hydroxymethylglutaric aciduria, 3-OH 3-CH3 glutaric aciduria, 3-OH 3-methyl glutaric aciduria

Definition:

3-hydroxy-3-methylglutaryl-CoA lyase (HMG-CoA lyase) deficiency is a disorder of organic acid metabolism (inherited metabolic disorder).

A component of protein (leucine) is broken down as part of the normal metabolism of fatty acids for energy. The HMGCL gene provides instructions for an important enzyme in this process. If there is a mutation in HMGCL gene, the enzyme does not function, leucine builds up and fatty acids cannot be used for energy. Toxic metabolites also accumulate and may cause symptoms.

Diagnosis:

Diagnostic testing may include urine organic acid analysis, plasma acylcarnitine analysis, HMGCL gene sequencing and enzyme analysis in fibroblasts.

How it is inherited:

HMG-CoA lyase deficiency is inherited in an autosomal recessive pattern. Normally a person has two functional HMGCL genes. In people with HMG-CoA lyase deficiency, both genes have a mutation and there is a deficiency of the critical enzyme activity. Each parent of a newborn with HMG-CoA lyase deficiency typically has one functional and one mutated gene and is considered a carrier. When both parents are carriers, the chance of a newborn inheriting two mutated genes is 25%.

Newborn screening:

  • Incidence: HMG-CoA lyase deficiency is very rare. It is more common in people from Saudi Arabia.
  • New York State Method of Screening (First Tier): Screening for HMG-CoA lyase deficiency is accomplished by measuring the acylcarnitine C5OH by tandem mass spectrometry (MS/MS).
  • Second Tier Screening: None
  • Testing can be affected by: Newborn screening cannot distinguish between HMG-CoA lyase deficiency and other disorders with elevated C5OH (3-MCC, 3-MGA and BKT deficiencies).
  • Interpretation/reporting of data: Results are reported as screen negative, borderline or as a referral. A repeat specimen should be collected for a borderline result. Prompt consultation with a specialist is required for a referral.
  • Referral to Specialty Care Center: Patients with an abnormal newborn screen for HMG-CoA lyase deficiency are referred to an Inherited Metabolic Disorder Specialty Care Center for evaluation by a biochemical geneticist trained in the diagnosis and treatment of HMG-CoA lyase deficiency.

Prognosis:

Some patients completely recover from their first episode, but others continue to have neurological symptoms.

Symptoms:

The age of onset of symptoms varies from the first 5 days of life (30%), the first year of life or as late as adulthood (very rarely). The symptoms may include vomiting, low muscle tone, lethargy and coma. Blood tests show hypoglycemia (low blood sugar), elevated lactate and low ketones (produced when the body uses fats for energy). Symptoms may be caused by an illness or fasting. Some patients are inaccurately diagnosed with Reye syndrome.

Some patients will recover completely from their first episode, but others will have neurological symptoms including seizures and intellectual disability.

There are reports of people with HMG-CoA lyase deficiency that never develop symptoms.

Symptoms in carriers:

None known

Treatment:

Treatment is typically dietary management, including careful monitoring of fat, protein and carbohydrate intake.  Additional medical care, including admission to the hospital for intravenous feedings, may be required during times of illness.

Educational materials:

More information:

3-Methylcrotonyl-CoA carboxylase deficiency (3-MCC)

Also known as:

BMCC deficiency, deficiency of methylcrotonoyl-CoA carboxylase, 3MCC, MCC deficiency, 3-methylcrotonyl-coenzyme A carboxylase deficiency, 3-methylcrotonylglycinuria

Definition:

3-methylcrotonyl CoA carboxylase (3-MCC) deficiency is a disorder of organic acid metabolism (inherited metabolic disorder).

A component of protein (leucine) is broken down as part of normal metabolism. Two genes, MCCC1 and MCCC2 provide instructions for an enzyme in this process. If there are mutations in one of these genes, the enzyme does not function and leucine is not broken down. Toxic metabolites accumulate and cause symptoms.

Diagnosis:

Diagnostic testing may include urine organic acid analysis, plasma amino acid analysis, enzyme analysis in fibroblasts (skin cells) and gene sequencing.

How it is inherited:

3-MCC deficiency is inherited in an autosomal recessive pattern. Normally a person has two functional MCCC1 and MCCC2 genes. In people with 3-MCC deficiency, both copies of one of these genes have a mutation and there is a deficiency of the critical enzyme activity. Each parent of a newborn with 3-MCC deficiency typically has one functional and one mutated gene and is considered a carrier. When both parents are carriers, the chance of a newborn inheriting two mutated genes is 25%.

Newborn screening:

  • Incidence: The incidence of 3-MCC deficiency is 1 in 36,000.
  • New York State Method of Screening (First Tier): Screening for 3-MCC deficiency is accomplished by measuring the acylcarnitine C5OH by tandem mass spectrometry (MS/MS).
  • Second Tier Screening: None
  • Testing can be affected by: Maternal 3-MCC deficiency can cause a false positive in a newborn. Newborn screening cannot distinguish between 3-MCC deficiency and other disorders with elevated C5OH, including HMG-CoA lyase deficiency, beta-ketothiolase deficiency and 3-methylglutaconic acidemia.
  • Interpretation/reporting of data: Results are reported as screen negative, borderline or as a referral. A repeat specimen must be collected for a borderline result. Prompt consultation with a specialist is required for a referral.
  • Referral to Specialty Care Center: Patients with an abnormal newborn screen for 3-MCC deficiency are referred to an Inherited Metabolic Disorder Specialty Care Center for evaluation by a biochemical geneticist trained in the diagnosis and treatment of 3-MCC deficiency.

Prognosis:

For most patients with 3-MCC deficiency, prognosis is excellent and they never develop symptoms.  For patients with symptoms, prognosis is variable and dependent on many factors, including severity of disease and response to treatment.

Symptoms:

The severity and age of onset of symptoms in people with 3-MCC deficiency is variable. Most of the newborns identified through newborn screening in NYS have never developed symptoms. Other newborns develop vomiting, lethargy, low muscle tone and feeding difficulty, which progresses to developmental delay, seizures and coma.

Symptoms in carriers:

None known

Treatment:

Treatment is typically dietary management, including careful monitoring of protein intake.  Additional medical care, including admission to the hospital for intravenous feedings, may be required during times of illness.

Educational materials:

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3-methylglutaconic acidemia, type 1 (3-MGA)

Also known as:

3-methylglutaconyl-CoA hydratase deficiency, 3-MG-CoA-hydratase deficiency

Definition:

3-methylglutaconic acidemia, type 1 (3-MGA) is a disorder of organic acid metabolism (inherited metabolic disorder).

Multiple steps in the body are required to break down leucine, a component of protein. The AUH gene provides instructions for an important step in this process. If there is a mutation in the AUH gene, then leucine is not completely broken down, and toxic metabolites accumulate and may cause neurological symptoms.

Diagnosis:

Diagnostic testing may include urine organic acid analysis and total and free carnitine.

How it is inherited:

3-MGA is inherited in an autosomal recessive pattern. Normally a person has two functional AUH genes. In people with 3-MGA, both genes have a mutation and there is a deficiency of the critical enzyme activity. Each parent of a newborn with 3-MGA typically has one functional and one mutated gene and is considered a carrier. When both parents are carriers, the chance of a newborn inheriting two mutated genes is 25%.

Newborn screening:

  • Incidence: 3-MGA is very rare with only a few cases reported in the literature.
  • New YorkState Method of Screening (First Tier): Screening for 3-MGA is accomplished by measuring the acylcarnitine C5OH by tandem mass spectrometry (MS/MS).
  • Second Tier Screening: None
  • Testing can be affected by: Newborn screening cannot distinguish between 3-MGA and other disorders with elevated C5OH including 3-MCC and HMG.
  • Interpretation/reporting of data: Results are reported as screen negative, borderline or as a referral. A repeat specimen should be collected for a borderline result. Prompt consultation with a specialist is required for a referral.
  • Referral to Specialty Care Center: Patients with an abnormal newborn screen for 3-MGA are referred to an Inherited Metabolic Disorder Specialty Care Center for evaluation by a biochemical geneticist trained in the diagnosis and treatment of 3-MGA.

Prognosis:

Prognosis is not well known because 3-MGA is rare.

Symptoms:

The symptoms of 3-MGA, type 1 are extremely variable. There have been reports of patients with no symptoms. Other patients are reported to have a wide range of neurological symptoms from very mild to a severe movement disorder.

Symptoms in carriers:

Carriers of 3-MGA do not typically have symptoms.

Treatment:

There is not a standard treatment protocol. Supplementation with carnitine may be helpful.

Educational materials:

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Adrenoleukodystrophy (ALD)

Definition:

X-linked adrenoleukodystrophy (ALD) is a genetic disorder caused by mutations in the ABCD1 gene. It is a progressive metabolic condition affecting the adrenal glands and nervous system in males. The ABCD1 gene codes for a peroxisomal membrane protein which is necessary for the degradation of very long chain fatty acids (VLCFAs). Mutations in ABCD1 result in an accumulation of saturated VLCFAs in the brain, adrenal glands, and plasma.

Diagnosis:

All babies who have a positive ALD newborn screen should be assessed by testing the plasma for VLCFAs, and females with an ABCD1 mutation or newborns without a mutation should have their plasmalogen levels measured as well. Babies with confirmed diagnoses must be assessed for adrenal insufficiency and neurological function at a Specialty Care Center with a Pediatric Endocrinologist and Pediatric Neurologist. Assessments of adrenal function include measurements of serum ACTH and cortisol. In addition to a clinical examination, neurological assessment includes regular brain MRIs beginning at 6 months of age.

How it is inherited:

ALD is inherited in an X-linked pattern, meaning that the ABCD1 gene is located on the X chromosome. Males have one X chromosome and one Y chromosome, whereas females have two X chromosomes (and thus two copies of the ABCD1 gene). Therefore, males with an ABCD1 mutation will be affected with the symptoms typically associated with ALD, while females with a mutation are carriers because they have a second, functional ABCD1 gene, and therefore usually don't experience symptoms in childhood. When a woman carries an ABCD1 mutation, the chance for her to pass this mutation on to a son is 50%. The chance for her to pass the ABCD1 mutation to a daughter is also 50%, and the daughter will be a carrier of ALD as well.

Newborn screening:

  • Incidence: The overall incidence of ALD is approximately 1 in 17,000 births. It is panethnic.
  • New York State Method of Screening (First Tier): Screening for ALD is accomplished by analysis of very long chain fatty acids (VLCFAs) by mass spectrometry, specifically the concentration of C26:0. If concentrations are normal, the sample is deemed within acceptable limits. If abnormal, second tier screening is performed.
  • Second Tier Screening: Samples with VLCFA concentrations above a certain threshold will be tested a second time using a more specific assay. If concentrations are normal, the sample is deemed within acceptable limits. If abnormal, third tier screening is performed, however persistent elevations of VLCFAs still warrant referral and further work-up regardless of whether an ABCD1 mutation is present.
  • Third Tier Screening: Sequencing of the ABCD1 gene.
  • Testing can be affected by: Elevations in VLCFAs, including C26:0, may be caused by other Peroxisomal Biogenesis Disorders besides ALD. These include Zellweger Syndrome (ZS), Neonatal Adrenoleukodystrophy (NALD), and Infantile Refsum Disease (IRD). VLCFAs may also be elevated in healthy newborns, thus giving a false positive result. Interpretation/Reporting of data: Results are reported as screen negative, borderline or as a referral. A repeat specimen should be collected for a borderline result. Prompt consultation with a specialist is required for a referral. Referrals are reported out as one mutation or no mutations.
    • When an ABCD1 mutation is identified in a male, it is consistent with a diagnosis of ALD.
    • When an ABCD1 mutation is identified in a female, it is consistent with her being a carrier of ALD.
    • When no mutation is identified in ABCD1, the baby must be evaluated for other Peroxisomal Biogenesis Disorders.
  • Referral to Specialty Care Center: Babies with an abnormal newborn screen for ALD are referred to an Inherited Metabolic Disease Specialty Care Center for a diagnostic evaluation. If diagnosed with ALD, patients will be referred to Pediatric Endocrinology and Pediatric Neurology for clinical assessments of adrenal and neurological function and need for treatment.

Prognosis:

Prognosis is variable and dependent on multiple factors including the severity of disease and response to treatments. The childhood cerebral form of ALD is fatal, but at varying ages. 

Symptoms:

There are three types of ALD, each with different symptoms and age of onset. Disease phenotype cannot be predicted based on VLCFAs, ABCD1 mutation, or family history.

  • Childhood cerebral form - Age of onset is usually between 4 and 8 years. Presenting symptoms may mimic ADHD or hyperactivity, but progress to impaired cognition, behavior, vision, hearing and motor function. Rapid symptom progression usually leads to total disability within 2 years. Brain MRIs are always abnormal in neurologically symptomatic males.
  • Adrenomyeloneuropathy (AMN) - Age of onset is approximately in the late 20’s. Most common symptoms are paraparesis, sphincter disturbances, sexual dysfunction, and often, impaired adrenocortical function. Progression is slower, occurring over several decades.
  • Addison disease only - Age of onset is between 2 and adulthood, but most often by 8 years. Presents with adrenal insufficiency without evidence of neurologic abnormality, but some degree of neurologic dysfunction (usually AMN) may develop later in life.

Symptoms in carriers:

Approximately 20% of female carriers of an ABCD1 mutation develop mild to moderate spastic paraparesis in middle age or later. Their adrenal function is not affected.

Treatment:

Adrenal insufficiency – Adrenal replacement therapy can prevent a potentially life-threatening adrenal crisis, and improves general strength and well-being. It does not slow neurological progression.

Neurological – Hematopoietic stem cell transplant (HSCT) is considered in asymptomatic males with ALD in whom mild MRI abnormalities are present. In these individuals, HSCT has shown long-term benefit and increased survival. HSCT is not needed in individuals who do not have the cerebral form of ALD, and is of limited benefit to males already showing neurological symptoms. Use of Lorenzo’s Oil (a 4:1 mixture of glyceryl-trioleate and glyceryl-trierucate) normalizes plasma VLCFA levels and is under investigation as a preventative measure.

Educational materials:

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Argininemia (ARG)

Also known as:

Arginase deficiency, hyperargininemia

Definition:

Argininemia is a urea cycle disorder (inherited metabolic disorder).

Argininemia is caused by mutations in the ARG1 gene. Individuals with this disorder are unable to break down the amino acid arginine. The urea cycle happens in the liver to remove nitrogen from the body. The breakdown of arginine is the final step of the urea cycle. Without this step, arginine and ammonia accumulate in the body.

Diagnosis:

Diagnostic testing may include quantification of plasma amino acids, ammonia, arginase enzyme and molecular genetic testing of the ARG1 gene.

How it is inherited:

Argininemia is inherited in an autosomal recessive pattern. Normally a person has two functional ARG1 genes. In people with argininemia, both genes have a mutation and there is a deficiency of the critical enzyme activity. Each parent of a newborn with argininemia typically has one functional and one mutated gene and is considered a carrier. When both parents are carriers, the chance of a newborn inheriting two mutated genes is 25%.

Newborn screening:

  • Incidence: The overall incidence is approximately 1 in 300,000 to 1 in 1,000,000.
  • New YorkState Method of Screening (First Tier): Screening for argininemia is accomplished by measuring arginine by tandem mass spectrometry (MS/MS).
  • Second Tier Screening: None
  • Testing can be affected by: Screening for this disorder is not reliable in newborns receiving total parenteral nutrition. In addition, the screen may be within acceptable limits in some patients with argininemia because arginine may not be elevated until 4-5 days of age in some cases.
  • Interpretation/reporting of data: Results are reported as within acceptable limits, borderline or as a referral. A repeat specimen should be collected for a borderline result. Prompt consultation with a specialist is required for a referral.
  • Referral to Specialty Care Center: Patients with an abnormal newborn screen for argininemia are referred to an Inherited Metabolic Disorder Specialty Care Center for evaluation by a biochemical geneticist trained in the diagnosis and treatment of argininemia.

Prognosis:

Prognosis is variable and dependent on multiple factors including the severity of disease.

Symptoms:

Untreated, the first symptom of argininemia is typically slowed growth starting at age one to three years followed by spasticity and loss of developmental milestones.

Symptoms in carriers:

Carriers of argininemia do not typically have symptoms.

Treatment:

Treatment is usually a protein restricted diet and medication to remove nitrogen from the body (sodium benzoate and sodium phenylbutyrate). The specialized diet includes drinking an arginine-free protein formula. If ammonia is very elevated from high protein meals, fasting or illness, in-patient treatment including intravenous fluids, sodium benzoate, sodium phenylbutyrate and dietary management may be required.

Educational materials:

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Argininosuccinic aciduria (ASA) deficiency

Also known as:

Arininosuccinate lyase (ASL) deficiency

Definition:

Argininosuccinic aciduria (ASA) deficiency is a urea cycle disorder (inherited metabolic disorder).

ASA deficiency is caused by mutations in the ASL gene. The urea cycle removes nitrogen from the body in the form of ammonia. Also during the urea cycle, an essential amino acid, arginine, is processed for use by the body. Individuals with ASA deficiency are unable to remove ammonia or process arginine. The accumulation of ammonia is highly toxic.

Diagnosis:

Diagnostic testing may include quantification of plasma amino acids, ammonia, ASL enzyme and molecular genetic testing of the ASL gene.

How it is inherited:

ASA deficiency is inherited in an autosomal recessive pattern. Normally a person has two functional ASL genes. In people with ASA deficiency, both genes have a mutation and there is a deficiency of the critical enzyme activity. Each parent of a newborn with ASA deficiency typically has one functional and one mutated gene and is considered a carrier. When both parents are carriers, the chance of a newborn inheriting two mutated genes is 25%.

Newborn screening:

  • Incidence: The overall incidence is 1 in 70,000.
  • New York State Method of Screening (First Tier): Screening for ASA deficiency is accomplished by measuring citrulline by tandem mass spectrometry (MS/MS).
  • Second Tier Screening: None
  • Testing can be affected by: Screening for this disorder is not reliable in newborns receiving total parenteral nutrition.
  • Interpretation/reporting of data: Results are reported as screen negative, borderline or as a referral. A repeat specimen should be collected for a borderline result. Prompt consultation with a specialist is required for a referral.
  • Referral to Specialty Care Center: Patients with an abnormal newborn screen for ASA deficiency are referred to an Inherited Metabolic Disorder Specialty Care Center for evaluation by a biochemical geneticist trained in the diagnosis and treatment of ASA deficiency.

Prognosis:

Prognosis is variable and dependent on multiple factors, including the severity of disease.

Symptoms:

There are two forms of ASA deficiency, severe neonatal-onset and late-onset.

Severe neonatal onset: Ammonia is very elevated in the first few days of life, causing vomiting and lethargy. Untreated infants will develop seizures and go into a coma, which may result in death.

Late-onset: Elevated ammonia is triggered by illness or stress in this form. The symptoms may be neurological (developmental delay, intellectual disability, seizures, ADHD), liver disease, coarse, brittle hair and high blood pressure.

Symptoms in carriers:

Carriers of ASA deficiency do not typically have symptoms.

Treatment:

 Treatment is usually a protein restricted diet and supplementation with arginine. Medication may also be given to remove nitrogen from the body (sodium benzoate and sodium phenylbutyrate). If ammonia is very elevated from high protein meals, fasting or illness, in-patient treatment including intravenous fluids, sodium benzoate, sodium phenylbutyrate and dietary management may be required. If these treatments fail, hemodialysis may be needed. There have been reports of liver transplants as a treatment for ASA deficiency.

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Beta-ketothiolase (BKT) deficiency

Also known as:

2-alpha-methyl-3-hydroxybutyricacidemia, 3-alpha-ketothiolase deficiency, 3-alpha-ktd deficiency, 3-alpha-oxothiolase deficiency, alpha-Methylacetoacetic aciduria, 3-Ketothiolase deficiency, MAT deficiency, 3-Methylhydroxybutyric acidemia, Mitochondrial acetoacetyl-CoA thiolase deficiency

Definition:

Beta-ketothiolase (BKT) deficiency is a disorder of organic acid metabolism (inherited metabolic disorder).

A component of protein (isoleucine) is broken down as part of normal metabolism. The ACAT1 gene provides instructions for an important enzyme in this process. If there is a mutation in the ACAT1 gene, the enzyme does not function and isoleucine is not broken down. The breakdown of ketones, which are needed for the body to make energy, is also impacted. Toxic metabolites accumulate and may cause symptoms. The accumulation of ketones is called ketoacidosis.

Diagnosis:

Diagnostic testing may include urine organic acid analysis, plasma acylcarnitine analysis, ACAT1 gene sequencing and enzyme analysis in fibroblasts.  The urine organic acid analysis and acylcarnitine profile may be normal in milder cases unless the patient is given an isoleucine challenge.

How it is inherited:

BKT deficiency is inherited in an autosomal recessive pattern. Normally a person has two functional ACAT1 genes. In people with BKT deficiency, both genes have a mutation and there is a deficiency of the critical enzyme activity. Each parent of a newborn with BKT deficiency typically has one functional and one mutated gene and is considered a carrier. When both parents are carriers, the chance of a newborn inheriting two mutated genes is 25%.

Newborn screening:

  • Incidence: BKT deficiency is very rare. It occurs in less than 1 in 1 million newborns.
  • New York State Method of Screening (First Tier): Screening for BKT deficiency is accomplished by measuring the acylcarnitines C5:1 and C5OH by tandem mass spectrometry (MS/MS).
  • Second Tier Screening: None
  • Testing can be affected by: Newborn screening cannot distinguish between BKT deficiency and other disorders with elevated C5OH (3-MCC and HMG-CoA lyase deficiency) or elevated C5:1 (MHBD deficiency).
  • Interpretation/reporting of data: Results are reported as screen negative, borderline or as a referral. A repeat specimen must be collected for a borderline result. Prompt consultation with a specialist is required for a referral.
  • Referral to Specialty Care Center: Patients with an abnormal newborn screen for BKT deficiency are referred to an Inherited Metabolic Disorder Specialty Care Center for evaluation by a biochemical geneticist trained in the diagnosis and treatment of BKT deficiency.

Prognosis:

Most patients make a full recovery between episodes, although some patients are left with remaining developmental delay.

Symptoms:

The severity and age of onset of symptoms in people with BKT deficiency is variable. The symptoms usually begin during the first 2 years of life, but some people with BKT deficiency never develop symptoms. The symptoms of BKT deficiency may be brought on by an illness, fasting or a high protein meal. Symptoms usually begin with vomiting and breathing difficulty and may progress to lethargy, seizures and coma. There are some reports of patients with developmental delay.

Symptoms in carriers:

None known

Treatment:

Treatment is typically dietary management including careful monitoring of protein and carbohydrate intake.  Additional medical care, including admission to the hospital for intravenous feedings, may be required during times of illness.

Educational materials:

More information:

Biotinidase Deficiency (BIOT)

Also known as:

BIOT, BTD deficiency, late-onset biotin responsive multiple carboxylase deficiency

Definition:

Biotinidase deficiency is a disorder of vitamin metabolism (inherited metabolic disorder).

Biotinidase deficiency is caused by mutations in the BTD gene. Biotin is in many foods (milk, egg yolk). The enzyme biotinidase is needed to make additional biotin available for processes in the body, including the break down of other components of food (fat, protein, carbohydrates).

Diagnosis:

Diagnostic testing includes measuring serum biotinidase enzyme activity. There may also be abnormalities on urine organic acid analysis and plasma acylcarnitine analysis. Molecular genetic testing of the BTD gene is available.

How it is inherited:

Biotinidase deficiency is inherited in an autosomal recessive pattern. Normally a person has two functional BTD genes. In people with biotinidase deficiency, both genes have a mutation and there is a deficiency of the critical enzyme activity. Each parent of a newborn with biotinidase deficiency typically has one functional and one mutated gene and is considered a carrier. When both parents are carriers, the chance of a newborn inheriting two mutated genes is 25%.

Newborn screening:

  • Incidence: The overall incidence is approximately 1 in 60,000.
  • New York State Method of Screening (First Tier): Screening for biotinidase deficiency is accomplished by a qualitative colorimetric assay.
  • Second Tier Screening: None
  • Testing can be affected by: False positive results can be caused by improper specimen collection or drying, including samples placed in plastic prior to drying, exposure to heat and humidity or delayed transit. Impaired liver function and prematurity can also cause a false positive result. A false negative may be caused by the administration of antibiotic or blood transfusion.
  • Interpretation/reporting of data: Results are reported as within acceptable limits, borderline or as a referral. A repeat specimen should be collected for a borderline result. Prompt consultation with a specialist is required for a referral.
  • Referral to Specialty Care Center: Patients with an abnormal newborn screen for biotinidase deficiency are referred to an Inherited Metabolic Disorder Specialty Care Center for evaluation by a biochemical geneticist trained in the diagnosis and treatment of biotinidase deficiency.

Prognosis:

Prognosis is excellent if biotin treatment is started before the onset of symptoms and taken continuously.

Symptoms:

If treated prior to the onset of symptoms, most people with biotinidase deficiency do not have symptoms. If untreated, symptoms may appear between 1 and 10 weeks of age. The symptoms are variable and may include seizures, hypotonia (low muscle tone), developmental delay, hearing loss, vision problems, ataxia (poor balance and coordination), skin rashes, hair loss and candidiasis (fungal infection). If treated prior to onset, symptoms will not appear in most cases.

Symptoms in carriers:

Carriers of biotinidase deficiency do not typically have symptoms.

Treatment:

Treatment is oral supplementation with biotin.

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Carnitine acylcarnitine translocase (CAT) deficiency

Also known as:

CACT deficiency

Definition:

CAT deficiency is caused by mutations in the SLC25A20 gene. Individuals with this disorder are unable to convert certain fats to energy and may develop symptoms during times of high energy need such as fasting or illness.

Diagnosis:

Diagnostic testing may include quantification of plasma acylcarnitines, molecular genetic testing of the SLC25A20 gene and functional analysis of fatty acid oxidation on fibroblasts (skin cells).

How it is inherited:

CAT deficiency is inherited in an autosomal recessive pattern. Normally a person has two functional SLC25A20 genes. In people with CAT deficiency, both genes have a mutation and there is a deficiency of the critical enzyme activity. Each parent of a newborn with CAT deficiency typically has one functional and one mutated gene and is considered a carrier. When both parents are carriers, the chance of a newborn inheriting two mutated genes is 25%.

Newborn screening:

  • Incidence: CAT deficiency is very rare. There are less than 50 reported cases.
  • New York State Method of Screening (First Tier): Screening for CAT deficiency is accomplished by measuring acylcarnitines (C16 and C18:1) by tandem mass spectrometry (MS/MS) in combination with a low value for the ratio of C0/(C16+C18:1).
  • Second Tier Screening: None
  • Testing can be affected by: Newborn screening cannot distinguish CAT deficiency from Carnitine palmitoyltransferase 2 (CPT-II) deficiency.
  • Interpretation/reporting of data: Results are reported as screen negative or as a referral. Prompt consultation with a specialist is required for a referral.
  • Referral to Specialty Care Center: Patients with an abnormal newborn screen for CAT deficiency are referred to an Inherited Metabolic Disorder Specialty Care Center for evaluation by a biochemical geneticist trained in the diagnosis and treatment of CAT deficiency.

Prognosis:

Prognosis is poor and most infants die before 3 months. The prognosis for the milder form is not well known because the disorder is so rare.

Symptoms:

CAT deficiency is very rare and not well described. Symptoms are usually severe and most patients have died by 3 months of age from hypoglycemia, liver dysfunction, seizures, cardiomyopathy and arrhythmias. There have been reports of milder cases associated with hypoglycemia encephalopathy during times of high energy need.

Symptoms in carriers:

Carriers of CAT deficiency do not typically have symptoms.

Treatment:

Treatment is dietary, including avoidance of fasting. There is a single report of successful treatment using a specialized diet and peritoneal dialysis.

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Carnitine palmitoyltransferase 2 (CPT-II) deficiency

Definition:

Carnitine palmitoyltransferase 2 (CPT-II) deficiency is a fatty acid oxidation disorder (inherited metabolic disorder).

CPT-II deficiency is caused by mutations in the CPT-2 gene. Individuals with this disorder are unable to convert certain fats to energy and may develop symptoms during times of high energy need such as fasting or illness.

Diagnosis:

Diagnostic testing may include an acylcarnitine profile, CPT-2 enzyme analysis and molecular genetic analysis of the CPT-2 gene.

How it is inherited:

CPT-II deficiency is inherited in an autosomal recessive pattern. Normally a person has two functional CPT-2 genes. In people with CPT-II deficiency, both genes have a mutation and there is a deficiency of the critical enzyme activity. Each parent of a newborn with CPT-II deficiency typically has one functional and one mutated gene and is considered a carrier. When both parents are carriers, the chance of a newborn inheriting two mutated genes is 25%.

Newborn screening:

  • Incidence: CPT-II deficiency is rare. There have been less than 50 patients with the severe infantile and neonatal form reported in the literature. Although more common than the early onset forms, the myopathic form is still very rare, and has been reported in less than 500 people.
  • New York State Method of Screening (First Tier): Screening for CPT-II deficiency is accomplished by measuring acylcarnitines (C16 and C18:1) by tandem mass spectrometry (MS/MS), in combination with a low value for the ratio of C0/(C16+C18:1).
  • Second Tier Screening: None
  • Testing can be affected by: Screening may be normal in patients who received IV glucose or who were not ill when the specimen was collected. Newborn screening cannot distinguish CPT-II from carnitine acylcarnitine translocase (CAT) deficiency.
  • Interpretation/reporting of data: Results are reported as screen negative or as a referral. Prompt consultation with a specialist is required for a referral.
  • Referral to Specialty Care Center: Patients with an abnormal newborn screen for CPT-II deficiency are referred to an Inherited Metabolic Disorder Specialty Care Center for evaluation by a biochemical geneticist trained in the diagnosis and treatment of CPT-II deficiency.

Prognosis:

Prognosis is poor for the neonatal and severe infantile forms. For the myopathic form, prognosis is variable and dependent on multiple factors, including the severity of disease and response to treatments.

Symptoms:

There are three types of CPT-II: neonatal, severe infantile and myopathic.

Neonatal: The neonatal form is lethal and appears in the first few days of life. Symptoms include respiratory distress, liver failure, hypoketotic hypoglycemia (low ketones and low blood sugar), cardiomyopathy (heart muscle disease) and seizures.

Severe infantile: Infants with severe CPT-II deficiency typically have liver failure, hypoketotic hypoglycemia (low ketones and low blood sugar), cardiomyopathy (heart muscle disease) and seizures. The symptoms begin within the first year of life.

Myopathic: The symptoms of this form of CPT-II deficiency can begin anytime during the lifespan. Symptoms include muscle pain and weakness due to extensive exercise, physical stress or illness and myoglobinuria (myoglobin in the urine).

Symptoms in carriers:

Carriers of CPT-II deficiency do not typically have symptoms.

Treatment:

Treatment is dietary, including avoidance of fasting, a high-carbohydrate, low fat diet and carnitine supplementation. During times of illness, hospitalization may be required to monitor and treat hypoglycemia.

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Carnitine palmitoyltransferase I (CPT-I) deficiency

Also known as:

CPT-1A

Definition:

Carnitine palmitoyltransferase I (CPT-I) deficiency is a fatty acid oxidation disorder (inherited metabolic disorder).

CPT-I deficiency is caused by mutations in the CPT-1A gene. Individuals with this disorder are unable to convert certain fats to energy and may develop symptoms during times of high energy need such as fasting or illness.

Diagnosis:

Diagnostic testing may include quantification of total and free carnitines, Creatine Kinase (CK), liver enzymes, molecular genetic analysis of the CPT-1A gene and fatty acid oxidation studies on fibroblasts (skin cells).

How it is inherited:

CPT-I deficiency is inherited in an autosomal recessive pattern. Normally a person has two functional CPT-1A genes. In people with CPT-I deficiency, both genes have a mutation and there is a deficiency of the critical enzyme activity. Each parent of a newborn with CPT-I deficiency typically has one functional and one mutated gene and is considered a carrier. When both parents are carriers, the chance of a newborn inheriting two mutated genes is 25%.

Newborn screening:

  • Incidence: CPT-I deficiency is rare. There have been about 50 patients reported in the literature. It is more common in the Inuit and Hutterite populations.
  • New York State Method of Screening (First Tier): Screening for CPT-I deficiency is accomplished by measuring the ratio of acylcarnitines C0/C16+C18 by tandem mass spectrometry (MS/MS).
  • Second Tier Screening: None
  • Testing can be affected by: Screening may be normal in patients who received IV glucose or who were not ill when the specimen was collected.
  • Interpretation/reporting of data: Results are reported as within acceptable limits, borderline or as a referral. A repeat specimen should be collected for a borderline result. Prompt consultation with a specialist is required for a referral.
  • Referral to Specialty Care Center: Patients with an abnormal newborn screen for CPT-I deficiency are referred to an Inherited Metabolic Disorder Specialty Care Center for evaluation by a biochemical geneticist trained in the diagnosis and treatment of CPT-I deficiency.

Prognosis:

Prognosis is variable and dependent on multiple factors, including the severity of disease and response to treatments.

Symptoms:

The symptoms of CPT-I are variable from one individual to the next. The first symptom of CPT-I deficiency, hypoketotic hypoglycemia (low ketones and low blood sugar), usually begins before 2 years of age during an illness (fever or vomiting). Other symptoms may include liver dysfunction, hepatomegaly (enlarged liver), muscle weakness, cardiomyopathy (heart muscle disease) and rhabdomyolysis (breakdown of muscle). There is also an adult onset form of CPT-I that causes myopathy (muscle disease).

Symptoms in carriers:

Carriers of CPT-I deficiency do not typically have symptoms. However, a mother who is pregnant with a baby with CPT-I deficiency is at risk of illness during pregnancy. The mother may develop AFLP (acute fatty liver of pregnancy).

Treatment:

Treatment is dietary, including avoidance of fasting, a high-carbohydrate, low fat diet and supplementation with medium-chain triglycerides (MCT) as a source of supplemental calories.  Treatment for cardiac involvement or rhabdomyolysis is supportive.  During times of illness, hospitalization may be required to monitor and treat hypoglycemia.  Some physicians may recommend consuming uncooked cornstarch before bedtime.

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Carnitine Uptake Defect (CUD)

Also known as:

carnitine transporter deficiency, carnitine uptake deficiency, renal carnitine transport defect, systemic carnitine deficiency

Definition:

Carnitine uptake defect (CUD) is a fatty acid oxidation disorder (inherited metabolic disorder).

CUD is caused by mutations in the SLC22A5 gene, which provides instructions for a protein that moves carnitine into the cells. Carnitine is needed in the cell to convert certain fats to energy. People with CUD may have symptoms during times of high energy need such as when fasting or ill.

Diagnosis:

Diagnostic testing includes quantification of plasma acylcarnitines and molecular genetic testing of the SLC22A5 gene. Testing may also include carnitine transport studies on fibroblasts (skin cells).

How it is inherited:

CUD is inherited in an autosomal recessive pattern. Normally a person has two functional SLC22A5 genes. In people with CUD, both genes have a mutation and there is a deficiency of the critical protein. Each parent of a newborn with CUD typically has one functional and one mutated gene and is considered a carrier. When both parents are carriers, the chance of a newborn inheriting two mutated genes is 25%.

Newborn screening:

  • Incidence: The overall incidence is approximately 1 in 100,000.
  • New York State Method of Screening (First Tier): Screening for CUD is accomplished by measuring total acylcarnitines and free carnitine by tandem mass spectrometry (MS/MS).
  • Second Tier Screening: None
  • Testing can be affected by: Maternal CUD
  • Interpretation/reporting of data: Results are reported as within acceptable limits, borderline or as a referral. A repeat specimen should be collected for a borderline result. Prompt consultation with a specialist is required for a referral.
  • Referral to Specialty Care Center: Patients with an abnormal newborn screen for CUD are referred to an Inherited Metabolic Disorder Specialty Care Center for evaluation by a biochemical geneticist trained in the diagnosis and treatment of CUD.

Prognosis:

Prognosis is good as long as carnitine supplementation is taken.

Symptoms:

The symptoms are extremely variable. Some people with CUD never develop symptoms. In some children, symptoms may begin in infancy or early childhood and include cardiac (heart) symptoms (cardiomyopathy), irritability, lethargy, hepatomegaly (enlarged liver) and intermittent hypoglycemia (low blood sugar). Symptoms may also begin in early childhood (myopathy and cardiomyopathy) or adulthood (chronic fatigue). Myopathy is a muscle disease.

Symptoms in carriers:

Carriers of CUD do not typically have symptoms.

Treatment:

Treatment is carnitine supplementation.

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Citrullinemia (CIT)

Also known as:

Citrullinuria, CIT, argininosuccinate synthase deficiency

Definition:

Citrullinemia is a urea cycle disorder (inherited metabolic disorder).

Type 1 citrullinemia is caused by mutations in the ASS1 gene. Individuals with mutations in ASS1 have low or absent argininosuccinate synthase enzyme activity, which is needed for the third step of the urea cycle. The urea cycle is a process in the liver to remove nitrogen from the body. Nitrogen (in the form of ammonia) accumulates in the body. The accumulation of ammonia is highly toxic.

Diagnosis:

Diagnostic testing may include quantification of plasma amino acids, ammonia, argininosuccinate synthase enzyme activity and molecular genetic testing of the ASS1 gene.

How it is inherited:

Citrullinemia is inherited in an autosomal recessive pattern. Normally a person has two functional ASS1 genes. In people with citrullinemia, both genes have a mutation and there is a deficiency of the critical enzyme activity. Each parent of a newborn with citrullinemia typically has one functional and one mutated gene and is considered a carrier. When both parents are carriers, the chance of a newborn inheriting two mutated genes is 25%.

Newborn screening:

  • Incidence: The overall incidence is approximately 1 in 57,000 births.
  • New York State Method of Screening (first tier): Screening for citrullinemia is accomplished by measuring citrulline by tandem mass spectrometry (MS/MS).
  • Confirmatory testing (second tier): None
  • Testing can be affected by: Screening for this disorder is not reliable in newborns receiving total parenteral nutrition.
  • Interpretation/reporting of data: Results are reported as screen negative, borderline or as a referral. A repeat specimen should be collected for a borderline result. Prompt consultation with a specialist is required for a referral.
  • Referral to Specialty Care Center: Patients with an abnormal newborn screen for citrullinemia are referred to an Inherited Metabolic Disorder Specialty Care Center for evaluation by a biochemical geneticist trained in the diagnosis and treatment of citrullinemia.

Prognosis:

Prognosis is poor for the neonatal onset form. Infants that receive prompt treatment may survive, but often have remaining neurological symptoms. Prognosis for the milder form is variable, and dependent on response to treatment.

Symptoms:

The symptoms of citrullinemia are variable and there are three different types (classic neonatal-onset, mild later-onset, asymptomatic). The classic neonatal form is very serious. Infants appear healthy at birth, but can quickly become lethargic, begin vomiting and having seizures, and develop increased intracranial pressure. Untreated, infants can progress to coma and death. Infants with the milder form are at risk for similar symptoms to the neonatal form, but they are less severe.

Symptoms in carriers:

Carriers of citrullinemia do not typically have symptoms.

Treatment:

Treatment is usually a protein restricted diet and medication to remove nitrogen from the body (sodium benzoate and phenylacetate). If ammonia is very elevated from high protein meals, fasting or illness, in-patient treatment including intravenous fluids, sodium benzoate, phenylacetate and dietary management may be required. If these treatments fail, hemodialysis may be needed. There have been reports of liver transplants as a treatment for citrullinemia.

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Cobalamin A,B cofactor deficiency (Cbl A,B)

Also known as:

CblA is also referred to as: Methylmalonic acidemia cblA type; CblB is also referred to as: Methylmalonic acidemia cblB typ

Definition:

Cobalamin A cofactor deficiency (cblA) and cobalamin B cofactor deficiency (cblB) are forms of methylmalonic acidemia, a disorder of organic acid metabolism. Methylmalonyl-CoA is a product of the breakdown of several amino acids, as well as some fats and cholesterol. Methylmalonyl-CoA mutase breaks down methylmalonyl-CoA. Partial or complete absence of methylmalonyl-CoA mutase results in accumulation of methylmalonic acid and other damaging substances.

Cobalamin A cofactor deficiency results from a reduction or absence of adenosylcobalamin (AdoCbl), a coenzyme for methylmalonyl-CoA mutase. Mutations in the MMAA gene cause dysfunction or absence of AdoCbl, which results in accumulation of methylmalonic acid.

Cobalamin B cofactor deficiency results from a reduction or absence of cob(I)alamin transferase, which is involved in the synthesis of adenosylcobalamin (AdoCbl). Mutations in the MMAB gene cause dysfunction or absence of cob(I)alamin transferase, and therefore, AdoCbl.

Diagnosis:

Diagnostic testing may include urine and plasma organic acid analyses, vitamin B12 analysis, enzyme analysis and genetic testing of the MMAA or MMAB genes.

How it is inherited:

CblA and cblB are inherited in autosomal recessive patterns. Normally a person has two functional copies of the MMAA and MMAB genes. In people with cblA, both copies of the MMAA gene have a mutation and there is a deficiency of the critical enzyme. Each parent of a newborn with cblA typically has one functional and one mutated copy of the gene and is considered a carrier. When both parents are carriers, the chance of a newborn inheriting two mutated genes is 25%. The same is true for cblB and MMAB mutations.

Newborn screening:

  • Incidence: Methylmalonic acidemia has an incidence of approximately 1 in 50,000 to 1 in 100,000. CblA and CblB are rare.
  • New York State Method of Screening (First Tier): Screening for cblA and cblB is accomplished by measuring the acylcarnitines C3 (propionylcarnitine) and C4DC (methylmalonylcarnitine) by tandem mass spectrometry (MS/MS).
  • Second Tier Screening: None
  • Testing can be affected by: Maternal B12 deficiency
  • Interpretation/reporting of data: Results are reported as screen negative, borderline or as a referral. A repeat specimen should be collected for a borderline result. Prompt consultation with a specialist is required for a referral.
  • Referral to Specialty Care Center: Patients with an abnormal newborn screen for cblA or cblB are referred to an Inherited Metabolic Disorder Specialty Care Center for evaluation by a biochemical geneticist trained in the diagnosis and treatment of cblA and cblB.

Prognosis:

If the low-protein diet is started promptly, most children with cblA and cblB have normal growth and development and symptoms may be prevented. A delay in treatment can not reverse symptoms that are already present.

Symptoms:

CblA: Onset of symptoms occurs in the first few months or years of life. Infants with cblA may exhibit vomiting, anorexia, failure to thrive, hypotonia, and developmental delay. Some individuals may present with an aversion to protein, and/or have vomiting or lethargy after protein intake. These babies are at risk for catastrophic decompensation.

CblB: Onset of symptoms usually occurs in the first few weeks or months of life. While normal-appearing at birth, babies with cblB quickly develop lethargy, vomiting, dehydration, hepatomegaly, hypotonia and encephalopathy. Laboratory tests done at this point will typically show metabolic acidosis, ketosis and ketonuria, hyperammonemia, and hyperglycemia. A less severe clinical presentation of cblB is also possible.

Symptoms in carriers:

Carriers of cblA or cblB do not typically have symptoms.

Treatment:

Management requires a low-protein, high-calorie diet, as well as carnitine supplementation. Individuals with cblA and cblB are usually responsive to vitamin B12 therapy. It is recommended that children and adults with cblA and cblB should avoid going for long periods without food. Special management protocols are recommended for critically ill individuals.

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Cobalamin C,D cofactor deficiency (Cbl C,D)

Also known as:

CblC is also referred to as: Methylmalonic acidemia and homocystinuria cblC type, vitamin B12-responsive methylmalonic aciduria and homocystinuria; CblD is also referred to as: Methylmalonic acidemia and homocystinuria cblD type

Definition:

Cobalamin C cofactor deficiency (cblC) and cobalamin D cofactor deficiency (cblD) are forms of methylmalonic acidemia with homocystinuria, a disorder of organic acid metabolism. Methylmalonyl-CoA is a product of the breakdown of several amino acids, as well as some fats and cholesterol. Methylmalonyl-CoA mutase breaks down methylmalonyl-CoA. Partial or complete absence of methylmalonyl-CoA mutase results in accumulation of methylmalonic acid and other damaging substances.

Cobalamin C cofactor deficiency is caused by mutations in the MMACHC gene. This gene produces a protein that helps regulate cobalamin, which is converted into adenosylcobalamin (AdoCbl) or methylcobalamin (MeCbl). AdoCbl is a coenzyme for methylmalonyl-CoA mutase, so mutations in MMACHC result in accumulation of methylmalonic acid. MeCbl is a cofactor for methionine synthase, which converts homocysteine to methionine. Therefore, mutations in MMACHC also result in homocystinuria.

Cobalamin D cofactor deficiency is caused by mutations in the MMADHC gene. This gene produces a protein that helps to convert cobalamin into AdoCbl or MeCbl. AdoCbl is a coenzyme for methylmalonyl-CoA mutase, so mutations in MMADHC result in accumulation of methylmalonic acid. MeCbl is a cofactor for methionine synthase, which converts homocysteine to methionine. Therefore, mutations in MMADHC also result in homocystinuria.

Diagnosis:

Diagnostic testing may include urine and plasma organic acid analyses, vitamin B12 analysis, plasma and urine total homocysteine levels, enzyme analysis and genetic testing of the MMACHC or MMADHC genes.

How it is inherited:

CblC and cblD are inherited in autosomal recessive patterns. Normally a person has two functional copies of the MMACHC gene and two of the MMADHC gene. In people with cblC, both copies of the MMACHC gene have a mutation and there is a deficiency of the critical enzyme. Each parent of a newborn with cblC typically has one functional and one mutated copy of the gene and is considered a carrier. When both parents are carriers, the chance of a newborn inheriting two mutated genes is 25%. The same is true for cblD and MMADHC mutations.

Newborn screening:

  • Incidence: Methylmalonic acidemia has an incidence of approximately 1 in 50,000 to 1 in 100,000. CblC and CblD are rare.
  • New York State Method of Screening (First Tier): Screening for cblC and cblD is accomplished by measuring the acylcarnitine C3 (propionylcarnitine) and methionine by tandem mass spectrometry (MS/MS).
  • Second Tier Screening: None
  • Testing can be affected by: Maternal B12 deficiency
  • Interpretation/reporting of data: Results are reported as screen negative, borderline or as a referral. A repeat specimen should be collected for a borderline result. Prompt consultation with a specialist is required for a referral.
  • Referral to Specialty Care Center: Patients with an abnormal newborn screen for cblC or cblD are referred to an Inherited Metabolic Disorder Specialty Care Center for evaluation by a biochemical geneticist trained in the diagnosis and treatment of cblC and cblD.

Prognosis:

Prognosis is variable and dependent on multiple factors including the severity of disease and response to treatment. 

Symptoms:

CblC: CblC has a variable age of onset. Some infants with cblC are small for gestational age, or have congenital microcephaly. Within the first two weeks of life, failure to thrive is common and many infants experience acidosis. Infantile spasms are seen in some babies with cblC. Children with the deficiency may present with poor head growth, cytopenias, global developmental delay, encephalopathy, hypotonia and seizures. Adults may present with confusion, cognitive decline and megaloblastic anemia, and a brain MRI may show leukodystrophy. Retinopathy and renal and hepatic dysfunction are also seen in cblC at all ages.

CblD: CblD has a variable age of onset and presentation, however most children present in the first years of life with failure to thrive, megaloblastic anemia, developmental delay, weakness, hypotonia, seizures, and/or altered mental status.

Symptoms in carriers:

Carriers of cblC or cblD do not typically have symptoms.

Treatment:

A special diet is not needed for cblC or cblD, although supplementation with carnitine, pyridoxine, folate and methionine may be of benefit.  Individuals with cblC and cblD are usually responsive to vitamin B12 therapy.  Treatment with betaine is helpful for individuals with homocystinuria.  Special management protocols are recommended for critically ill individuals.

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Congenital Adrenal Hyperplasia (CAH)

Also known as:

CAH1, CYP21 deficiency, Hyperandrogenism, nonclassic type, due to 21-hydroxylase deficiency

Definition:

Congenital adrenal hyperplasia (CAH) is a group of inherited endocrine disorders of impaired steroid hormone production by the adrenal glands. The synthesis of cortisol in the adrenal gland requires the production of a number of different enzymes, the lack of which will result in CAH. In 95% of CAH cases, 21-hydroxylase deficiency causes CAH and therefore newborn screening tests for the deficiency in this enzyme. In 21-hydroxylase deficiency CAH, the adrenal glands produce too much male sex hormone (androgens) which cause many of the symptoms of CAH. Additionally, in severe forms of CAH, the resultant lack of cortisol and aldosterone can cause life threatening complications. Cortisol is important for the body’s stress response and for controlling blood sugar levels. Aldosterone is important for regulating sodium balance in the body.

Diagnosis:

Diagnostic testing may include 17-hydroxyprogesterone, plasma renin activity, serum electrolytes, steroid profile, adrenocorticotropic hormone (ACTH) stimulation testing and CYP21A2 DNA testing.

How it is inherited:

CAH is inherited in an autosomal recessive pattern. Normally a person has two functional CYP21A2 genes. In people with CAH due to 21-hydroxylase deficiency, both genes have a mutation and cortisol is not produced in the adrenal gland. Each parent of a newborn with CAH typically has one functional and one mutated gene and is considered a carrier. When both parents are carriers, the chance of a newborn inheriting two mutated genes is 25%.

Newborn screening:

  • Incidence: The incidence of classic CAH is 1 in 15,000.
  • New York State Method of Screening (First Tier): Screening for CAH due to 21-hydroxylase deficiency is accomplished by measuring 17-hydroxyprogesterone (17-OHP) by immunoassay. 21-hydroxylase deficiency leads to accumulation of the 17-OHP hormone and therefore elevated levels of 17-OHP could indicate CAH. The cut-off level for the test varies based on the baby’s birth weight and age.
  • Second Tier Screening: None
  • Testing can be affected by: Newborn screening cannot detect all cases of 21-hydroxylase deficiency related CAH. Prematurity and specimens collected at less than 24 hours of age can cause a false positive result. Infants with CAH may have a normal screen (false negative) if they are administered steroids prior to specimen collection. Steroids prescribed to the mother during pregnancy can also cause a false negative result. There have been reports of babies with classic, salt wasting CAH with a negative newborn screen, therefore the screening test is not 100% effective. If there is any clinical suspicion or family history of CAH, a diagnostic evaluation is indicated regardless of screening results. Newborn Screening will not detect the 5% of non-21-hydroxylase deficiency related CAH.
  • Interpretation/reporting of data: Results are reported as screen negative, borderline or as a referral. A repeat specimen should be collected for a borderline result. Prompt consultation with a specialist is required for a referral.
  • Referral to Specialty Care Center: Patients with an abnormal newborn screen for CAH are referred to an Endocrinology Specialty Care Center for evaluation by an Endocrinologist trained in the diagnosis and treatment of CAH.

Prognosis:

On treatment, many of the symptoms can be prevented including the risk for salt wasting adrenal crises.

Symptoms:

There are three types of 21-hydroxylase deficiency related CAH: simple virilizing classic form, salt wasting classic form and non-classic form. Adult height is usually shorter than other family members for all three types. Reduced fertility can also occur in all three types.

  • Salt wasting classic form: Babies with this form of CAH are at risk for life threatening adrenal crisis if not treated. Sodium is lost in the urine and the low sodium causes poor feeding, dehydration and vomiting. In addition, females have ambiguous genitalia (not clearly male or female).
  • Simple virilizing classic form: Virilizing is the development of male secondary sex characteristics. Females with this form of CAH have ambiguous genitalia (not clearly male or female), but are not at risk for adrenal crisis.
  • Non-classic CAH: The symptoms of non-classic CAH are not present at birth and people with non-classic CAH are not at risk for adrenal crisis. Females have male pattern baldness, excessive growth of hair on the body (hirsutism) and irregular menstruation. Males have early beard growth and small testes.

Symptoms in carriers:

Carriers of CAH do not typically have symptoms.

Treatment:

CAH is treated with oral glucocorticoid replacement therapy, usually hydrocortisone. A high dose of glucocorticoid may be needed during times of physical stress or illness. People with classic salt wasting CAH should carry an emergency letter regarding the need for glucocorticoids. The classic salt wasting form should also be treated with 9α-fludrohydrocortisone and sodium chloride. Some females with ambiguous genitalia undergo surgery.

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Congenital Hypothyroidism (CH)

Also known as:

CHT, Cretinism

Definition:

Congenital hypothyroidism (CH) is an endocrine disorder of impaired thyroid function. The thyroid gland is located in the neck. In most cases of CH, the gland is missing or small. In other cases, the gland is present, but does not function correctly. Thyroid hormones, which are made in the thyroid gland, are important for growth and development.

Diagnosis:

Diagnostic testing may include total T4, free T4, TSH and TBG. Treatment should not be started based on newborn screening results alone. Confirmatory testing is required.

How it is inherited:

CH may be inherited or sporadic. Most cases are sporadic, meaning there is no family history of the disorder. The cause of some sporadic cases of CH is a de novo mutation in one copy of a gene. That is, the mutation was not present in either parent but was acquired later. In this case the inheritance is autosomal dominant as there is a 50% chance of the new mutation being passed on to each future child and causing disease in that child. CH may also have an autosomal recessive inheritance pattern where a mutation is present in both copies of the gene. Normally a person has two functional copies of each gene. Each parent of a newborn with autosomal recessive CH typically has one functional and one mutated gene and is considered a carrier. When both parents are carriers, the chance of each of their children inheriting two mutated genes, and therefore being affected by CH, is 25%. There is also a 50% chance that a child will be a carrier (like their parents) and 25% chance that they will have 2 copies of a normal gene.

Newborn screening:

  • Incidence: The incidence of classic CH is 1 in 3,000 to 1 in 4,000. It affects more females than males.
  • New York State Method of Screening (First Tier): Screening for CH is accomplished by measuring total T4 levels in dried blood spot specimens by immunoassay.
  • Second Tier Screening: If the T4 value is below the daily cut-off level, TSH testing is done.
  • Testing can be affected by: Specimens collected at less than 24 hours of age can cause a false positive result.
  • Interpretation/reporting of data: Results are reported as screen negative, borderline low T4, borderline elevated TSH or as a referral. A repeat specimen should be collected for a borderline result. Results of thyroid function testing will also be accepted for a borderline result, but a repeat specimen is preferred. If results of thyroid function testing are submitted, the date of collection, normal ranges and a clinical interpretation are required. Also, we require both T4 and TSH results, even if only T4 or TSH was abnormal on the screen. For a referral, prompt consultation with a specialist is required.
  • Referral to Specialty Care Center: Patients with an abnormal newborn screen for CH are referred to an Endocrinology Specialty Care Center for evaluation by an Endocrinologist trained in the diagnosis and treatment of CH.

Prognosis:

Initiation of prompt treatment will prevent symptoms and result in normal development.

Symptoms:

If babies with CH do not receive treatment, they have lifelong intellectual disability and slow physical growth. With treatment, symptoms can be prevented. Some newborns with a positive screen will have something other than permanent CH. Newborns with thyroxine binding globulin (TBG) deficiency may screen positive due to low total thyroxine (T4), even though free T4 and thyroid stimulating hormone (TSH) levels are normal. Premature infants may have thyroid hormone deficiency related to prematurity.

Symptoms in carriers:

Carriers of congenital hypothyroidism do not typically have symptoms.

Treatment:

Treatment is daily supplementation with an oral thyroid replacement hormone.  Lifelong treatment and dose adjustments are required.  For some cases of CH, at three years of age, therapy is discontinued for a trial period to determine whether lifelong treatment is needed.

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Cystic Fibrosis (CF)

Also known as:

Mucoviscidosis

Definition:

Cystic fibrosis (CF) is a genetic disorder caused by mutations in the CFTR gene. Mutations in the CFTR gene may also cause CFTR-related metabolic syndrome (CRMS) and congenital absence of the vas deferens (CAVD).

The CFTR protein plays an important role in moving sodium and chloride across the cell wall. In CF patients, symptoms can develop in the lungs, pancreas, liver and intestines. When the CFTR protein is not functioning correctly, there is mucus build-up and inflammation in the lungs, blockage in the intestines, blockage of the biliary duct in the liver, and blockage in the pancreas. In addition, people with CF often suffer from malnutrition and infertility.

Diagnosis:

Any baby who has a positive CF newborn screen result must be assessed for symptoms of malabsorption and respiratory problems and referred for a sweat test. The sweat test measures the amount of salt in the sweat. The sweat test takes about one hour from start to finish. A special machine causes a small part of the baby's arm or leg to sweat. The skin may feel warm and tingly for 5 minutes while the machine is on. The baby may cry during this part of the test, but the test does not inflict pain. The sweat is collected on a gauze pad or disc. After 30 minutes, the gauze or disc is removed and the collected sweat is tested in the lab.

The possible outcomes of the sweat test are:

Negative result: This means that a normal amount of salt was found in the sweat. It is very rare for a person to have CF if the sweat test result is negative. The baby subsequently should receive regular healthcare.

Positive result: A positive sweat test means that the baby probably has CF. The baby should have a second sweat test shortly thereafter and a check-up with a doctor who specializes in treating people with CF.

Borderline result: Sometimes the sweat test result will be in-between positive and negative. The baby will need to return for another sweat test in 1-2 months, and perhaps an exam by a pulmonologist trained in the diagnosis of CF and a blood test for additional genetic testing.   

"QNS": means Quantity Not Sufficient (there was not enough sweat on the gauze or disc). The baby will need to return for another test as soon as possible.

How it is inherited:

CF is inherited in an autosomal recessive pattern. Normally a person has two functional CFTR genes. In people with cystic fibrosis, both genes have a mutation. Each parent of a newborn with CF typically has one functional and one mutated gene and is considered a carrier. When both parents are carriers, the chance of their newborn inheriting two mutated genes is 25%.

Many women have genetic testing for CF during pregnancy or when they are planning a pregnancy. If a mutation is identified in the woman, carrier testing is recommended for her partner. If her partner has a negative carrier test and the baby has a positive newborn screen, follow-up testing is recommended as the baby could still have CF. CF carrier testing could be negative in a person with a rare mutation, because testing is not performed for rare mutations.

Newborn screening:

  • Incidence: The overall incidence of CF is approximately 1 in 2,500 Caucasian births. The disease is less common in other ethnic groups.
  • New York State Method of Screening (First Tier): Screening for CF is accomplished by analysis of immuno-reactive trypsinogen (IRT). Trypsinogen is produced in the pancreas and is the precursor of trypsin, which is required for protein digestion. IRT is elevated in most people with CF due to abnormal pancreatic function. Even though this assay is designed to detect CF, newborns with CRMS, CAVD, and even carriers with no CF disease may also screen positive.
  • Second Tier Screening: Specimens with IRT levels in the top 5% are tested for a panel of the most common CF-causing gene mutations. Parents should not be told that a negative mutation screen rules out CF carrier status or CF disease.
  • Testing can be affected by: IRT may be normal in some patients with CF, including some babies with meconium ileus, and then give a false negative result. It may also be elevated within the first 24 hours after birth in healthy newborns, thus giving a false positive result.
  • Interpretation/reporting of data: Results are reported as within acceptable limits or as a referral. Prompt consultation with a specialist is required for a referral. The referrals are reported out as “two mutations,” “one mutation” or “IRT elevated only,” which means that although IRT was elevated, no mutations were detected.
    • When two mutations are identified, it is usually consistent with a diagnosis of CF and the baby must be referred to an accredited Cystic Fibrosis Specialty Care Center.
    • When the screen identifies “one mutation” or “elevated IRT only”, further testing is required to determine if the baby has CF. It is possible for newborns without two mutations on the NYS panel to have CF. Over 1000 mutations have been identified in the CFTR gene, and NYS screens for only a fraction of the most common mutations.
  • Referral to Specialty Care Center: Patients with an abnormal newborn screen for CF are referred to a Cystic Fibrosis Specialty Care Center for an evaluation by a pulmonologist trained in the diagnosis and treatment of CF.

Prognosis:

Prognosis is variable and dependent on multiple factors, including the severity of disease and response to treatments. 

Symptoms:

Lungs - Thickened mucus builds up in the lungs of people with CF. They often have breathing problems and lung infections. There is eventually permanent damage to the lungs.

Pancreas – The pancreas produces enzymes that aid digestion and insulin that controls blood sugar. The lack of pancreatic enzymes affects the GI tract’s ability to break down and use nutrients from food. People with CF may develop a form of diabetes called CF-related diabetes mellitus.

Gastrointestinal tract – Babies with CF may also have an intestinal blockage called meconium ileus. Malnutrition and poor growth are concerns for people with CF.

Reproductive tract in males – Males with CF are usually infertile. The tube that carries sperm out of the body (vas deferens) does not develop.

Congenital absence of the vas deferens (CAVD) - Some men with mutations in the CFTR gene have no other symptoms of CF except infertility.

CFTR-related metabolic syndrome (CRMS) – Many people with CRMS never develop symptoms. Others may develop some of the symptoms of CF, but they are usually milder.

Symptoms in carriers:

Carriers of CF do not typically have symptoms.

Treatment:

Lungs – Antibiotics to prevent infections, medications to improve breathing and lung function (bronchodilators, mucolytic agents), chest physiotherapy to remove fluid and mucus from the lungs) and lung transplant in later stages of disease

Pancreas – Oral pancreatic enzymes and monitoring and treatment for diabetes 

Digestion – Enemas or surgery for meconium ileus and vitamins and supplemental feedings with high calorie formula

There are new treatments available and in development to target specific mutation types in the CFTR gene to restore function. Because these treatments are mutation dependent, they will not work for all people with CF.

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Galactosemia (GALT)

Also known as:

Classic Galactosemia, GALT Deficiency, Galactose-1-Phosphate Uridyl Transferase Deficiency, Type I Galactosemia

Definition:

Galactosemia is a disorder of carbohydrate metabolism caused by a defective or absent enzyme, galatose-1-phosphate uridyltransferase (GALT). This enzyme is responsible for metabolizing galactose to produce glucose. Lactose, which is ingested via milk and milk products, is broken down into galactose and glucose. Infants with a defective or absent GALT enzyme cannot metabolize the galactose produced as a by-product of milk digestion. As a result, galactose accumulates in the blood which can become a life-threatening situation. Mutations in the GALT gene cause dysfunction or absence of the GALT enzyme.

Diagnosis:

Diagnostic testing may include measurement of galactose-1-phosphate uridyl transferase enzyme activity in erythrocytes and/or additional molecular genetic testing of the GALT gene.

How it is inherited:

Galactosemia is inherited in an autosomal recessive pattern. Normally a person has two functional copies of the GALT gene. In people with galactosemia, both copies of the gene have a mutation and there is a deficiency of the critical enzyme. Each parent of a newborn with galactosemia typically has one functional copy and one mutated copy of the GALT gene and is considered a carrier. When both parents are carriers, the chance of a newborn inheriting two mutated genes is 25%.

Newborn screening:

  • Incidence: Galactosemia has an incidence of approximately 1 in 58,000 newborns.
  • New York State Method of Screening (First Tier): Screening for galactosemia is accomplished by measuring galactose-1-phosphate uridyl transferase enzyme activity by the Beutler assay.
  • Second Tier Screening: Any specimen lacking galactose-1-phosphate uridyl transferase enzyme activity is verified using the Hill metabolite assay which measures total galactose. In addition, any specimen on a newborn whom has received a transfusion is verified by measuring total galactose.
  • Third Tier Screening: Mutation analysis is done on all specimens where the enzyme activity is absent or the amount of galactose is ≥ 10mg/dL. The GALT mutations tested for in this analysis, S135L, Q188R, K285N, N314D, and L195P, account for 60-70% of classic galactosemia.
  • Testing can be affected by: Exposure of the specimen to heat and humidity can cause breakdown of the GALT enzyme, resulting in a false positive. Transfusion in a newborn may also affect the Beutler test result. There are two other forms of galactosemia: type II (also called galactokinase deficiency), caused by mutations in the GALK1 gene, and type III (also called galactose epimerase deficiency), caused by mutations in the GALE gene. Neither of these conditions are detected on the New York State Newborn Screen.
  • Interpretation/reporting of data: Results are reported as screen negative or as a referral. Prompt consultation with a specialist is required for a referral.
  • Referral to Specialty Care Center: Patients with an abnormal newborn screen for galactosemia are referred to an Inherited Metabolic Disorder Specialty Care Center for evaluation by a biochemical geneticist trained in the diagnosis and treatment of galactosemia.

Prognosis:

If the lactose-restricted diet is started promptly, the early symptoms of galactosemia resolve or are prevented entirely. Even with early and adequate therapy, the long-term effects in older children and adults can include cataracts, speech defects, poor growth, poor intellectual function, neurologic deficits and premature ovarian failure. These potential long-term complications are due to endogenous production of galactose.

Symptoms:

The life-threatening complications of galactosemia present in the first 7 - 10 days after birth if the infant is untreated. Symptoms include jaundice, feeding difficulty, lethargy, failure to thrive, hepatomegaly and bleeding diasthesis. Other complications may include sepsis and shock. Long term symptoms included delayed developmental milestones, verbal dyspraxia, cataracts, intellectual disability, and, in females, premature ovarian insufficiency.

There are variants of galactosemia that may be detected on newborn screening. One example of this is the Duarte variant, N314D in the GALT gene. When present with a second GALT gene mutation, this produces about 25% the normal amount of GALT enzyme and results in mild or asymptomatic cases of galactosemia.

Symptoms in carriers:

Carriers of galactosemia do not typically have symptoms.

Treatment:

Newborns who screen positive for galactosemia should immediately begin a lactose-restricted diet. Lifelong dietary restriction of lactose is recommended. 

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Glutaric acidemia, type I (GA-I)

Also known as:

Glutaric aciduria I, Glutaryl-CoA dehydrogenase deficiency

Definition:

Glutaric acidemia, type I (GA-I) is a disorder of organic acid metabolism (inherited metabolic disorder).

GA-I is caused by mutations in the GCDH gene. Components of protein (the amino acids lysine, hydroxylysine, and tryptophan) are broken down as part of normal metabolism. Mutations in the GCDH gene cause a deficiency of an important enzyme, glutaryl-CoA dehydrogenase. Without this enzyme, the amino acids are not broken down, accumulate in the brain and cause neurologic symptoms.

Diagnosis:

Diagnostic testing may include urine organic acid analysis, enzyme analysis and genetic testing of the GCDH gene.

How it is inherited:

GA-I is inherited in an autosomal recessive pattern. Normally a person has two functional GCDH genes. In people with GA-I, both genes have a mutation and there is a deficiency of the critical enzyme activity. Each parent of a newborn with GA-I typically has one functional and one mutated gene and is considered a carrier. When both parents are carriers, the chance of a newborn inheriting two mutated genes is 25%.

Newborn screening:

  • Incidence: Published estimates for the incidence of GA-I range from 1 in 30,000 to 1 in more than 250,000. In New York, the incidence has been closer to 1 in 250,000. GA-I is more common in Amish and Ojibwa populations.
  • New York State Method of Screening (First Tier): Screening for GA-I is accomplished by measuring the acylcarnitine C5DC by tandem mass spectrometry (MS/MS).
  • Second Tier Screening: None
  • Testing can be affected by: There have been reports of a positive newborn screen for GA-I due to the mother having the disorder.
  • Interpretation/reporting of data: Results are reported as screen negative, borderline or as a referral. A repeat specimen should be collected for a borderline result. Prompt consultation with a specialist is required for a referral.
  • Referral to Specialty Care Center: Patients with an abnormal newborn screen for GA-I are referred to an Inherited Metabolic Disorder Specialty Care Center for evaluation by a biochemical geneticist trained in the diagnosis and treatment of GA-I.

Prognosis:

Outcome is variable, and dependent on multiple factors, including the severity of disease and response to treatments.

Symptoms:

Newborns with GA-I may not have obvious symptoms at birth, aside from large head size (macrocephaly). Untreated, symptoms may include poor growth and episodes of dystonia and athetosis (unusual movements of the limbs), rigidness and spasticity. The episodes are usually triggered by an illness.

Symptoms in carriers:

Carriers of GA-I do not typically have symptoms.

Treatment:

Treatment is typically dietary management, including a diet low in lysine and tryptophan. Supplementation with carnitine may also be indicated. Additional medical care may be required during times of illness.

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Guanidinoacetate Methyltransferase (GAMT) Deficiency

Definition:

The GAMT gene provides instructions for making the enzyme guanidinoacetate methyltransferase. This enzyme works to produce creatine, which is needed for the body to store and use energy correctly. When mutations exist in the GAMT gene, not enough creatine gets produced in the body. This causes symptoms to appear in parts of the body that require lots of energy, like the brain and muscles.

Diagnosis:

Sequencing of the GAMT gene will be performed as part of the screening algorithm. Diagnostic confirmation, under the direction of a specialist, may include measurement of guanidinoacetate (GUAC), creatine, and/or creatinine in urine and plasma. Cerebral creatine deficiency in brain MR spectroscopy is a hallmark characteristic of GAMT deficiency.

How it is inherited:

GAMT deficiency is inherited in an autosomal recessive pattern. Normally a person has two functional copies of the GAMT gene. In people with GAMT deficiency, both genes have a mutation. Each parent of a newborn with GAMT deficiency typically has one functional gene and one mutated gene, and is considered a carrier. When both parents are carriers, the chance of a newborn inheriting two mutated genes is 25%.

Newborn screening:

  • Incidence: The estimated incidence of GAMT deficiency in the general population ranges from 1 in 2,640,000 to 1 in 550,000.
  • New York State Method of Screening (First Tier): Screening for GAMT is accomplished by analysis of GUAC and creatine by mass spectrometry.  If concentrations are normal, the sample is deemed within acceptable limits. If abnormal, second tier testing is performed.
  • Second Tier Screening:  Samples with GUAC concentrations above a certain threshold will be tested a second time using a more specific assay.  If concentrations are normal, the sample is deemed within acceptable limits. If abnormal, third tier screening is performed.
  • Third Tier Screening:  Sequencing of the GAMT gene.
  • Testing can be affected by:  Timing of sample collection; samples collected at less than 24 hours of age will be considered unsuitable.  This is an enzyme reaction that may require time for the marker to accumulate.
  • Interpretation/reporting of data: Results are reported as screen negative, borderline or as a referral. A repeat specimen should be collected for a borderline result. Prompt consultation with a specialist is required for a referral.
  • Referral to Specialty Care Center:  Babies with an abnormal newborn screen for GAMT are referred to an Inherited Metabolic Disease Specialty Care Center for a diagnostic evaluation.

Prognosis:

Prognosis is best for individuals who are diagnosed early in life, and begin treatment before the onset of symptoms. If individuals are diagnosed and treated later in life, intellectual disabilities and developmental delays cannot be reversed. However, treatment can prevent symptoms from worsening, and can help with movement coordination and behavioral problems. GAMT deficiency has not been shown to reduce an individual’s lifespan.

Symptoms:

Symptoms of this disease may include mild to severe developmental delays, intellectual disabilities, poor muscle tone, seizures, speech delays, hyperactivity, and involuntary movements. These symptoms usually appear between three months and three years of life.

Symptoms in carriers:

Carriers do not typically have symptoms.

Treatment:

Treatment includes taking an oral creatine to supplement the amount of creatine in an individual’s system. GUAC levels can be reduced by ornithine supplementation and Benzoate to reduce glycine levels and GUAC synthesis.

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Homocystinuria (HCY)

Also known as:

cystathionine beta synthase deficiency and homocysteinemia

Definition:

Homocystinuria is a disorder of amino acid metabolism (inherited metabolic disorder). Multiple steps in the body are required to break down components of protein (amino acids), homocysteine and methionine. The CBS gene provides instructions for an important enzyme in this process, cystathionine β-synthase. If there are mutations in this gene, then the enzyme does not function and the amino acids are not broken down. Toxic metabolites accumulate and cause symptoms.

Diagnosis:

Diagnostic testing may include plasma homocysteine, plasma amino acids, urine homocysteine and CBS gene testing.

How it is inherited:

Homocystinuria is inherited in an autosomal recessive pattern. Normally a person has two functional CBS genes. In people with homocystinuria, both copies of this gene have a mutation and there is a deficiency of the critical enzyme activity. Each parent of a newborn with homocystinuria typically has one functional and one mutated gene and is considered a carrier. When both parents are carriers, the chance of a newborn inheriting two mutated genes is 25%.

Newborn screening:

  • Incidence: The incidence of homocystinuria is not well known, but it is estimated at 1 in 200,000. It is more common in people from Qatar, Ireland, Germany and Norway.
  • New York State Method of Screening (First Tier): Screening for homocystinuria is accomplished by measuring methionine by tandem mass spectrometry (MS/MS).
  • Second Tier Screening: None. Testing can be affected by: Methionine may be elevated in newborns receiving total parenteral nutrition, who are premature, or who have liver immaturity. A newborn screening sample collected prior to 24 hours of age may be negative in infants with hypermethioninemia who have not been fed enough protein to have an elevated methionine concentration. In some cases of hypermethioninemia, methionine may not be elevated enough for a positive screen until after 5 days of age.
  • Interpretation/reporting of data: Results are reported as screen negative, borderline or as a referral. A repeat specimen should be collected for a borderline result. Prompt consultation with a specialist is required for a referral.
  • Referral to Specialty Care Center: Patients with an abnormal newborn screen for homocystinuria are referred to an Inherited Metabolic Disorder Specialty Care Center for evaluation by a biochemical geneticist trained in the diagnosis and treatment of homocystinuria.

Prognosis:

On treatment, prognosis is significantly improved.

Symptoms:

There are two types of homocystinuria: vitamin B6 responsive and non-vitamin B6 responsive. The symptoms of vitamin B6 responsive homocystinuria are usually milder. The symptoms of untreated homocystinuria vary from one person to the next, but may include developmental delay, near sightedness (myopia), skeletal abnormalities (long limbs) and increased risk of blood clots (thromboembolism). There is also a risk for a dislocation of the lens in the eye (ectopia lentis). Intellectual disability is usually more severe in untreated non-vitamin B6 responsive homocystinuria.

Symptoms in carriers:

Carriers do not typically have symptoms.

Treatment:

Treatment usually includes a low protein diet and the oral medication, betaine. Vitamin B6 responsive homocystinuria is also treated with pyridoxine. Surgery may be needed for the dislocation of the lens (ectopia lentis).

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Human Immunodeficiency Virus (HIV)

Definition:

Human immunodeficiency virus (HIV) can be transmitted from mother to baby during pregnancy, during delivery or through breast milk. Without treatment, infants born to mothers with HIV have up to a 35% chance of contracting the virus. Pregnant women are offered testing for HIV and newborns are tested at the hospital at birth if the mother’s status is unknown. HIV testing as part of newborn screening is another way to confirm that every infant exposed to HIV is identified and can receive monitoring and treatment.

Diagnosis:

Testing protocols and forms for follow-up through the Wadsworth Center can be found at the Center's Pediatric HIV Testing Service page.

How it is inherited:

Not applicable.

Newborn screening:

  • New York State Method of Screening (First Tier): Screening for HIV exposure is accomplished by enzyme-linked immunosorbent assay (ELISA) which detects antibodies to HIV-1, the most common form of HIV.
  • Second Tier Screening: Western blot, which detects specific HIV proteins.
  • Interpretation/reporting of data: Results are reported as:
    • ELISA reactive, Western blot non-reactive
    • ELISA reactive, Western blot indeterminate
    • ELISA reactive, Western blot reactive
    • Screen negative
  • Testing can be affected by: ELISA will not detect acute or very early infections because the antibody response has not yet reached detectable levels. Western blot is used as a confirmatory test, but has lower sensitivity than ELISA. Therefore, newborns with a positive ELISA test and negative or indeterminate Western blot should be evaluated for exposure to HIV-1.
  • Newborn screening for exposure to HIV-1 will not identify HIV-2.
  • Referral to Specialty Care Center: There are no Specialty Care Centers for exposure to HIV-1. Abnormal newborn screens for exposure to HIV-1 are reported to the HIV designee at each hospital of birth for coordination of follow-up confirmatory testing with the primary care provider. A pediatric infectious disease specialist should manage follow-up care.

Prognosis:

With treatment, the chance for mother to child transmission is less than 5%.

Symptoms:

Symptoms in carriers:

Not applicable.

Treatment:

The mother will be treated with antiretroviral medication during pregnancy and the baby will be treated shortly after birth until several weeks of age.  The baby may be delivered via C-section to reduce the risk of transmission and the mother may be instructed not to breastfeed.

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Hypermethionemia (HMET)

Also known as:

Deficiency of methionine adenosyltransferase, glycine N-methyltransferase deficiency, GNMT deficiency, Hepatic methionine adenosyltransferase deficiency, MAT deficiency, MET, methionine adenosyltransferase deficiency, methioninemia, S-adenosylhomocysteine hydrolase deficiency

Definition:

Hypermethioninemia is a term used to describe several metabolic disorders with a common finding of elevated methionine. Multiple steps in the body are required to breakdown the component of protein (amino acid), methionine. The AHCY, GNMT and MAT1A genes provide instructions for three important enzymes in this process. If there are mutations in any one of these genes, then the enzymes do not function and methionine is not broken down.

Diagnosis:

Diagnostic testing may include plasma S-adenosylmethionine, plasma S-adenosylhomocysteine, plasma homocysteine and plasma amino acid analysis.

How it is inherited:

Hypermethioninemia is most often inherited in an autosomal recessive pattern. Normally a person has two functional copies of the AHCY, GNMT and MAT1A genes. In people with hypermethioninemia, both copies of any one of these genes have a mutation and there is a deficiency of the critical enzyme activity. Each parent of a newborn with hypermethioninemia typically has one functional and one mutated gene and is considered a carrier. When both parents are carriers for the same gene, the chance of a newborn inheriting two mutated genes is 25%. There have been reports of autosomal dominant hypermethioninemia, which means that a mutation in one copy of the gene causes the disease and the chance for each child of a person with the disease to inherit it is 50%.

Newborn screening:

  • Incidence: The published incidence of hypermethioninemia due to MAT1A mutations is estimated at 1 in 28,163 births. However, the incidence in New York State has been much lower. Hypermethioninemia due to mutations in the other genes appears to be rare with only a few cases reported in the literature.
  • New York State Method of Screening (First Tier): Screening for hypermethioninemia is accomplished by measuring methionine by tandem mass spectrometry (MS/MS).
  • Second Tier Screening: None
  • Testing can be affected by: Methionine may be elevated in newborns receiving total parenteral nutrition, who are premature or who have liver immaturity. A newborn screening sample collected prior to 24 hours of age may be negative in infants with hypermethioninemia who have not been fed enough protein to have an elevated methionine concentration. In some cases of hypermethioninemia, methionine may not be elevated enough for a positive screen until after 5 days of age.
  • Interpretation/reporting of data: Results are reported as screen negative, borderline or as a referral. A repeat specimen should be collected for a borderline result. Prompt consultation with a specialist is required for a referral.
  • Referral to Specialty Care Center: Patients with an abnormal newborn screen for hypermethioninemia are referred to an Inherited Metabolic Disorder Specialty Care Center for evaluation by a biochemical geneticist trained in the diagnosis and treatment of hypermethioninemia.

Prognosis:

Some patients with hypermethioninemia never develop symptoms. For patients with symptoms, prognosis is variable and dependent on response to treatments and severity of disease.

Symptoms:

Hypermethioninemia due to mutations in the AHCY gene is a rare, but serious disorder. The symptoms include developmental delay, loss of white matter in the brain and liver disease.
Hypermethioninemia due to mutations in MAT1A is usually a benign disorder. Very rarely, people with hypermethioninemia have neurological symptoms including developmental delay and muscle weakness.
Hypermethioninemia due to mutations in GNMT has been reported in a small number of patients with elevated liver enzymes and mildly enlarged liver.

Symptoms in carriers:

Carriers of hypermethioninemia do not typically have symptoms.

Treatment:

Treatment is often not needed for the most common causes of hypermethioninemia. For patients with MAT1A-related hypermethioninemia and symptoms, treatment may include S-adenosylmethionine. Patients with GNMT-related hypermethioninemia may benefit from a low methionine diet and cystine supplementation. Treatment is not well defined for AHCY-related hypermethioninemia, but some patients benefited from a low methionine diet with phosphatidylcholine supplementation.

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Isobutyryl-CoA dehydrogenase (IBCD) deficiency

Also known as:

IBD deficiency, isobutyryl-coenzyme A dehydrogenase deficiency, IBG, isobutyrylglycinuria

Definition:

Isobutyryl-CoA dehydrogenase (IBCD) deficiency is a disorder of organic acid metabolism (inherited metabolic disorder).

Multiple steps in the body are required to break down valine, a component of protein. The ACAD8 gene provides instructions for an important enzyme in this process. If there is a mutation in ACAD8, the enzyme does not function and valine is not broken down. Toxic metabolites accumulate and may cause symptoms.

Diagnosis:

Diagnostic testing may include urine organic acid analysis and an acylcarnitine profile.

How it is inherited:

IBCD deficiency is inherited in an autosomal recessive pattern. Normally a person has two functional ACAD8 genes. In people with IBCD, both genes have a mutation and there is a deficiency of the critical enzyme activity. Each parent of a newborn with IBCD deficiency typically has one functional and one mutated gene and is considered a carrier. When both parents are carriers, the chance of a newborn inheriting two mutated genes is 25%.

Newborn screening:

  • Incidence: IBCD deficiency is very rare. There are less than 20 patients reported in the literature.
  • New York State Method of Screening (First Tier): Screening for IBCD deficiency is accomplished by measuring the acylcarnitine C4 by tandem mass spectrometry (MS/MS).
  • Second Tier Screening: None
  • Testing can be affected by: Newborn screening cannot distinguish between IBCD deficiency and short-chain acyl-CoA dehydrogenase (SCAD) deficiency.
  • Interpretation/reporting of data: Results are reported as within acceptable limits, borderline or as a referral. A repeat specimen should be collected for a borderline result. Prompt consultation with a specialist is required for a referral.
  • Referral to Specialty Care Center: Patients with an abnormal newborn screen for IBCD deficiency are referred to an Inherited Metabolic Disorder Specialty Care Center for evaluation by a biochemical geneticist trained in the diagnosis and treatment of IBCD deficiency.

Prognosis:

Prognosis is not well known because IBCD deficiency is rare.

Symptoms:

Because this disorder is so rare, the symptoms are not well defined. Most patients never develop symptoms. A single patient had anemia (low iron levels) and cardiomyopathy (heart muscle disease). Other patients have had delayed speech development.

Symptoms in carriers:

None known

Treatment:

There are no established treatment protocols.

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Isovaleric Acidemia (IVA)

Also known as:

Isovaleric acid-CoA dehydrogenase deficiency, Isovaleryl-CoA dehydrogenase deficiency

Definition:

Isovaleric acidemia (IVA) is a disorder of organic acid metabolism (inherited metabolic disorder).

IVA is caused by mutations in the IVD gene. A component of protein, the amino acid leucine, is broken down as part of normal metabolism. Mutations in the IVD gene cause a deficiency of an important enzyme, isovaleryl-CoA dehydrogenase. Without this enzyme, leucine is not broken down; the toxic metabolite isovaleric acid accumulates and causes neurologic symptoms.

Diagnosis:

Diagnostic testing may include urine organic acid analysis, plasma amino acid analysis, enzyme analysis and genetic testing of the IVD gene.

How it is inherited:

IVA is inherited in an autosomal recessive pattern. Normally a person has two functional genes. In people with IVA, both genes have a mutation and there is a deficiency of the critical enzyme activity. Each parent of a newborn with IVA typically has one functional and one mutated gene and is considered a carrier. When both parents are carriers, the chance of a newborn inheriting two mutated genes is 25%.

Newborn screening:

  • Incidence: The incidence of IVA is estimated to be 1 in 250,000.
  • New York State Method of Screening (First Tier): Screening for IVA is accomplished by measuring the acylcarnitine C5 by tandem mass spectrometry (MS/MS).
  • Second Tier Screening: None
  • Testing can be affected by: Newborn screening cannot distinguish between IVA and 2-Methylbutyrylglycinuria (2-MBCD). Pivalic acid, common in many medications (including some antibiotics), produces an elevated C5 and thus a false positive newborn screen.
  • Interpretation/reporting of data: Results are reported as screen negative, borderline or as a referral. A repeat specimen should be collected for a borderline result. Prompt consultation with a specialist is required for a referral.
  • Referral to Specialty Care Center: Patients with an abnormal newborn screen for IVA are referred to an Inherited Metabolic Disorder Specialty Care Center for evaluation by a biochemical geneticist trained in the diagnosis and treatment of IVA.

Prognosis:

Outcome of the neonatal-onset form is poor, although early treatment improves prognosis. Outcome of the late-onset form is variable and dependent on multiple factors, including the severity of disease and response to treatments.

Symptoms:

There are two forms of IVA, neonatal-onset and late-onset.

Neonatal-onset: The neonatal-onset form of this disorder is severe and symptoms typically begin in the first few days of life. Symptoms begin as vomiting and poor feeding, but progress to seizures, coma and eventually death. Newborns with IVA have a distinctive odor of sweaty feet.

Late-onset: The symptoms of late-onset IVA may be brought on by illness, fasting or eating a protein rich meal. Symptoms may include vomiting and seizures. Long-term symptoms include growth impairment and intellectual disability. Rarely, people with IVA remain asymptomatic.

Symptoms in carriers:

Carriers of IVA do not typically have symptoms.

Treatment:

Treatment is typically dietary management, including careful monitoring of protein intake and supplementing with specialized leucine-free formula. Additional medical care, including admission to the hospital for intravenous feedings, may be required during times of illness.

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Krabbe Disease

Also known as:

globoid cell leukodystrophy or galactosylceramide lipidosis

Definition:

Krabbe disease is an inherited metabolic disorder caused by the complete deficiency of the enzyme galactocerebrosidase. It is considered both a lysosomal storage disorder and a leukodystrophy involving the central and peripheral nervous systems.

Diagnosis:

Diagnostic testing includes measuring the galactocerebrosidase enzyme activity of the white blood cells isolated from the blood sample taken at the follow-up visit. Enzyme testing is performed at the Jefferson Medical College, in Philadelphia, Pennsylvania. If the GALC enzyme activity measured at this laboratory are greater than or equal to 0.3 nmol/mg/hr, then the infant is not at risk for Krabbe disease. However, if there is borderline activity, the child may be at risk for Krabbe disease and she/he will require further diagnostic testing and clinical evaluation in order to determine if the child has Krabbe disease. In this case the child will be closely monitored by the Child Neurologist.

If there is very low enzyme activity, the infant is at high risk for Krabbe disease. The Child Neurologist and Inherited Metabolic Disease Specialist coordinate an immediate inpatient neurodiagnostic evaluation to determine whether signs of infantile Krabbe disease are present. This evaluation includes a detailed neurologic exam, lumbar puncture, MRI, nerve conduction studies, visual evoked response and brain stem auditory evoked response. If the neurodiagnostic evaluation is not consistent with infantile Krabbe disease, the infant is closely monitored by the Child Neurologist. If the neurodiagnostic evaluation is consistent with infantile Krabbe disease, the infant is referred for treatment.

How it is inherited:

Krabbe disease is inherited in an autosomal recessive pattern. Normally a person has two functional GALC genes. In people with Krabbe disease, both genes have a mutation and there is a deficiency of the critical enzyme activity. Each parent of a newborn with Krabbe disease typically has one functional and one mutated gene and is considered a carrier. When both parents are carriers, the chance of a newborn inheriting two mutated genes is 25%.

Newborn screening:

  • Incidence: The overall incidence is reported to be approximately 1 in 100,000. However, the incidence in New York State has been found to be approximately 1 in 300,000.
  • New York State Method of Screening (First Tier): Screening for Krabbe disease is accomplished by measuring galactocerebrosidase activity using mass spectrometry. An infant with confirmed GALC activity that is less than or equal to 12% of the daily mean that has one or more mutations (see below) in the GALC gene is considered to be screen positive. For these infants, a physician is notified immediately by telephone. An infant with confirmed activity greater than 12% of the daily mean is considered to be screen-negative.
  • Second Tier Screening: DNA analysis is initiated for any sample with enzyme activity less than 12% of the daily mean. The specimen is tested for three polymorphisms and five common mutations using a rapid assay, and sequence analysis is performed. If one or more mutations are found and confirmed, the infant is considered to be screen-positive as indicated above and a physician is notified immediately. If no mutations are found, but known polymorphisms are detected, a report will be issued that indicates which polymorphisms were detected. Infants with polymorphisms only are not considered to be at risk for Krabbe disease and are not referred for a follow-up diagnostic work-up.
  • Testing can be affected by: Improper storage of the blood specimen including extreme heat, which may cause lower GALC enzyme activity. In addition, low white cell counts may cause enzyme activity to be below our 12% of daily mean cutoff and lead to false positive results.
  • Interpretation/reporting of data: Results are reported as within acceptable limits or as a referral. Prompt consultation with a specialist is required for a referral. We also report “Polymorphisms Only”. For this report, the GALC enzyme activity is at or below 12% of the daily mean and only polymorphisms (benign changes) were detected in the DNA. These infants are considered screen negative and no follow-up testing is required, but the identification of polymorphisms is reported as part of the newborn screen result.
  • Referral to Specialty Care Center: Patients with an abnormal newborn screen for Krabbe disease are referred to an Inherited Metabolic Disorder Specialty Care Center for evaluation by a biochemical geneticist trained in the diagnosis and treatment of Krabbe disease.

Prognosis:

HSCT prior to the onset of symptoms has been shown to stabilize the disease, although gross motor skills may still be affected. Unfortunately, symptomatic infants receiving umbilical cord blood transplantation continue to show declining cognitive and physical functions.

Symptoms:

Infantile Krabbe disease generally presents in the first six months of life. There are usually no obvious congenital anomalies present at birth. Early symptoms of the infantile form include feeding difficulties, gastroesophageal reflux, irritability and clasped thumbs. Late symptoms include hypertonicity followed by hypotonicity, flaccidity, deafness and blindness. In the infantile form, there is rapid mental deterioration, which usually leads to death before the age of two.

Late infantile Krabbe disease presents between 6 months and 3 years. The symptoms and progression are similar to the infantile group. Juvenile Krabbe disease presents between 3 and 8 years of age and has similar symptoms to the infantile forms, but a slower progression.

Adult onset Krabbe is extremely variable with symptoms ranging from weakness to significant decline in intellectual abilities.

Symptoms in carriers:

Carriers of Krabbe disease do not typically have symptoms.

Treatment:

The only treatment available is hematopoetic stem cell transplantation (HSCT) from umbilical cord blood following myeloablative chemotherapy prior to the onset of symptoms.

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Long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency

Also known as:

3-hydroxyacyl-CoA dehydrogenase, long-chain 3-hydroxyacyl CoA dehydrogenase deficiency, long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency, long-chain 3-OH acyl-CoA dehydrogenase deficiency, trifunctional protein deficiency, type 1

Definition:

Long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency is a fatty acid oxidation disorder (inherited metabolic disorder).

LCHAD deficiency is caused by mutations in the HADHA gene. Individuals with this disorder are unable to convert certain fats to energy and may develop symptoms during times of high energy need such as fasting or illness.

Diagnosis:

Diagnostic testing may include quantification of plasma acylcarnitines, molecular genetic testing of the HADHA gene and functional analysis of fatty acid oxidation on fibroblasts (skin cells).

How it is inherited:

LCHAD deficiency is inherited in an autosomal recessive pattern. Normally a person has two functional HADHA genes. In people with LCHAD deficiency, both genes have a mutation and there is a deficiency of the critical enzyme activity. Each parent of a newborn with LCHAD deficiency typically has one functional and one mutated gene and is considered a carrier. When both parents are carriers, the chance of a newborn inheriting two mutated genes is 25%.

Newborn screening:

  • Incidence: The overall incidence is unknown.
  • New York State Method of Screening (First Tier): Screening for LCHAD deficiency is accomplished by measuring acylcarnitines (C16OH and C18:1OH) by tandem mass spectrometry (MS/MS).
  • Second Tier Screening: None
  • Testing can be affected by: Screening may be normal in patients with mild LCHAD deficiency who were recently fed, received IV glucose or who were not ill when the specimen was collected. Newborn screening cannot distinguish between LCHAD and Trifunctional protein deficiency (TFP).
  • Interpretation/reporting of data: Results are reported as screen negative or as a referral. Prompt consultation with a specialist is required for a referral.
  • Referral to Specialty Care Center: Patients with an abnormal newborn screen for LCHAD deficiency are referred to an Inherited Metabolic Disorder Specialty Care Center for evaluation by a biochemical geneticist trained in the diagnosis and treatment of LCHAD deficiency.

Prognosis:

Prognosis is variable and dependent on multiple factors, including the severity of disease and response to treatments.

Symptoms:

The symptoms of LCHAD deficiency may begin anytime during infancy through early childhood. They are variable from one individual to the next but may include hypoglycemia (low blood sugar), liver problems, cardiomyopathy (disease of the heart muscle), retinopathy (disease of the eye) and hypotonia (low muscle tone). Later in childhood, rhabdomyolysis (muscle breakdown) and muscle pain may occur.

Symptoms in carriers:

Carriers of LCHAD deficiency do not typically have symptoms. However, a mother who is pregnant with a baby with LCHAD deficiency is at risk of illness during pregnancy. The mother may develop HELLP syndrome (haemolysis, elevated liver enzymes, low platelets) or AFLP (acute fatty liver of pregnancy).

Treatment:

Treatment is through dietary management, including avoidance of fasting, drinking low-fat formula and supplementation with medium-chain triglycerides (MCT) as a source of supplemental calories. Treatment for cardiac involvement or rhabdomyolysis is supportive. During times of illness, hospitalization may be required to monitor and treat hypoglycemia.

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Malonic Aciduria (MA)

Also known as:

malonyl-CoA decarboxylase deficiency, MAL

Definition:

Malonic aciduria (MA) is a disorder of organic acid metabolism (inherited metabolic disorder). MA is caused by mutations in the MLYCD gene.

Diagnosis:

Diagnostic testing may include urine organic acid analysis, total and free carnitine, MLYCD gene sequencing and MLYCD enzyme activity analysis.

How it is inherited:

MA is inherited in an autosomal recessive pattern. Normally a person has two functional MLYCD genes. In people with MA, both genes have a mutation and there is a deficiency of the critical enzyme activity. Each parent of a newborn with MA typically has one functional and one mutated gene and is considered a carrier. When both parents are carriers, the chance of a newborn inheriting two mutated genes is 25%.

Newborn screening:

  • Incidence: MA is rare, with less than 30 cases reported in the literature.
  • New York State Method of Screening (First Tier): Screening for MA is accomplished by measuring the acylcarnitine C3DC by tandem mass spectrometry (MS/MS).
  • Second Tier Screening: None
  • Testing can be affected by: None known
  • Interpretation/reporting of data: Results are reported as screen negative, borderline or as a referral. A repeat specimen should be collected for a borderline result. Prompt consultation with a specialist is required for a referral.
  • Referral to Specialty Care Center: Patients with an abnormal newborn screen for MA are referred to an Inherited Metabolic Disorder Specialty Care Center for evaluation by a biochemical geneticist trained in the diagnosis and treatment of MA.

Prognosis:

Prognosis is not well known because MA is rare.

Symptoms:

There are two forms of MA, neonatal-onset and late-onset. Some patients patients diagnosed by expanded newborn screening have remained asymptomatic.

Neonatal-onset: The neonatal-onset form of this disorder is more severe and symptoms typically begin in the first few days of life. Symptoms include lethargy, low muscle tone, enlarged liver and cardiomyopathy (heart muscle disease).

Late-onset: Episodes in late-onset MA may be brought on by illness. Long-term symptoms include developmental delay, low muscle tone and cardiomyopathy (heart muscle disease).

Symptoms in carriers:

Carriers of MA do not typically have symptoms.

Treatment:

There is not a standard treatment protocol. Supplementation with carnitine or dietary management including careful monitoring of fat intake may be helpful.

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Maple Syrup Urine Disease (MSUD)

Also known as:

BCKD deficiency, Branched-chain alpha-keto acid dehydrogenase deficiency, Branched-chain ketoaciduria, Ketoacidemia

Definition:

Components of protein (the branched chain amino acids leucine, isoleucine and valine) are broken down as part of normal metabolism. Three genes, BCKDHA, BCKDHB and DBT provide instructions for a group of important enzymes in this process. If there are two mutations in any one of these genes, the enzymes do not function and the branched chain amino acids are not broken down. Toxic metabolites accumulate and cause symptoms.

Diagnosis:

Diagnostic testing may include urine organic acid analysis, plasma amino acid analysis, and gene sequencing.

How it is inherited:

MSUD is inherited in an autosomal recessive pattern. Normally a person has two functional BCKDHA, BCKDHB and DBT genes. In people with MSUD, both copies of one of these genes have a mutation and there is a deficiency of the critical enzyme activity. Each parent of a newborn with MSUD typically has one functional and one mutated gene and is considered a carrier. When both parents are carriers, the chance of a newborn inheriting two mutated genes is 25%.

Newborn screening:

  • Incidence: MSUD is very rare. It occurs in less than 1 in 185,000 newborns. It is more common in the Amish and Mennonite populations.
  • New York State Method of Screening (First Tier): Screening for MSUD is accomplished by measuring leucine by tandem mass spectrometry (MS/MS).
  • Second Tier Screening: None
  • Testing can be affected by: In the classic type, branched chain amino acids are not elevated until 12-24 hours of life. Therefore, a blood sample collected before 24 hours of life may be screen negative in a newborn with MSUD. Also, supplementation with total parenteral nutrition can cause a false positive screen. Newborn screening may not be able to identify the intermittent or intermediate type unless the sample is collected during a time of illness.
  • Interpretation/reporting of data: Results are reported as screen negative, borderline or as a referral. A repeat specimen must be collected for a borderline result. Prompt consultation with a specialist is required for a referral.
  • Referral to Specialty Care Center: Patients with an abnormal newborn screen for MSUD are referred to an Inherited Metabolic Disorder Specialty Care Center for evaluation by a biochemical geneticist trained in the diagnosis and treatment of MSU.

Prognosis:

Prognosis is variable, and dependent on many factors, including severity of disease and response to treatment.

Symptoms:

The severity and age of onset of symptoms in people with MSUD is variable. The earwax and urine of babies with MSUD has an odor of maple syrup. The symptoms of the classic type begin in the first few days to weeks of life as poor feeding, vomiting and lethargy and progress to seizures, coma and death. The intermediate type of MSUD is milder, with symptoms (including developmental delay) beginning anytime after early infancy until childhood. There is also an intermittent type. Patients with this type have completely normal leucine levels unless they are ill. The thiamine response type has symptoms similar to the intermediate type, but thiamine supplementation reduces symptoms.

Symptoms in carriers:

Treatment:

Treatment is typically dietary management including careful monitoring of leucine and supplementation with isoleucine and valine. Additional medical care, including admission to the hospital for intravenous feedings, may be required during times of illness.  Liver transplant has been used as a treatment for classic cases. In some patients, thiamine supplementation allows them to eat more leucine.

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Medium-chain 3-ketoacyl-CoA thiolase (MCKAT) deficiency

Definition:

Medium-chain 3-ketoacyl-CoA thiolase (MCKAT) deficiency is a fatty acid oxidation disorder (inherited metabolic disorder). Individuals with this disorder are unable to convert certain fats to energy. The gene that causes MCKAT deficiency is not known.

Diagnosis:

Diagnostic testing may include quantification of plasma acylcarnitines and fatty acid oxidation studies on fibroblasts (skin cells).

How it is inherited:

MCKAT deficiency is inherited in an autosomal recessive pattern. Normally a person has two functional genes. In people with MCKAT deficiency, both genes have a mutation and there is a deficiency of the critical enzyme activity. Each parent of a newborn with MCKAT deficiency typically has one functional and one mutated gene and is considered a carrier. When both parents are carriers, the chance of a newborn inheriting two mutated genes is 25%.

Newborn screening:

  • Incidence: MCKAT deficiency is extremely rare. The overall incidence is unknown.
  • New York State Method of Screening (First Tier): Screening for MCKAT deficiency is accomplished by measuring an acylcarnitine (C8) by tandem mass spectrometry (MS/MS).
  • Second Tier Screening: None
  • Testing can be affected by: None known due to lack of information available about this disorder. Newborn screening cannot distinguish among MCAD deficiency, MAD deficiency and MCKAT deficiency; however, MCKAT deficiency and MAD deficiency are rarer than MCAD deficiency.
  • Interpretation/reporting of data: Results are reported as within acceptable limits, borderline or as a referral. A repeat specimen should be collected for a borderline result. Prompt consultation with a specialist is required for a referral.
  • Referral to Specialty Care Center: Patients with an abnormal newborn screen for MCKAT deficiency are referred to an Inherited Metabolic Disorder Specialty Care Center for evaluation by a biochemical geneticist trained in the diagnosis and treatment of MCKAT deficiency.

Prognosis:

Prognosis is unknown. Outcome was poor in the single patient reported.

Symptoms:

The single known baby with MCKAT deficiency died at 13 days of age and had low blood sugar, elevated ammonia, vomiting, dehydration and myoglobinuria (myoglobin in the urine due to muscle breakdown).

Symptoms in carriers:

There has only been one report of a patient with MCKAT deficiency. It is unknown if carriers would have any symptoms.

Treatment:

No treatment information available due to rarity of the disorder.

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Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency

Also known as:

ACADM deficiency, MCADD, MCADH deficiency, medium-chain acyl-coenzyme A dehydrogenase deficiency

Definition:

Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency is a fatty acid oxidation disorder (inherited metabolic disorder).

MCAD deficiency is caused by mutations in the ACADM gene. Individuals with this disorder are unable to convert certain fats to energy and may have symptoms during times of high energy need such as when fasting or ill.

Diagnosis:

Diagnostic testing includes quantification of plasma acylcarnitines, urine organic acids, and urine acylglycines. Molecular genetic testing of the ACADM gene may be used for confirmation of the diagnosis.

How it is inherited:

MCAD deficiency is inherited in an autosomal recessive pattern. Normally a person has two ACADM genes. In people with MCAD deficiency, both genes have a mutation and there is a deficiency of the critical enzyme activity. Each parent of a newborn with MCAD deficiency typically has one functional and one mutated gene and is considered a carrier. When both parents are carriers, the chance of a newborn inheriting two mutated genes is 25%.

Newborn screening:

  • Incidence: The incidence is approximately 1 in 17,000 in the United States. MCAD deficiency is more common in those with Northern European ancestry.
  • New York Method of Screening (First Tier): Screening for MCAD deficiency is accomplished by measuring acylcarnitines (C6 and C8) by tandem mass spectrometry (MS/MS).
  • Second Tier Screening: If an elevation of C8 is identified, DNA testing is performed for a single common mutation, p.K329E. In the literature, approximately 90% of people with MCAD deficiency have at least one p.K329E mutation. However, a p.K329E mutation has been identified in 45 to 55% of patients with MCAD deficiency in NYS.
  • Testing can be affected by: C8 may be elevated in infants fed medium-chain triglycerides (MCT) oil or taking valproate.
  • Interpretation/reporting of data: Results are reported as within acceptable limits, borderline or as a referral. A repeat specimen should be collected for a borderline result. Prompt consultation with a specialist is required for a referral.
  • Referral to Specialty Care Center: Patients with an abnormal newborn screen for MCAD deficiency are referred to an Inherited Metabolic Disorder Specialty Care Center for evaluation by a biochemical geneticist trained in the diagnosis and treatment of MCAD deficiency.

Prognosis:

The best results occur in those individuals identified by newborn screening and treated shortly after birth. The prognosis is excellent in patients who avoid fasting and seek additional treatment during times of illness.

Symptoms:

Newborns may not show any symptoms, but left untreated, the disorder can cause hypoglycemia, lethargy, liver disease, vomiting, seizures, coma and sudden death.

Symptoms in carriers:

Carriers of MCAD deficiency do not typically have symptoms.

Treatment:

There is no cure for the disorder. In infancy, treatment includes frequent feeding. Treatment includes lifelong avoidance of fasting. Some physicians may recommend consuming uncooked cornstarch before bedtime. Additional medical care, including intravenous feedings, may be required during times of illness.

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Medium/short-chain 3-hydroxyacyl-CoA dehydrogenase (M/SCHAD) deficiency

Also known as:

Medium/short-chain 3-hydroxyacyl-CoA dehydrogenase deficiency was formerly known as short-chain 3-hydroxyacyl-CoA dehydrogenase (SCHAD) deficiency.

Definition:

Medium/short-chain 3-hydroxyacyl-CoA dehydrogenase (M/SCHAD) deficiency is a fatty acid oxidation disorder (inherited metabolic disorder).

M/SCHAD deficiency is caused by mutations in the HADH genes. Individuals with this disorder are unable to convert certain fats to energy and may develop symptoms during times of high energy need such as fasting or illness.

Diagnosis:

Diagnostic testing may include quantification of plasma acylcarnitines, molecular genetic testing of the gene and functional analysis of fatty acid oxidation on fibroblasts (skin cells).

How it is inherited:

M/SCHAD deficiency is inherited in an autosomal recessive pattern. Normally a person has two functional HADH genes. In people with M/SCHAD deficiency, both genes have a mutation and there is a deficiency of the critical enzyme activity. Each parent of a newborn with M/SCHAD deficiency typically has one functional and one mutated gene and is considered a carrier. When both parents are carriers, the chance of a newborn inheriting two mutated genes is 25%.

Newborn screening:

  • Incidence: The overall incidence is unknown, but M/SCHAD deficiency is very rare with only a small number of patients reported in the literature.
  • New York State Method of Screening (First Tier): Screening for M/SCHAD deficiency is accomplished by measuring acylcarnitines (C4OH and C6OH) by tandem mass spectrometry (MS/MS).
  • Second Tier Screening: None
  • Testing can be affected by: None known
  • Interpretation/reporting of data: Results are reported as screen negative, borderline or as a referral. A repeat specimen should be collected for a borderline result. Prompt consultation with a specialist is required for a referral.
  • Referral to Specialty Care Center: Patients with an abnormal newborn screen for M/SCHAD deficiency are referred to an Inherited Metabolic Disorder Specialty Care Center for evaluation by a biochemical geneticist trained in the diagnosis and treatment of M/SCHAD deficiency.

Prognosis:

Prognosis is variable and dependent on multiple factors, including the severity of disease and response to treatments.

Symptoms:

People with M/SCHAD deficiency usually have hyperinsulinism (increased insulin), which causes hypoglycemia (low blood sugar). Symptoms may include vomiting, diarrhea, and lethargy. There have also been reports of hypotonia (muscle weakness) and liver problems.

Symptoms in carriers:

Carriers of M/SCHAD deficiency do not typically have symptoms.

Treatment:

Treatment may include an oral medication, diazoxide. Treatment may also be dietary management including avoidance of fasting.

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Methylmalonyl-CoA mutase deficiency (MUT)

Also known as:

Methylmalonic acidemia due to methylmalonyl-CoA mutase deficiency, MMA due to MCM deficiency, methylmalonic aciduria MUT type

Definition:

Methylmalonyl-CoA mutase deficiency (MUT) is the most common form of methylmalonic acidemia, a disorder of organic acid metabolism. Methylmalonyl-CoA is a product of the breakdown of several amino acids, as well as some fats and cholesterol. Methylmalonyl-CoA mutase breaks down methylmalonyl-CoA, and this enzyme is made by the MUT gene. Mutations in this gene cause partial or complete absence of methylmalonyl-CoA mutase, resulting in accumulation of methylmalonic acid and other damaging substances.

Diagnosis:

Diagnostic testing may include urine and plasma organic acid analyses, enzyme analysis and genetic testing of the MUT gene.

How it is inherited:

MUT is inherited in an autosomal recessive pattern. Normally a person has two functional MUT genes. In people with MUT, both genes have a mutation and there is a deficiency of the critical enzyme. Each parent of a newborn with MUT typically has one functional and one mutated gene and is considered a carrier. When both parents are carriers, the chance of a newborn inheriting two mutated genes is 25%.

Newborn screening:

  • Incidence: MUT has an incidence of approximately 1 in 80,000.
  • New York State Method of Screening (First Tier): Screening for MUT is accomplished by measuring the acylcarnitines C3 (propionylcarnitine) and C4DC (methylmalonylcarnitine) by tandem mass spectrometry (MS/MS).
  • Second Tier Screening: None
  • Testing can be affected by: Newborn screening cannot distinguish between MUT and propionic acidemia or severe maternal vitamin B12 deficiency.
  • Interpretation/reporting of data: Results are reported as screen negative, borderline or as a referral. A repeat specimen should be collected for a borderline result. Prompt consultation with a specialist is required for a referral.
  • Referral to Specialty Care Center: Patients with an abnormal newborn screen for MUT are referred to an Inherited Metabolic Disorder Specialty Care Center for evaluation by a biochemical geneticist trained in the diagnosis and treatment of MUT.

Prognosis:

If the low-protein diet is started promptly, most children with MUT have normal growth and development and symptoms are prevented. A delay in treatment can not reverse symptoms that are already present. On treatment, the prognosis for babies diagnosed with MUT is good.

Symptoms:

The symptoms of MUT in which there is a complete absence of methylmalonyl-CoA mutase usually appear within the first few months of life with the rapid onset of lethargy, vomiting and dehydration. On examination, these babies usually have hypotonia, hepatomegaly and encephalopathy. Laboratory studies done at this point will typically show metabolic acidosis, ketosis and ketonuria, hyperammonemia, and hyperglycemia. If untreated, MUT symptoms may include delayed developmental milestones, chronic renal disease, and pancreatitis. The symptoms of MUT in which there is a partial absence of methylmalonyl-CoA mutase are less severe. They typically present in the first months or years of life with feeding difficulties such as anorexia and vomiting, failure to thrive, hypotonia and developmental delay. These babies may have protein aversion and are at risk for metabolic crises.

Symptoms in carriers:

Carriers of MUT do not typically have symptoms.

Treatment:

Management requires a low-protein diet, as well as carnitine supplementation. Individuals with MUT are not responsive to vitamin B12 therapy. It is recommended that children and adults with MUT should avoid going for long periods without food.

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Mucopolysaccharidosis type I

Also known as:

MPS I, Hurler-Scheie syndrome, Hurler syndrome, IDUA deficiency, MPS I H, MPS I H-S, MPS I S, Scheie syndrome

Definition:

The IDUA gene provides instructions to produce the alpha-L-iduronidase (IDUA) enzyme that breaks down large sugar molecules in the body, which are called glycosaminoglycans. Mutations in the IDUA gene reduce or eliminate the function of the IDUA enzyme, which leads to a dangerous buildup of glycosaminoglycans within cells, specifically the lysosomes. The buildup of glycosaminoglycans increases the size of the lysosomes, which can lead to enlarged tissues/organs and cause a variety of symptoms. This buildup may also interfere with the function of some proteins inside the lysosomes, and disrupt the movement of molecules within the cell. There are two main types of MPS I, which are referred to as severe MPS I and attenuated MPS I.

Diagnosis:

Sequencing of the IDUA gene will be performed as part of the screening algorithm.  Diagnostic confirmation, under the direction of a specialist, may include measurement of glycosaminoglycans in urine and IDUA enzyme activity in blood.

How it is inherited:

MPS I is inherited in an autosomal recessive pattern. Normally, a person has two functional copies of the IDUA gene. In people with MPS I, both copies of the gene have a mutation. Each parent of a newborn with MPS I typically has one functional gene and one mutated gene, and is considered a carrier. When both parents are carriers, the chance of a newborn inheriting two mutated genes is 25%.

Newborn screening:

  • Incidence: The estimated incidence of severe MPS I in the general population is 1 in 100,000, while the incidence of attenuated (less severe) MPS is 1 in 500,000.
  • New York State Method of Screening (First Tier):  Screening for MPS I disease is accomplished by analysis of IDUA enzyme activity by mass spectrometry. If concentrations are normal, the sample is deemed within acceptable limits. If abnormal, second tier screening is performed.
  • Second Tier Screening:  Sequencing of the IDUA gene.
  • Testing can be affected by:  IDUA enzyme activity may be low in healthy newborns, thus giving a false positive result. Within the IDUA gene, at least one pseudodeficiency allele has been identified which results in lower IDUA enzyme activity but no clinical symptoms of MPS I.
  • Interpretation/reporting of data: Results are reported as screen negative, borderline or as a referral. A repeat specimen should be collected for a borderline result. Prompt consultation with a specialist is required for a referral.
  • Referral to Specialty Care Center: Babies with an abnormal newborn screen for MPS I with an identified IDUA mutation are referred to an Inherited Metabolic Disease Specialty Care Center for a diagnostic evaluation.

Prognosis:

The prognosis is best for newborns who are diagnosed and treated quickly, prior to two years of age. There is no cure for this condition, but treatments can help to delay some symptoms, and manage others. Without treatment, babies with severe MPS I will experience a progressive decline in intellectual function, worsening of symptoms, and a shorter lifespan.  

Symptoms:

There are many symptoms associated with MPS I, including enlarged head, lips, tongue, nose and vocal cords. Symptoms also include frequent upper respiratory infections, sleep apnea, hearing loss, recurrent ear infections, corneal clouding, narrowing of the spinal canal, joint deformities, and developmental delays and regressions. Because the symptoms of this disease vary from person to person, there may be additional symptoms in a person with MPS I that do not appear on this list. Usually, individuals with severe MPS I experience an earlier onset of symptoms than those with attenuated MPS I.

Symptoms in carriers:

Carriers do not typically have symptoms.

Treatment:

The two main treatment options for MPS I include hematopoietic stem cell transplant and enzyme replacement therapy. These treatments work by replacing the missing IDUA enzyme.

Educational materials:

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Multiple acyl-CoA dehydrogenase deficiency (MADD)

Also known as:

glutaric aciduria, type 2 (GA-2)

Definition:

Multiple acyl-CoA dehydrogenase deficiency (MADD) is a disorder of fatty acid oxidation (inherited metabolic disorder).

MADD is caused by mutations in one of three genes, ETFA, ETFB, or ETFDH. Individuals with this disorder are unable to convert certain fats to energy and may have symptoms during times of high energy need such as fasting or illness.

Diagnosis:

Diagnostic testing may include quantification of plasma acylcarnitines, urine acylglycines, urine organic acid analysis, molecular genetic testing of the ETFAETFB, and ETFDH genes and functional analysis of fatty acid oxidation on fibroblasts (skin cells).

How it is inherited:

MADD is inherited in an autosomal recessive pattern. Normally a person has two functional genes. In people with MADD, both genes have a mutation and there is a deficiency of the critical enzyme activity. Each parent of a newborn with MADD typically has one functional and one mutated gene and is considered a carrier. When both parents are carriers, the chance of a newborn inheriting two mutated genes is 25%.

Newborn screening:

  • Incidence: MADD is very rare. The incidence is unknown.
  • New York State Method of Screening (First Tier): Screening for MADD is accomplished by measuring acylcarnitines (C6 and C8) by tandem mass spectrometry (MS/MS). Other acylcarnitines including C4, C5, C14, C16 and C16OH may also be elevated.
  • Second Tier Screening: None
  • Testing can be affected by: C8 may be elevated in infants fed MCT oil or taking valproate.
  • Interpretation/reporting of data: Results are reported as screen negative, borderline or as a referral. A repeat specimen should be collected for a borderline result. Prompt consultation with a specialist is required for a referral.
  • Referral to Specialty Care Center: Patients with an abnormal newborn screen for MADD are referred to an Inherited Metabolic Disorder Specialty Care Center for evaluation by a biochemical geneticist trained in the diagnosis and treatment of MADD.

Prognosis:

Prognosis is good for patients with mild MADD who respond to riboflavin. Patients with neonatal onset MADD typically die in the first days to weeks of life.

Symptoms:

There is a wide range of symptoms in MADD. Patients with neonatal onset may develop hypoglycemia (low blood sugar), hyperammonaemia (elevated ammonia), hypotonia (low muscle tone) and hepatomegaly (enlarged liver). Some patients also have congenital birth defects. Symptoms of the later onset, less severe type of MADD may include any combination of hypoglycemia (low blood sugar), liver dysfunction, cardiomyopathy (heart muscle disease), recurrent infections and muscle weakness.

Symptoms in carriers:

Carriers of MADD do not typically have symptoms.

Treatment:

Patients with mild MADD may benefit from treatment with riboflavin. Dietary modifications may also be recommended.

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Multiple carboxylase deficiency (MCD)

Also known as:

Holocarboxylase synthetase deficiency, HLCS deficiency, neonatal form of multiple carboxylase defiency, early onset multiple carboxylase deficiency

Definition:

Multiple carboxylase deficiency (MCD) is a term used to describe inborn errors of biotin metabolism. There are two primary forms: biotinidase deficiency and holocarboxylase synthetase deficiency. Each of these causes reduced activity of biotin-dependent enzymes; specifically in holocarboxylase synthetase deficiency the defective enzyme is holocarboxylase synthetase. Mutations in the HLCS gene cause this defective enzyme which ultimately results in multiple carboxylase deficiency. Biotin-dependent carboxylases are involved in the breakdown of protein, fats and carbohydrates, therefore individuals with MCD have impaired metabolism of these substances.

Diagnosis:

Diagnostic testing may include urine organic acid analysis, acylcarnitine profile, enzyme analysis and genetic testing of the HLCS gene.

How it is inherited:

MCD is inherited in an autosomal recessive pattern. Normally a person has two functional HLCS genes. In people with MCD, both genes have a mutation and there is a deficiency of the critical enzyme. Each parent of a newborn with MCD typically has one functional and one mutated gene and is considered a carrier. When both parents are carriers, the chance of a newborn inheriting two mutated genes is 25%.

Newborn screening:

  • Incidence: MCD has an incidence of less than 1 in 100,000.
  • New York State Method of Screening (First Tier): Screening for MCD is accomplished by measuring the acylcarnitines C3 (propionylcarnitine) and C5OH (hydroxyisovalerylcarnitine) by tandem mass spectrometry (MS/MS).
  • Second Tier Screening: None
  • Testing can be affected by: Newborn screening cannot distinguish between MCD and propionic acidemia, methylmalonic acidemia or severe maternal vitamin B12 deficiency.
  • Interpretation/reporting of data: Results are reported as screen negative, borderline or as a referral. A repeat specimen should be collected for a borderline result. Prompt consultation with a specialist is required for a referral.
  • Referral to Specialty Care Center: Patients with an abnormal newborn screen for MCD are referred to an Inherited Metabolic Disorder Specialty Care Center for evaluation by a biochemical geneticist trained in the diagnosis and treatment of MCD.

Prognosis:

If biotin supplementation is started promptly, most children with MCD have normal growth and development and symptoms are prevented. A delay in treatment can not reverse symptoms that are already present. On treatment, the prognosis for babies diagnosed with MCD is good.

Symptoms:

The symptoms of MCD usually appear within the first few months of life, and include feeding difficulty, breathing problems, dermatitis, alopecia and lethargy. If untreated, MCD symptoms may include delayed developmental milestones, seizures, and coma.

Symptoms in carriers:

Carriers of MCD do not typically have symptoms.

Treatment:

The recommended treatment for MCD is biotin supplementation, which is very effective.

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Phenylketonuria (PKU)

Also known as:

phenylalanine hydroxylase deficiency, PAH deficiency

Definition:

A component of protein (phenylalanine) is broken down as part of normal metabolism. The PAH gene provides instructions for an important enzyme in this process, phenylalanine hydroxylase. If there is a mutation in PAH gene, the enzyme does not function and phenylalanine is not broken down. Toxic metabolites accumulate and cause symptoms.

Diagnosis:

Diagnostic testing includes blood tests for phenylalanine and tyrosine levels.  Urine pterins, a test for BH4 (tetrahydrobiopterin) defect, may also be done to rule out an enzyme cofactor deficiency.

How it is inherited:

PKU is inherited in an autosomal recessive pattern. Normally a person has two functional PAH genes. In people with PKU, both genes have a mutation and there is a deficiency of the critical enzyme activity. Each parent of a newborn with PKU typically has one functional and one mutated gene and is considered a carrier. When both parents are carriers, the chance of a newborn inheriting two mutated genes is 25%.

Newborn screening:

  • Incidence and New York State Method of Screening (First Tier): Screening for PKU is accomplished by measuring phenylalanine (phe) by tandem mass spectrometry (MS/MS).
  • Second Tier Screening: None
  • Testing can be affected by: Phenylalanine may be elevated in newborns receiving total parenteral nutrition. False positive results may be caused by an unsuitable newborn screen sample, liver immaturity, protein overload, and possible heterozygosity for PAH deficiency in premature babies. Newborn screening cannot differentiate between tetrahydrobiopterin (BH4) defect, hyperphenylalanemia and classic PKU. A newborn screen sample collected prior to 24 hours of age may be falsely negative in infants with PKU who have not been fed enough protein to have an elevated level of phe.
  • Interpretation/reporting of data: Results are reported as screen negative, borderline or as a referral. A repeat specimen should be collected for a borderline result. Prompt consultation with a specialist is required for a referral.
  • Referral to Specialty Care Center: Patients with an abnormal newborn screen for PKU are referred to an Inherited Metabolic Disorder Specialty Care Center for evaluation by a biochemical geneticist trained in the diagnosis and treatment of PKU.

Prognosis:

The symptoms of PKU are completely prevented in people on dietary therapy.

Symptoms:

Without treatment, children with PKU develop the classic symptoms of intellectual disability, behavior problems, light colored hair, seizures, eczema, a musty body odor and a small head size.

Symptoms in carriers:

Treatment:

Treatment is typically dietary management, including careful monitoring of protein intake.  Most people with PKU need to drink a special formula low in phenylalanine, but containing other essential amino acids.  More recently, a medication (sapropterin dihydrochloride) is available as a treatment.  In some patients, this medication is used to lower phe levels, usually in combination with a low protein diet.

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Pompe Disease (GAA)

Also known as:

Glycogen Storage Disease Type II, Acid Maltase Deficiency, Acid Alpha-glucosidase Deficiency

Definition:

Pompe disease is a genetic disorder caused by mutations in the GAA gene. It is a progressive metabolic condition that causes muscle weakness. The GAA gene codes for an enzyme called acid alpha-glucosidase (GAA) which is necessary for the degradation of glycogen in the lysosome. Mutations in GAA result in an accumulation of glycogen in the lysosomes. It is therefore considered a Lysosomal Storage Disorder.

Diagnosis:

All babies who have a positive Pompe newborn screen with at least one GAA gene mutation should be assessed with leukocyte GAA enzyme analysis, and babies with two mutations will require a cardiac evaluation (echocardiogram and EKG) to look for signs of cardiomyopathy, and also have a urine tetrasaccharide (Glc4).  Babies with a confirmed diagnosis will be referred to Pediatric Cardiology, and may require assessments by Pulmonology, Ophthalmology, Gastroenterology/Nutrition, Developmental Pediatrics, Audiology and/or Immunology.  These assessments may help determine when treatment should be initiated.  The infant’s cross reactive immunologic material (CRIM) status should be determined by GAA genotype or by measuring GAA enzyme activity in fibroblasts.  

How it is inherited:

Pompe disease is inherited in an autosomal recessive pattern. Normally a person has two functional GAA genes. In people with Pompe disease, both copies of this gene have a mutation and there is a deficiency of the critical enzyme activity. Each parent of a newborn with Pompe disease typically has one functional and one mutated gene and is considered a carrier. When both parents are carriers, the chance of a newborn inheriting two mutated genes is 25%.

Newborn screening:

  • Incidence: The overall incidence of Pompe disease is approximately 1 in 17,000 births. It is panethnic.
  • New York State Method of Screening (First Tier): Screening for Pompe disease is accomplished by analysis of GAA enzyme activity by mass spectrometry. If concentrations are normal, the sample is deemed within acceptable limits. If abnormal, second tier screening is performed.
  • Second Tier Screening: Sequencing of the GAA gene.
  • Testing can be affected by: GAA enzyme activity may be low in healthy newborns, thus giving a false positive result. Within the GAA gene, at least one pseudodeficiency allele has been identified which results in lower GAA enzyme activity but no clinical symptoms of Pompe disease.
  • Interpretation/Reporting of data: Results are reported as within acceptable limits, repeat specimen required or as a referral. Prompt consultations with specialists are required for each referral.
    • When two GAA mutations are identified in an infant, it is consistent with a diagnosis of Pompe disease. The baby will be referred to a Metabolic Geneticist at one of the designated Specialty Care Centers.
    • When one mutation is identified in an infant, additional testing by a Metabolic Geneticist is needed in order to determine if the baby is affected by Pompe disease or a carrier. This is because DNA sequence analysis may not detect all possible mutations in the GAA gene. These evaluations include leukocyte GAA enzyme analysis and creatine kinase (CK). If low GAA activity persists, follow recommendations for reaching a diagnosis (see below). If GAA activity is normal in leukocytes, the baby is a carrier of Pompe disease.
    • When no mutation is identified in the GAA gene, but one or more variants of uncertain significance or polymorphisms are found, a repeat newborn screen is requested. If low GAA enzyme activity persists, follow recommendations for one mutation (see above).
    • When GAA gene sequencing reveals a pseudodeficiency allele only, which results in lower GAA enzyme activity but no clinical symptoms of Pompe disease, this is considered screen negative. The presence of the pseudodeficiency allele will be indicated on the report, but no follow-up testing is recommended.
  • Referral to Specialty Care Center: Babies with an abnormal newborn screen for Pompe disease with an identified GAA mutation are referred to an Inherited Metabolic Disease Specialty Care Center for a diagnostic evaluation.

Prognosis:

Prognosis is variable and dependent on multiple factors including the severity of disease and response to treatment, however clinical outcomes have improved substantially since the advent of ERT. 

Symptoms:

The symptoms of Pompe disease vary in terms of age of onset and severity, which correspond to degree of GAA enzyme activity.

  • Early-onset - Results from complete or near absence of GAA enzyme activity. Symptoms begin at birth or shortly thereafter, with hypotonia, hypertrophic cardiomyopathy, failure to thrive, and respiratory insufficiency. Without treatment progression is rapid and most babies die from cardiac or respiratory complications before a year of age.
  • Late-onset - Results from partial deficiency of GAA enzyme. The age of onset is variable; symptoms may appear as early as the first few months of life, or as late as adulthood. The primary symptom is a slowly progressive myopathy primarily involving skeletal muscle. There is not usually cardiac involvement with the late onset form of Pompe disease.

Symptoms in carriers:

Treatment:

Enzyme replacement therapy (ERT)-  This entails replacement of the defective GAA enzyme with a recombinant form called alglucosidase alfa (this is also called recombinant human GAA, or rhGAA), which is administered via biweekly infusions.   Babies with early-onset Pompe disease in whom ERT is initiated before six months of age demonstrate improved survival, are less likely to need ventilator assistance, acquire more developmental milestones and show improvement in cardiac size and function.  In individuals with late-onset disease, ERT stabilizes ventilatory function and motor ability. 

An individual’s CRIM status is an important predictor of his or her clinical response to ERT.  CRIM is the endogenous GAA protein produced by most patients with Pompe disease.  CRIM negative (CN) means there is no residual GAA enzyme activity. Pompe patients who are CN produce anti-rhGAA antibodies and do not respond to ERT unless immune tolerance induction (ITI) is done prior to the start of or concurrent with ERT.  Approximately 20% of early-onset Pompe disease patients are CRIM negative.  CRIM positive means there is residual GAA enzyme activity of at least 1%.  These individuals usually do not produce anti-rhGAA antibodies and tend to have a better response to ERT.

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Propionic Acidemia (PA)

Also known as:

Ketotic hyperglycinemia, PROP

Definition:

Propionic acidemia (PA) is an organic acid disorder (inherited metabolic disorder) because abnormal levels of organic acids build up in the bodies of those affected.

PA is caused by mutations in one of two genes, PCCA or PCCB. Several components of protein (amino acids) are converted to propionyl-CoA as part of normal metabolism. Mutations in the PCCA or PCCB gene cause a deficiency of propionyl-CoA carboxylase (PCCA, PCCB and biotin), which breaks down propionyl-CoA. If this does not happen, toxic metabolites accumulate and cause vomiting and neurological symptoms.

Diagnosis:

Diagnostic testing may include urine organic acid analysis, plasma amino acid analysis, PCCA and PCCB gene sequencing and PCC enzyme activity analysis.

How it is inherited:

PA is inherited in an autosomal recessive pattern. Normally a person has two functional genes. In people with PA, both genes have a mutation and there is a deficiency of the critical enzyme activity. Each parent of a newborn with PA typically has one functional and one mutated gene and is considered a carrier. When both parents are carriers, the chance of a newborn inheriting two mutated genes is 25%.

Newborn screening:

  • Incidence: The incidence of PA is estimated to be 1 in 50,000 to 1 in 100,000. PA is more common in the Inuit population and Saudi Arabians.
  • New York State Method of Screening (First Tier): Screening for propionic acidemia is accomplished by measuring the acylcarnitine C3 by tandem mass spectrometry (MS/MS).
  • Second Tier Screening: None. Testing can be affected by: Newborn screening cannot distinguish between PA and methylmalonic acidemia or severe maternal vitamin B12 deficiency.
  • Interpretation/reporting of data: Results are reported as within acceptable limits, borderline or as a referral. A repeat specimen should be collected for a borderline result. Prompt consultation with a specialist is required for a referral.
  • Referral to Specialty Care Center: Patients with an abnormal newborn screen for propionic acidemia are referred to an Inherited Metabolic Disorder Specialty Care Center for evaluation by a biochemical geneticist trained in the diagnosis and treatment of propionic acidemia.

Prognosis:

Outcome of the neonatal-onset form is poor. Outcome of the late-onset form is variable and dependent on multiple factors, including the severity of disease and response to treatments.

Symptoms:

There are two forms of PA, neonatal-onset and late-onset.

Neonatal-onset: The neonatal-onset form of this disorder is severe and symptoms typically begin in the first few days of life. Symptoms begin as vomiting and poor feeding, but progress to seizures, coma and eventually death.

Late-onset: The symptoms of late-onset PA may be brought on by illness, injury or other physical stress including vomiting, protein intolerance and seizures. Long-term symptoms include a loss of developmental milestones, low muscle tone, susceptibility to infections, cardiomyopathy (heart muscle disease) and pancreatitis. Other symptoms may include growth impairment and intellectual disability. Damage may also occur to a specific part of the brain (basal ganglia).

Symptoms in carriers:

Carriers of propionic acidemia do not typically have symptoms.

Treatment:

Treatment is typically dietary management, including careful monitoring of protein intake. Medications may include carnitine, metronidazole and N-carbamoylglutamate. There have been reports of liver transplant as a treatment of PA. Additional medical care including admission to the hospital for intravenous feedings may be required during times of illness. In some cases, hemodialysis may be needed.

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Severe Combined Immunodeficiency (SCID)

Definition:

Severe combined immunodeficiency (SCID) is a group of rare genetic disorders caused by a deficiency or absence of T cells. B cells and/or NK cells may also be low or absent. T cells, B cells and NK cells have an important role in the immune system. Therefore, people with SCID do not have a functioning immune system and are susceptible to infections.

Mutation(s) in one of several genes can cause SCID. In some cases of SCID, a genetic cause is never identified.

Diagnosis:

Diagnostic testing includes complete blood count and flow cytometry for T, B and NK cell subsets. Additional testing may include mitogen stimulation, chromosome analysis and genetic testing.

How it is inherited:

SCID is inherited in an autosomal recessive or X-linked pattern, depending on the gene.

Normally a person has two functional genes. In people with autosomal recessive SCID, both genes have a mutation that impacts T cell production. Each parent of a newborn with SCID typically has one functional and one mutated gene and is considered a carrier. When both parents are carriers, the chance of a newborn inheriting two mutated genes is 25%.

X-linked SCID is caused by a mutation in the IL2RG gene on the X chromosome. Because females have two X chromosomes, they have two IL2RG genes. Because males have one X chromosome, they have one IL2RG gene. Males with a nonfunctioning IL2RG gene have SCID and females with one IL2RG gene mutation will be carriers. When a mother is a carrier of X-linked SCID, each son has a 50% chance of inheriting the disorder.

Newborn screening:

  • Incidence: The overall incidence of SCID in NYS is approximately 1 in 45,000.
  • New York State Method of Screening (First Tier): SCID screening is accomplished by qPCR of T cell receptor excision circles (TRECs), a piece of DNA produced during the formation of T cells in the thymus. Newborns with SCID have little to no TRECs. Although this testing is DNA-based, TREC analysis is not a test for gene mutations.
  • Second Tier Screening: None
  • Testing can be affected by: TRECs are often lower in premature infants. TRECs may also be low in newborns with congenital birth defects or other syndromes with T cell impairment (DiGeorge syndrome, CHARGE syndrome).
  • Interpretation/reporting of data: Results are reported as within acceptable limits, borderline, premature infant or as a referral. A repeat specimen should be collected promptly for a borderline result. For premature infants, a repeat specimen should be collected at 37 weeks gestation. Prompt consultation with a specialist is required for a referral.
  • Referral to Specialty Care Center: Patients with an abnormal newborn screen for SCID are referred to a Specialty Care Center for evaluation by an immunologist or infectious disease specialist trained in the diagnosis and treatment of SCID.

Prognosis:

Without treatment, the mortality rate is high and the majority of infants will expire before one year of age. The survival rate is at least 94% when infants with SCID are treated by 3.5 months of age.

Symptoms:

Untreated, essentially all infants with SCID will contract life-threatening infections including bacterial, fungal and viral. Frequent infections can cause poor growth (failure to thrive). With treatment, the immune system becomes functional and infants do not have frequent infections.

Symptoms in carriers:

Carriers of SCID do not have symptoms.

Treatment:

Treatment is dependent on the type of SCID and includes hematopoietic stem cell transplant (HSCT), enzyme replacement therapy and gene therapy. Enzyme replacement therapy is available for one type of SCID (adenosine deaminase deficiency). Prior to transplant, newborns may need to be placed in isolation and receive antibiotics to prevent infection.

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Short-chain acyl-CoA dehydrogenase (SCAD) deficiency

Also known as:

ACADS deficiency, deficiency of butyryl-CoA dehydrogenase, lipid-storage myopathy secondary to short-chain acyl-coa dehydrogenase deficiency, SCADH deficiency, short-chain acyl-coenzyme A dehydrogenase deficiency.

Definition:

Short-chain acyl-CoA dehydrogenase (SCAD) deficiency is a fatty acid oxidation disorder (inherited metabolic disorder).

SCAD deficiency is caused by mutations in the ACADS gene. Individuals with this disorder are unable to convert certain fats to energy and may have symptoms during times of high energy need such as when fasting or ill.

Diagnosis:

Diagnostic testing includes quantification of plasma acylcarnitines, urine organic acids, and urine acylglycines. Molecular genetic testing of the ACADS gene may be used for confirmation of the diagnosis.

How it is inherited:

SCAD deficiency is inherited in an autosomal recessive pattern. Normally a person has two functioning ACADS genes. In people with SCAD deficiency, both genes have a mutation and there is a deficiency of the critical enzyme activity. Each parent of a newborn with SCAD deficiency typically has one functional and one mutated gene and is considered a carrier. When both parents are carriers, the chance of a newborn inheriting two mutated genes is 25%.

Newborn screening:

  • Incidence: The overall incidence is approximately 1 in 40,000 to 1 in 100,000.
  • New York State Method of Screening (First Tier): Screening for SCAD deficiency is accomplished by measuring an acylcarnitine (C4) by tandem mass spectrometry (MS/MS).
  • Second Tier Screening: None
  • Testing can be affected by: None known.
  • Interpretation/reporting of data: Results are reported as within acceptable limits, borderline or as a referral. A repeat specimen should be collected for a borderline result. Prompt consultation with a specialist is required for a referral.
  • Referral to Specialty Care Center: Patients with an abnormal newborn screen for SCAD deficiency are referred to an Inherited Metabolic Disorder Specialty Care Center for evaluation by a biochemical geneticist trained in the diagnosis and treatment of SCAD deficiency.

Prognosis:

Prognosis is variable and dependent on multiple factors including the severity of disease.

Symptoms:

Neonates with SCAD deficiency are usually asymptomatic and there is a range of symptoms in older individuals. Many people with SCAD deficiency never develop symptoms. Possible symptoms include hypoglycemia, failure to thrive, microcephaly (small head size), hypotonia (low muscle tone), developmental delay, feeding difficulties and seizures. The symptoms are extremely variable, even within the same family.

Symptoms in carriers:

Carriers of SCAD deficiency do not typically have symptoms.

Treatment:

There is no cure for this disorder. The need for treatment is unclear, but may include avoidance of fasting. During times of illness, care givers and health care providers should be aware of an increased risk for hypoglycemia, metabolic acidosis and dehydration.

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Sickle Cell Disease (S/S and S/C) and Sickle Cell Trait (carrier)

Also known as:

Hemoglobin S disease, SCD

Definition:

Sickle cell disease (S/S and S/C) is a genetic disorder of the blood. Red blood cells bring oxygen from the lungs to every part of the body. Oxygen is stored in the red blood cell by hemoglobin (Hgb). There are several different types of hemoglobin. Normal hemoglobin is called Hgb A and the sickling type is called Hgb S. A person with sickle cell disease has no Hgb A. Instead, they only have Hgb S or a combination of other hemoglobins, like Hgb C. In a person with sickle cell disease, the red blood cells have an abnormal shape.

Diagnosis:

Diagnostic testing may include cellulose acetate electrophoresis, HPLC and genetic testing of the HBB gene.

How it is inherited:

Sickle cell disease is inherited in an autosomal recessive pattern. Normally a person has two HBB genes that produce Hgb A. In people with sickle cell disease, both HBB genes have a mutation and they only produce abnormal hemoglobin (Hgb S only or Hgb S and Hgb C). Each parent of a newborn with sickle cell disease has sickle cell trait (one gene that produces Hgb A and one gene that produces abnormal hemoglobin, like S or C). When both parents have sickle cell trait, the chance of their newborn inheriting two mutated genes is 25%.

Newborn screening:

  • Incidence: The incidence of sickle cell disease is different for each ethnic group. It is most common in African Americans with an incidence of 1 in 500.
  • New York State Method of Screening (First Tier): Screening for sickle cell disease is accomplished by high-performance liquid chromatography (HPLC).
  • Second Tier Screening: Second tier testing uses IEF (isoelectric focusing).
  • Testing can be affected by: Transfusion of red cells can cause a false negative result.
  • Interpretation/reporting of data: Results are reported as within acceptable limits, evidence of a transfusion or as a referral. A repeat specimen should be collected 4 months after the most recent transfusion for infants that had a blood transfusion. For infants that are referred, the result is reported as a list of the hemoglobins identified on HPLC and IEF. For example, an infant with sickle cell disease is reported as hemoglobin F (fetal) and hemoglobin S (sickle) and no hemoglobin A (adult).
  • Referral to Specialty Care Center: Patients with an abnormal newborn screen for sickle cell disease are referred to a Specialty Care Center for evaluation by a hematologist trained in the diagnosis and treatment of sickle cell disease.

Prognosis:

Prognosis is variable and dependent on multiple factors including the severity of disease and response to treatments.

Symptoms:

Sickle cell disease is a serious medical condition. Symptoms usually start in childhood. The first symptom in most children is pain and swelling of the hands and feet. There is also a risk for severe infections. Over time, the sickle shaped red blood cells get stuck in the blood vessels and cause chronic pain and problems with the organs including the liver and spleen. People with sickle cell disease may also have a shortage of red blood cells, known as anemia, which can cause them to be pale, short of breath and tire easily. Chronic anemia can also cause delayed growth and development.

Symptoms in carriers:

The sickle cell trait does not usually cause health problems. Most people with sickle cell trait go through life without knowing they have it. In very rare instances, the blood cells in people with sickle cell trait can take on a sickle shape during times of extreme stress on their body (deep sea diving, mountain climbing, surgery) and then they may have symptoms.

Treatment:

There is not a cure for sickle cell disease.  Adequate rest and hydration, immunizations and a medication, hydroxyurea, can significantly reduce the complications of sickle cell disease.  Treatments may include blood transfusions and antibiotics.  Pain management includes supportive measures like massage, intravenous fluids and pain medication.  As the disease progresses, interventions like removal of the spleen or kidney transplant may be needed.

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Spinal Muscular Atrophy (SMA)

Definition:

Spinal Muscular Atrophy (SMA) is a genetic disorder that affects the control of muscle movement due to the loss of specialized nerve cells called motor neurons. This loss of motor neurons causes weakness and atrophy resulting from progressive degeneration. SMA affects muscles used for activities such as crawling, walking, sitting up, and controlling head movements. Severe cases of SMA affect the muscles used for breathing and swallowing.

Diagnosis:

Confirmatory genetic testing of SMN1 and SMN2 genes will be offered by the Newborn Screening Program. To establish the extent of disease and needs of an individual diagnosed with SMA, the specialty care center may perform additional nutrition and respiratory assessments

How it is inherited:

SMA is inherited in an autosomal recessive manner.

A couple who already has a child with SMA has an approximately 25% chance of having another affected child, a 50% chance of having a child who is an asymptomatic carrier, and an approximately 25% chance of having a child unaffected by SMA and who is not a carrier.

However, about 2% of affected individuals have a de novo SMN1 variant on one allele. This means that only one parent is a carrier of the SMN1 variant., and therefore future pregnancies are not at a 25% risk for SMA.

Newborn screening:

  • Incidence: The overall incidence of SMA in NYS is approximately 20-30 per 235,000 births a year.
  • New York State Method of Screening (First Tier): Screening for SMA is accomplished by performing SMN1 exon 7 deletion analysis. Homozygous deletion of exon 7 is the most common cause of SMA. Parents should not be told that a negative screen rules out SMA. This testing does not identify other types of mutations.
  •  Second Tier Screening: All specimens which are found to be homozygous for the exon 7 deletion will then undergo SMN2 dosage analysis. This testing aids in prediction of age at onset and disease course.
  • Testing can be affected by: N/A
  • Interpretation/reporting of data: Results are reported as within acceptable limits, repeat specimen required, or as a referral. Prompt consultations with specialists are required for each referral. When homozygous SMN1 exon 7 deletions are identified, it is usually consistent with a diagnosis of SMA and the baby must be referred to an accredited Neuromuscular Specialty Care Center. Individuals with higher SMN2 copy numbers may have a milder phenotype.
  • Referral to Specialty Care Center: Patients with an abnormal newborn screen for SMA are referred to a Specialty Care Center for evaluation by a neuromuscular specialist trained in the diagnosis and treatment of SMA.

Prognosis:

Prognosis is variable and dependent on multiple factors, including the subtype of disease.

Symptoms:

The symptoms of SMA vary in terms of age of onset and severity.

Type 1: Diagnosed within the first 6 months of life. This type is considered the most severe and common, occurring in about 60% of cases. Symptoms include: muscle weakness, difficulty breathing, coughing, and swallowing. Without treatment, survival beyond two years of age is rare.

Type 2: Diagnosed after 6 months of age, usually following failure to achieve motor function milestones. This type affects about 30% of SMA cases. Those with type 2 are able to sit up (may need assistance sitting), but are unable to walk and require a wheelchair for mobility.

Type 3: Diagnosed after 18 months of age up into late teenage years. It affects about 10% of SMA cases. Those affected may initially be able to walk, but this can deteriorate over time, making the use of a wheelchair common.

Type 4: Diagnosed in adulthood after age 18. This type is very rare, only affecting less than 1% of SMA cases. Those affected usually have mild motor impairment.

Symptoms in carriers:

Carriers of SMA do not have symptoms. Carriers of SMA will not be detected by the newborn screen.

Treatment:

At this time the only FDA-approved treatment for SMA is the medication Spinraza (nusinersen). This medication improves SMN protein expression using synthetic genetic material to fix splicing errors. Other clinical trials investigating additional treatments, including gene therapy, are ongoing.

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Trifunctional Protein (TFP) Deficiency

Also known as:

MTP deficiency, TPA deficiency

Definition:

Trifunctional protein (TFP) deficiency is a fatty acid oxidation disorder (inherited metabolic disorder).

TFP deficiency is caused by mutations in the HADHA and HADHB genes. Individuals with this disorder are unable to convert certain fats to energy and may develop symptoms during times of high energy need such as fasting or illness.

Diagnosis:

Diagnostic testing may include quantification of plasma acylcarnitines, molecular genetic testing of the gene and functional analysis of fatty acid oxidation on fibroblasts (skin cells).

How it is inherited:

TFP deficiency is inherited in an autosomal recessive pattern. Normally a person has two functional genes (HADHA and HADHB). In people with TFP deficiency, both copies of either the HADHA gene or HADHB gene have a mutation and there is a deficiency of the critical enzyme activity. Each parent of a newborn with TFP deficiency typically has one functional and one mutated gene and is considered a carrier. When both parents are carriers, the chance of a newborn inheriting two mutated genes is 25%.

Newborn screening:

  • Incidence: The overall incidence is unknown.
  • New York State Method of Screening (First Tier): Screening for TFP deficiency is accomplished by measuring acylcarnitines (C16OH and C18:1OH) by tandem mass spectrometry (MS/MS).
  • Second Tier Screening: None
  • Testing can be affected by: Screening may be normal in patients with mild TFP deficiency who were recently fed, received IV glucose or were not ill when the specimen was collected. Newborn screening cannot distinguish between TFP deficiency and Long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency.
  • Interpretation/reporting of data: Results are reported as screen negative or as a referral. Prompt consultation with a specialist is required for a referral.
  • Referral to Specialty Care Center: Patients with an abnormal newborn screen for TFP deficiency are referred to an Inherited Metabolic Disorder Specialty Care Center for evaluation by a biochemical geneticist trained in the diagnosis and treatment of TFP deficiency.

Prognosis:

Prognosis of the severe form is poor and most infants die in the first few months of life. Prognosis of the milder forms is variable, and dependent on multiple factors, including the severity of disease and response to treatments.

Symptoms:

Infants with the most severe form of the disease begin having symptoms as newborns, including hypoglycemia (low blood sugar), liver problems and cardiomyopathy (disease of the heart muscle). Most infants with this severe form die within the first few months of life.

The symptoms of less severe TFP deficiency may begin anytime during infancy through early childhood. They vary from one individual to the next, but may include hypoglycemia (low blood sugar), liver problems, cardiomyopathy (disease of the heart muscle), retinopathy (disease of the eye) and hypotonia (low muscle tone). Later in childhood, rhabdomyolysis (muscle breakdown) and muscle pain may occur.

The mildest form of TFP deficiency can begin anytime from childhood to adulthood. Symptoms include rhabdomyolysis (muscle breakdown) during exercise and peripheral neuropathy (nerve disorder in the limbs).

Symptoms in carriers:

Carriers of TFP deficiency do not typically have symptoms. However, a mother who is pregnant with a baby with TFP deficiency is at risk of illness during pregnancy. The mother may develop HELLP syndrome (haemolysis, elevated liver enzymes, low platelets) or AFLP (acute fatty liver of pregnancy).

Treatment:

Treatment is dietary, including avoidance of fasting, drinking low-fat formula and supplementation with medium-chain triglycerides (MCT) as a source of supplemental calories. Treatment for cardiac involvement or rhabdomyolysis is supportive. During times of illness, hospitalization may be required to monitor and treat hypoglycemia.

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Tyrosinemia type I

Also known as:

FAH deficiency, hepatorenal tyrosinemia, hereditary tyrosinemia type I, fumarylacetoacetase deficiency, fumarylacetoacetate hydrolase deficiency, TYR l

Definition:

Multiple steps in the body are required to breakdown components of protein (amino acids) tyrosine, methionine and phenylalanine. The FAH gene provides instructions for an important enzyme in this process, fumarylacetoacetate hydrolase. If there are mutations in this gene, the enzyme does not function and the amino acids are not broken down. Toxic metabolites accumulate and cause symptoms.

Diagnosis:

Diagnostic testing may include liver function testing, plasma amino acids, succinylacetone, urine organic acids and FAH gene testing.

How it is inherited:

Tyrosinemia is inherited in an autosomal recessive pattern. Normally a person has two functional FAH genes. In people with tyrosinemia type I, both of these genes have a mutation and there is a deficiency of the critical enzyme activity. Each parent of a newborn with tyrosinemia type l typically has one functional and one mutated gene and is considered a carrier. When both parents are carriers, the chance of a newborn inheriting two mutated genes is 25%.

Newborn screening:

  • Incidence: The incidence of tyrosinemia type l is about 1 in 100,000 to 1 in 120,000 births. It is more common in people from Norway, French Canada (Quebec) and Finland.
  • New York State Method of Screening (First Tier): Screening for tyrosinemia, type I is accomplished by measuring succinylacetone by tandem mass spectrometry (MS/MS).
  • Second Tier Screening: None
  • Testing can be affected by: None known
  • Interpretation/reporting of data: Results are reported as screen negative, borderline or as a referral. A repeat specimen should be collected for a borderline result. Prompt consultation with a specialist is required for a referral.
  • Referral to Specialty Care Center: Patients with an abnormal newborn screen for tyrosinemia type l are referred to an Inherited Metabolic Disorder Specialty Care Center for evaluation by a biochemical geneticist trained in the diagnosis and treatment of tyrosinemia.

Prognosis:

On treatment, prognosis is significantly improved and the survival rate is higher than 90%. Some forms may not respond to medication.

Symptoms:

The symptoms of tyrosinemia begin in the newborn period or in the first year of life. The symptoms impact many systems of the body including the liver, the kidneys and the nervous system. The liver symptoms may include liver failure and liver cancer (hepatocellular carcinoma). Untreated liver disease can cause increased bleeding, jaundice and a cabbage-like body odor. The renal disease is called renal tubular dysfunction and causes loss of nutrients in the urine. The neurological symptoms occur as a crisis with change in mental status, abdominal pain and respiratory failure.

Symptoms in carriers:

Carriers of tyrosinemia type l do not typically have symptoms.

Treatment:

Treatment usually includes a medication, Nitisitone, and a low tyrosine diet. For severe cases, a liver transplant may be considered.

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Tyrosinemia type II

Also known as:

Oculocutaneous tyrosinemia, TAT deficiency, Richner-Hanhart syndrome, Keratosis Palmoplantaris with Corneal Dystrophy, Oregon type tyrosinemia, TYR II

Definition:

Tyrosinemia type II is characterized by elevated blood levels of the amino acid tyrosine. Tyrosine is a building block of many proteins. Tyrosinemia type II is caused by a deficiency of tyrosine aminotransferase (TAT), one of the enzymes required to break down tyrosine. The TAT gene provides instructions for making the TAT enzyme; mutations in this gene cause dysfunction and therefore tyrosine is not broken down. Toxic metabolites accumulate and cause symptoms.

Diagnosis:

Diagnostic testing may include plasma amino acids, urine organic acids and TAT gene testing.

How it is inherited:

Tyrosinemia is inherited in an autosomal recessive pattern. Normally a person has two functional TAT genes. In people with tyrosinemia type II, both of these genes have a mutation and there is a deficiency of the TAT enzyme. Each parent of a newborn with tyrosinemia type II typically has one functional and one mutated TAT gene and is considered a carrier. When both parents are carriers, the chance of a newborn inheriting two mutated genes is 25%.

Newborn screening:

  • Incidence: The incidence of tyrosinemia type II is less than 1 in 250,000. It appears to be more common in individuals of Mediterranean and/or Arab descent.
  • New York State Method of Screening (First Tier): Screening for tyrosinemia type II is accomplished by measuring tyrosine by tandem mass spectrometry (MS/MS).
  • Second Tier Screening: None
  • Testing can be affected by: Prematurity, vitamin C deficiency, or high protein intake. Supplementation with total parenteral nutrition can cause a false positive screen.
  • Interpretation/reporting of data: Results are reported as screen negative, borderline or as a referral. A repeat specimen should be collected for a borderline result. Prompt consultation with a specialist is required for a referral.
  • Referral to Specialty Care Center: Patients with an abnormal newborn screen for tyrosinemia type II are referred to an Inherited Metabolic Disorder Specialty Care Center for evaluation by a biochemical geneticist trained in the diagnosis and treatment of tyrosinemia.

Prognosis:

Oculocutaneous manifestations quickly resolve when individuals with tyrosinemia type II restrict dietary consumption of phenylalanine and tyrosine.

Symptoms:

The symptoms of tyrosinemia type II include painful skin lesions (palmoplantar hyperkeratosis of the hands and feet) and ocular manifestations such as red eyes, photophobia, excessive tearing and pain, corneal clouding and ulceration, and pseudodendritic keratitis. The ocular features of tyrosinemia type II may affect vision. Ocular symptoms usually present first, most often in the first year of life. Skin symptoms usually appear after a year of age. Central nervous system involvement is less common, but can include intellectual disability, behavioral problems, nystagmus, tremors, ataxia and/or convulsions. There is no liver involvement in tyrosinemia type II.

Symptoms in carriers:

Carriers of tyrosinemia type ll do not typically have symptoms.

Treatment:

Management requires dietary restriction of phenylalanine and tyrosine.  A controlled diet results in reduction of plasma tyrosine levels and quick resolution of skin and ocular manifestations.  It is unclear how much, or if, the diet affects central nervous system involvement.  Oral retinoids may be helpful in treatment of the skin lesions.

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Tyrosinemia type III

Also known as:

Tyrosinemia due to HPD deficiency, tyrosinemia due to 4-hydroxyphenylpyruvate dioxygenase deficiency, TYR III

Definition:

Tyrosinemia type III is characterized by elevated blood levels of the amino acid tyrosine. Tyrosine is a building block of many proteins. Tyrosinemia type III is caused by a deficiency of 4-hydroxyphenylpyruvate dioxygenase (HPD), one of the enzymes required to break down tyrosine. The HPD gene provides instructions for making the HPD enzyme; mutations in this gene cause dysfunction and therefore tyrosine is not broken down. Toxic metabolites accumulate and cause symptoms.

Diagnosis:

Diagnostic testing may include plasma amino acids, urine organic acids and HPD gene testing.

How it is inherited:

Tyrosinemia is inherited in an autosomal recessive pattern. Normally a person has two functional HPD genes. In people with tyrosinemia type III, both of these genes have a mutation and there is a deficiency of the HPD enzyme. Each parent of a newborn with tyrosinemia type III typically has one functional and one mutated HPD gene and is considered a carrier. When both parents are carriers, the chance of a newborn inheriting two mutated genes is 25%.

Newborn screening:

  • Incidence: Tyrosinemia type III is rare, with an estimated incidence of less than 1 in 1,000,000.
  • New York State Method of Screening (First Tier): Screening for tyrosinemia type III is accomplished by measuring tyrosine by tandem mass spectrometry (MS/MS).
  • Second Tier Screening: None Testing can be affected by: Prematurity, vitamin C deficiency, or high protein intake. Supplementation with total parenteral nutrition can cause a false positive screen.
  • Interpretation/reporting of data: Results are reported as screen negative, borderline or as a referral. A repeat specimen should be collected for a borderline result. Prompt consultation with a specialist is required for a referral.
  • Referral to Specialty Care Center: Patients with an abnormal newborn screen for tyrosinemia type III are referred to an Inherited Metabolic Disorder Specialty Care Center for evaluation by a biochemical geneticist trained in the diagnosis and treatment of tyrosinemia.

Prognosis:

Many individuals with tyrosinemia type III are asymptomatic, particularly when diet is started early. Children with the condition do have a risk of intellectual disability.

Symptoms:

The symptoms of tyrosinemia type III are variable, but may include intellectual disability, seizures, and intermittent ataxia. Some individuals are asymptomatic. There is no liver, ocular or skin involvement in tyrosinemia type III.

Symptoms in carriers:

Carriers of tyrosinemia type lll do not typically have symptoms.

Treatment:

Management requires dietary restriction of phenylalanine and tyrosine. Vitamin C supplementation may be beneficial as well.

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Very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency

Also known as:

ACADVL, acyl-CoA dehydrogenase very long chain deficiency, very long-chain acyl coenzyme A dehydrogenase deficiency, VLCAD-C, VLCAD-H

Definition:

Very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency is a fatty acid oxidation disorder (inherited metabolic disorder).

VLCAD deficiency is caused by mutations in the ACADVL gene. Individuals with this disorder are unable to convert certain fats to energy and may develop symptoms during times of high energy need such as when fasting or ill.

Diagnosis:

Diagnostic testing may include quantification of plasma acylcarnitines, molecular genetic testing of the ACADVL gene, functional analysis of fatty acid oxidation on fibroblasts (skin cells), enzyme analysis on fibroblasts or enzyme analysis on lymphocytes.

How it is inherited:

VLCAD deficiency is inherited in an autosomal recessive pattern. Normally a person has two functional ACADVL genes. In people with VLCAD deficiency, both genes have a mutation and there is a deficiency of the critical enzyme activity. Each parent of a newborn with VLCAD deficiency typically has one functional and one mutated gene and is considered a carrier. When both parents are carriers, the chance of a newborn inheriting two mutated genes is 25%.

Newborn screening:

  • Incidence: The overall incidence is approximately 1 in 30,000.
  • New York State Method of Screening (First Tier): Screening for VLCAD deficiency is accomplished by measuring acylcarnitines (C14 and C14:1) by tandem mass spectrometry (MS/MS).
  • Second Tier Screening: None
  • Testing can be affected by: Screening may be normal in patients with mild VLCAD deficiency who were recently fed, who received IV glucose or who were not ill when the specimen was collected.
  • Interpretation/reporting of data: Results are reported as screen negative or as a referral. Prompt consultation with a specialist is required for a referral.
  • Referral to Specialty Care Center: Patients with an abnormal newborn screen for VLCAD deficiency are referred to an Inherited Metabolic Disorder Specialty Care Center for evaluation by a biochemical geneticist trained in the diagnosis and treatment of VLCAD deficiency.

Prognosis:

Prognosis is variable and dependent on multiple factors including the severity of disease and response to treatments.

Symptoms:

There are three types of VLCAD deficiency, which are all caused by mutations in the ACADVL gene. Symptoms of the most severe type typically begin in infancy and include cardiac (heart) symptoms (cardiomyopathy, arrhythmias), hypotonia (low muscle tone), hepatomegaly (enlarged liver) and intermittent hypoglycemia (low blood sugar). The second type has a childhood onset and symptoms may be similar to the infantile onset excluding cardiac symptoms. The third type has a later onset and episodes of rhabdomyolysis (breakdown of muscle fibers), muscle cramps and exercise intolerance.

Symptoms in carriers:

Carriers of VLCAD deficiency do not typically have symptoms.

Treatment:

Treatment is dietary including avoidance of fasting, drinking low-fat formula and supplementation with medium-chain triglycerides (MCT) as a source of supplemental calories. Treatment for cardiac involvement or rhabdomyolysis is supportive.

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