Early-Onset Metachromatic Leukodystrophy · MLD

Description

Metachromatic leukodystrophy, MLD, is an autosomal recessive lysosomal storage disorder. Two damaging copies of ARSA on chromosome 22q13.33 reduce or abolish arylsulfatase A activity. A rare variant form is caused by deficiency of saposin B, encoded by PSAP. Arylsulfatase A breaks down sulfatide, a sphingolipid concentrated in myelin. Sulfatide accumulates in oligodendrocytes, Schwann cells, and other tissues, and causes progressive demyelination of the central and peripheral nervous systems. The metachromatic granules in stained pathology specimens give the disease its name. Inheritance is autosomal recessive. Reported birth incidence is roughly 1 in 40,000 to 1 in 160,000 depending on the population.

MLD is classified by age of onset. The late infantile form, onset before about 30 months, is the most common and most severe and accounts for roughly half of cases. Children develop normally and then regress, with gait disturbance, hypotonia followed by spasticity, loss of speech, seizures, and progression to a vegetative state, typically within several years. The early juvenile form (onset 2.5 to 6 years) and late juvenile form (6 to 16 years) progress more slowly. Adult-onset MLD often presents with psychiatric symptoms and cognitive decline. Diagnosis combines decreased arylsulfatase A activity in leukocytes, elevated urinary sulfatide, biallelic ARSA variants, and brain magnetic resonance imaging showing symmetric periventricular and central white matter signal change. Pseudodeficiency alleles complicate enzyme-only testing and are why newborn screening for MLD is built around sulfatide measurement on dried blood spot rather than enzyme activity alone.

MLD was added to the federal Recommended Uniform Screening Panel in August 2024 following Secretary-level approval of the ACHDNC recommendation. State adoption is in progress as of 2026.

Treatments to date

Atidarsagene autotemcel, marketed as Lenmeldy in the United States and Libmeldy in the European Union, is an autologous CD34-positive hematopoietic stem cell gene therapy. Cells are collected from the child, transduced ex vivo with a lentiviral vector carrying functional ARSA, and infused back after myeloablative conditioning. The transduced cells engraft and continuously deliver arylsulfatase A to tissues including the central nervous system through cells of the monocyte lineage. The FDA approved Lenmeldy in March 2024 for children with pre-symptomatic late infantile, pre-symptomatic early juvenile, and early symptomatic early juvenile MLD. The European Medicines Agency approved Libmeldy in 2020 for the same indication classes. The pivotal data, reported by Fumagalli et al. (Lancet, 2022) for the late infantile and early juvenile cohorts treated at the San Raffaele-Telethon Institute in Milan, showed preserved motor and cognitive function in pre-symptomatic children at long follow-up compared with untreated natural-history controls. Outcomes after symptom onset in the late infantile form remain poor, which is why newborn screening matters for this indication.

Allogeneic hematopoietic stem cell transplant has been used historically with mixed results and is no longer the standard option where Lenmeldy is available. Supportive care includes seizure management, spasticity management, gastrostomy feeding, and palliative care. Active research includes intrathecal AAV-mediated ARSA gene therapy and other delivery strategies aimed at later-onset and post-symptomatic disease.