NEWBORN SCREENING PILOT STUDY FOR METACHROMATIC LEUKODYSTROPHY (MLD)

The goal of newborn screening (NBS) is to detect potentially fatal or disabling conditions in newborns, thereby providing a window of opportunity for early treatment, often while the child is still asymptomatic. Such early detection and treatment can have a profound impact on the clinical severity of the condition in the affected child. If left undiagnosed and untreated, the consequences of the targeted disorders can be dire, many causing irreversible neurological damage; intellectual, developmental, and physical disabilities; and even death. In 2006, the American College of Medical Genetics (ACMG) developed newborn screening guidelines that recommend that all newborn infants be screened for "core conditions" and that secondary conditions identified during the core evaluations be reported. These recommendations were accepted by the HHS Secretary's Advisory Committee on Heritable Disorders in Newborns and Children (ACHDNC) (authorized by the Children's Health Act of 2000) and by the Secretary of HHS, and formed the basis of the Recommended Uniform Screening Panel (RUSP), which now contains 37 core and 26 secondary conditions with one condition nomination pending Secretary approval. Most states now use the RUSP or very similar panels for newborn screening. Currently, there are thousands of rare disorders that have been identified and hundreds that could potentially benefit from newborn screening.
Metachromatic Leukodystrophy (MLD) is an autosomal recessive lysosomal storage disorder caused by pathogenic variants in the Arylsulfatase A (ARSA) gene, resulting in enzyme deficiency and accumulation of sulfatides in the brain, blood, and urine. Its manifestations include progressive cognitive, behavioral, and psychiatric decline with peripheral neuropathy and later loss of gross motor milestones, accompanied by characteristic brain MRI findings of destruction of the white matter (demyelination). The birth prevalence of MLD is estimated at 1 in 40,000-100,000 infants, and over 280 disease-associated variants in the ARSA gene have been identified. There are 4 clinical subtypes of MLD based on age of onset of symptoms: late-infantile (<30 months), early-juvenile (2.5-6 years), late-juvenile (>6-16 years), and adults (>16 years). The earlier onset of disease is correlated with more severe loss-of-function variants in the gene, with resulting minimal or no enzyme activity. In addition, 2 alleles in the ARSA gene are associated with pseudodeficiency with reduced enzyme activity that can be confused with the levels in affected individuals. Recent FDA approval of a gene therapy for MLD has made this condition an attractive one for piloting using the IDIQ contract mechanism.
The assay developed for MLD is based on biochemical measurement of C16:0 sulfatide in a sample from a dried blood spot using liquid chromatography tandem mass spectrometry (LC-MS/MS), with a second-tier test to measure ARSA enzyme activity to reduce false positives. A third-tier test consists of sequencing the ARSA gene to identify pathogenic mutations and exclude similar disorders due to mutations in the PSAP and SUMF1 genes. However, the sensitivity and specificity of the assay can be significantly improved by screening for C16:1-OH sulfatide, reducing the false positive rate to ~0.05%. Biochemical and genetic testing to confirm the diagnosis of MLD by ARSA activity in leukocytes, urine sulfatides, and ARSA genotyping are well-established. Reagents and internal standards are commercially available. The ARSA activity in leukocytes and ARSA genotype are expected to predict the age of disease-onset and disease progression for most individuals with a positive screen for MLD. Thus far, the only prospective population screening pilots have been performed based on testing ~158,000 newborns in Germany and Austria, where 4 infants were identified, and the diagnosis confirmed.
The purpose of this contract is to support the development, implementation, and provision of proof of concept for the identification of newborns with MLD in the newborn screening setting.

Grant Number: 75N94021D00018-0-759402400001-1
NIH Institute/Center: NIH
Principal Investigator: MICHELLE CAGGANA