Metachromatic leukodystrophy and related disorders

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By Alessandra Biffi MD and Maria Sessa MD

Metachromatic leukodystrophy is also known as or subsumes Arylsulfatase A pseudodeficiency, Metachromatic leukodystrophy, Multiple sulfatase deficiency, Sulfatide activator deficiency, and Sulfatase modifier factor 1. -ed.

Metachromatic leukodystrophy is an autosomal recessive disorder caused by mutations in the arylsulfatase A (ARSA) gene. The severity of the clinical syndrome varies from infantile regression, hypotonia, peripheral neuropathy, seizures, and cognitive deterioration to late adult-onset behavioral disturbance, often initially diagnosed as a primary psychiatric disorder followed by spastic paraparesis, seizures, and dementia. The syndrome severity is primarily determined by the level of residual enzymatic activity. Guidelines are presented to differentiate metachromatic leukodystrophy from the related syndromes of multiple sulfatase deficiency, and of sulfatide activator deficiency and from the “pseudodeficiency” state. In this update, Dr. Alessandra Biffi and Dr. Maria Sessa of the San Raffaele Scientific Institute in Milan, Italy, and Dr. James Garbern of the University of Rochester School of Medicine and Dentistry report on the more recent advances in genotype-phenotype correlation and on the status of therapy of metachromatic leukodystrophy by bone marrow transplantation, stem cell therapy, and gene therapy.

Key Points

  • Metachromatic leukodystrophy is an autosomal recessive disease due to mutations in the arylsulfatase A (ARSA) gene and is usually classified according to the age of onset in late infantile, early and late juvenile, and adult forms.
  • ARSA mutations can be functionally divided into 2 broad groups: null (0) alleles associated with no enzymatic activity and R alleles associated with some residual enzyme activity. Homozygosity for 0 alleles results mainly in late infantile metachromatic leukodystrophy. Compound heterozygosity for 0/R alleles is most frequent in the juvenile forms, and homozygosity for R alleles leads predominantly to adult metachromic leukodystrophy.
  • Metachromatic leukodystrophy is a progressive disorder that eventually leads to total disability and death. The absence of robust therapies emphasizes the need for the development of innovative therapeutic approaches.
  • A phase I/II dose-escalation clinical trial of enzyme replacement therapy has recently been conducted, but results have not, thus far, been published.
  • A phase I/II clinical trial of gene therapy using autologous hematopoietic stem cells and lentiviral vectors has recently started and is currently recruiting late infantile and early juvenile metachromatic leukodystrophy patients (