Additional Testing

Babies born in New York State may be eligible for screening for additional disorders beyond those mandated by New York State Public Health Law. These include consented pilot studies offered to families whose babies are born at participating hospitals, as well as testing for conditions available to all babies in the state.

Metachromatic Leukodystrophy (MLD)

The New York State Newborn Screening Program was awarded a contract from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) to perform a pilot screen for Metachromatic Leukodystrophy (MLD). MLD will be provisionally added to the screening panel for one year. Testing for the MLD pilot study will be carried out beginning on September 12, 2025. Testing will be conducted during a baby’s routine newborn screening. All infants will be screened for MLD.

What is Metachromatic Leukodystrophy (MLD)?

Metachromatic leukodystrophy (MLD) is a rare, progressive lysosomal disorder with an autosomal recessive pattern of inheritance. MLD is almost always caused by defects in the ARSA gene. For someone to have MLD, they typically have inherited two clinically significant variants, one from each parent. The ARSA gene encodes a lysosomal enzyme called arylsulfatase A (ARSA). This enzyme is responsible for breaking down sulfatides, and low or absent enzyme activity causes sulfatides to accumulate in the cells to toxic levels. This accumulation primarily impacts the nervous system and causes damage and death to the glial cells that produce myelin. Myelin forms a protective layer around nerves and enables cell signaling between neurons to transmit quickly. Damaged myelin leads to the loss of nerve fibers and impairs nervous system function.

There are different forms of MLD, and each form is characterized by the age at the onset of symptoms as well as the predicted rate of disease progression without treatment.

The most severe form, the late infantile form, is the most common. Children with late infantile disease usually develop symptoms of deteriorating nervous system function between 6 months and 2 years of age. Symptoms include diminished senses, loss of motor skills, poor muscle function and paralysis, intellectual impairment, loss of bladder and bowel control, gallbladder problems, seizures, and ultimately, death.
Symptoms for the juvenile form begin between 4 years of age and adolescence. The disease progresses more slowly for these individuals. Symptoms may include difficulty with balance and coordination, tremors, learning difficulties, regression in fine motor skills, behavioral difficulties, and concentration issues.
For individuals with the adult form, symptoms can begin anytime in adulthood, and presenting symptoms may vary. These individuals may experience psychiatric changes, cognitive dysfunction, weakness, loss of coordination, seizures, and dementia.

MLD occurs in approximately 1 in 40,000 – 1 in 170,000 live-born infants in the United States.

How is Screening for Metachromatic Leukodystrophy (MLD) Performed?

First Tier Screening: C16:0-sulfatide and C16:1OH-sulfatide are measured using mass spectrometry. If sulfatides are normal, the sample is deemed within acceptable limits and no further action is required. If sulfatide levels are elevated, second tier biochemical screening is performed.
Second Tier Screening: Analysis of arylsulfatase A (ARSA) enzyme activity by mass spectrometry is performed via send-out to a contract lab. If enzyme activity is normal, the sample is deemed within acceptable limits and no further action is required. If ARSA enzyme activity is abnormal (low or absent), third tier molecular analysis is performed.
Third Tier Screening: Sequencing of the ARSA gene is performed to determine if the infant has variants that cause MLD.

Positive test for Metachromatic Leukodystrophy (MLD) and next steps

The metachromatic leukodystrophy (MLD) screen is not a diagnostic test, it cannot clinically confirm if a baby has MLD. A positive result means that sulfatides were elevated, ARSA enzyme activity was low or absent, and at least one clinically significant variant was found in the ARSA gene. The baby is at increased risk for MLD and prompt evaluation by a specialist is required. All babies with a positive result will be referred to a specialist for additional testing. All babies who screen positive for MLD should be seen by a specialist as soon as possible. The specialist will order workups for diagnostic MLD testing. Confirmatory diagnostic testing is required to confirm the newborn screening results.

Prognosis for babies with Metachromatic Leukodystrophy (MLD)

There are three different forms of metachromatic leukodystrophy (MLD), the late infantile form, the juvenile form, and the adult form. The age at which symptoms first appear and the rate of disease progression is different for each type. Over half of individuals with MLD have the most severe late infantile form and may start experiencing symptoms as early as 6 months of age. Because MLD is a progressive disease that damages the nervous system, symptoms are wide-ranging and can be severe. There have been recent advances in available treatment options. Early diagnosis, before symptoms appear, gives a child the most treatment options.

Treatment options for infants with Metachromatic Leukodystrophy (MLD)

Early diagnosis provides opportunities for babies to receive treatments that can improve quality of life and delay progression of the disorder. In March 2024, the United States Food and Drug Administration (FDA) approved Lenmeldy (atidarsagene autotemcel), the first FDA-approved gene therapy treatment for metachromatic leukodystrophy (MLD). Infants and children with pre-symptomatic late infantile, pre-symptomatic early juvenile and early symptomatic early juvenile MLD are currently eligible for Lenmeldy. For infants and children with MLD who are pre-symptomatic or minimally symptomatic, stem cell transplantation can also be an option. For children who are already experiencing severe symptoms, the current treatment is supportive in nature and focused on symptom relief to improve quality of life. Early diagnosis, before symptoms appear, gives a child the most treatment options.

Resources

•    MLD Foundation
•    United Leukodystrophy Foundation
•    National Institute of Neurological Disorders and Stroke ALD Information Page
•    Hunter’s Hope
•    NORD
•    GeneReviews

Congenital Cytomegalovirus (cCMV) Infection

From October 2, 2023 to September 30, 2024, all newborn screen samples received by the New York State Newborn Screening (NBS) Program were screened for one extra condition for free: congenital cytomegalovirus (cCMV) infection. All babies were tested for cCMV unless parents chose to opt out of having their child’s cCMV screen result reported in their newborn screen record.

If your child has a positive newborn screen for congenital CMV your specialist may discuss participation in a long-term follow-up program called PROACTIVE NYS. For more information please click here.