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.
Carriers of MHBD deficiency may have symptoms including developmental delay.
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).
- 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.
Diagnostic testing may include urine organic acid analysis, HADH2 gene sequencing and MHBD enzyme activity analysis.
Treatment may include an isoleucine restricted diet.
Prognosis is not well known. In some patients, neurological symptoms were improved after starting treatment.
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.