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Metachromatic leukodystrophy

INTRODUCTION

Metachromatic leukodystrophy (MLD, sulfatide lipidosis) is an autosomal recessive lysosomal storage disease that occurs in 1 of 40,000 births. It 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 [1]. 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 (CNS), peripheral nerves, kidneys, and other visceral organs. The accumulation of cerebroside sulfate destroys oligodendroglial and Schwann cells, causing central and peripheral demyelination.

This topic will review the clinical manifestations, diagnosis and treatment of MLD. Other lysosomal storage disorders and hereditary disorders associated with peripheral neuropathy are discussed separately. (See "Neurologic manifestations of Fabry disease" and "Genetics; clinical manifestations; and diagnosis of Gaucher disease" and "Krabbe disease" and "Clinical features and diagnosis of the mucopolysaccharidoses" and "Complications and management of the mucopolysaccharidoses" and "Overview of Niemann-Pick disease" and "Hereditary neuropathies associated with generalized disorders".)

GENETICS

At least 60 mutations in the ARSA gene have been described in metachromatic leukodystrophy (MLD). Two alleles, A and I, together account for approximately 50 percent of cases [2,3]. These alleles contribute to the different clinical expressions of the disease [2].

  • Homozygosity for the I allele is associated with very low or undetectable residual ARSA activity and late infantile onset; compound heterozygotes (with the other allele unknown) also appear to have a late infantile onset.
  • Homozygosity for the A allele is associated with low but detectable residual ARSA activity and the juvenile or adult onset forms; compound heterozygotes have later onset of disease.
  • The presence of both alleles is associated with juvenile onset.
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References Top
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