Metachromatic leukodystrophy (MLD) is a lysosomal storage disorder characterized by progressive neurodegeneration due to a deficiency in the enzyme arylsulfatase-A (ARSA). This deficiency leads to the accumulation of toxic sulfatides, primarily in the nervous system.
From October 2021 through July 2023, we performed newborn screening for MLD on over 100,000 newborns during a prospective study conducted in the newborn screening laboratory in Hannover (Germany), and the University Children’s Hospital Tübingen (Germany).
A three-tiered algorithm was used to determine C16:0 and C16:1OH sulfatide levels, followed by a second-tier enzyme analysis of arylsulfatase-A (ARSA) activity for samples with elevated sulfatides. A third-tier genetic test was performed on samples with reduced or absent enzyme activity levels.
Second- and third-tier testing revealed abnormally low ARSA activity and two pathogenic ARSA variants (with presumed compound heterozygosity) in each of three newborns.
Two of the infants with predicted early-onset MLD received arsa-cel therapy at the age of 12 months. At the time of the report, the children identified by newborn screening had reached all developmental milestones appropriate for their age.
This study highlights the feasibility, effectiveness, and importance of implementing a high-throughput, three-tiered newborn screening algorithm for the detection of MLD.
Read the complete article in the New England Journal of Medicine.