Metachromatic leukodystrophy

Metachromatic leukodystrophy (MLD) is a lysosomal storage disease

• is an autosomal recessive hereditary neurodegenerative disease belonging to the group of lysosomal storage diseases (LSDs)
• one of the most common leukodystrophies, and has a prevalence rate of 1 in 40,000-160,000 worldwide (1)
  • in some isolated populations, the incidence of MLD is much higher. For example, in the group of Habbanite (Jews) it is estimated at 1 in 75, among the Navajo Indian people at 1 in 2,500, and among the Arab groups of Israel it is estimated at 1 in 8,000
• characterized by damage of the myelin sheath that covers most of nerve fibers of the central and peripheral nervous systems
• disease occurs due to a deficiency of the lysosomal enzyme arylsulfatase A (ARSA) or its sphingolipid activator protein B (SapB) and it clinically manifests as progressive motor and cognitive deficiency
  • ARSA and SapB protein deficiency are caused by mutations in the ARSA and PSAP genes, respectively
  • severity of clinical course in metachromatic leukodystrophy is determined by the residual ARSA activity, depending on the type of mutation
  • MLD causes demyelination to occur, leading to impaired motor function, spastic tetraparesis, ataxia, spasms, optic atrophy, and cognitive impairment
    • however, the exact mechanisms of demyelination in MLD remain unknown (1)

Atidarsagene autotemcel is recommended, within its marketing authorisation, as an option for treating metachromatic leukodystrophy with mutations in the arylsulphatase A (ARSA) gene (2):

• for children who have late infantile or early juvenile types, with no clinical signs or symptoms
• for children who have the early juvenile type, with early clinical signs or symptoms, and who can still walk independently and have no cognitive decline

Reference:

• Shaimardanova AA, Chulpanova DS, Solovyeva VV, et al. Metachromatic Leukodystrophy: Diagnosis, Modeling, and Treatment Approaches. Front Med (Lausanne). 2020;7:576221. Published 2020 Oct 20. doi:10.3389/fmed.2020.576221
• NICE (March 2022). Atidarsagene autotemcel for treating metachromatic leukodystrophy