- Raphael Schiffmann, MD, MHSc
Raphael Schiffmann, MD, MHSc
- Medical Director of the Institute of Metabolic Disease
- Adjunct Professor of Biomedical Studies
- Baylor University Medical Center
- Section Editors
- Marc C Patterson, MD, FRACP
Marc C Patterson, MD, FRACP
- Section Editor — Pediatric Neurology
- Professor of Neurology, Pediatrics, and Medical Genetics
- Chair, Division of Child and Adolescent Neurology
- Mayo Clinic College of Medicine
- Helen V Firth, DM, FRCP, DCH
Helen V Firth, DM, FRCP, DCH
- Section Editor — Genetics
- Consultant Clinical Geneticist
- Addenbrooke's Hospital, Cambridge, UK
Metachromatic leukodystrophy (sulfatide lipidosis) (MLD) is a rare autosomal recessive lysosomal storage disease that causes progressive demyelination of the central and peripheral nervous system.
This topic will review the clinical manifestations, diagnosis, and treatment of metachromatic leukodystrophy. Other lysosomal storage disorders and leukodystrophies are discussed separately. (See "Adrenoleukodystrophy" and "Alexander disease" and "Aspartoacylase deficiency (Canavan disease)" and "Cerebrotendinous xanthomatosis" and "Neurologic manifestations of Fabry disease" and "Krabbe disease" and "Mucopolysaccharidoses: Clinical features and diagnosis" and "Overview of Niemann-Pick disease" and "Pelizaeus-Merzbacher disease" and "Sjögren-Larsson syndrome" and "Vanishing white matter disease".)
Metachromatic leukodystrophy (MLD) is caused by deficient activity of arylsulfatase A as a result of, in almost all cases, mutations in the arylsulfatase A gene (ARSA gene). In a few patients, MLD is caused by a deficiency of sphingolipid activator protein SAP-B (saposin B), which normally stimulates the degradation of sulfatides by ARSA . This variant form of MLD is caused by mutations in the prosaposin gene (PSAP gene).
ARSA is responsible for the desulfation of cerebroside sulfate, a major glycolipid of myelin. As a result, decreased ARSA activity leads to the accumulation of cerebroside sulfate in the central nervous system, peripheral nerves, kidneys, and other visceral organs. The accumulation of cerebroside sulfate destroys oligodendroglial and Schwann cells, causing central and peripheral demyelination. Electron microscopy shows thickened lines in the myelin whorls and lamellar inclusions of sulfatides in the Schwann cells .
Genetics — At least 60 mutations in the ARSA gene have been described in MLD. Two alleles, A and I, together account for approximately 50 percent of cases [3,4]. These alleles contribute to the different clinical expressions of the disease .
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