Sunday 4 June 2006
Metachromatic Leukodystrophy is transmitted in an autosomal-recessive pattern.
It results mostly from a deficiency of the lysosomal enzyme arylsulfatase A (arylsulfatase A deficiency). This enzyme, present in a variety of tissues, cleaves the sulfate from sulfate-containing lipids (sulfatides), the first step in their degradation. Enzyme deficiency leads to an accumulation of the sulfatides, especially cerebroside sulfate; how this leads to myelin breakdown is not known. The gene for arylsulfatase A has been localized to chromosome 22q, and a wide range of mutations have been described.
However, the metachromatic leukodystrophies comprise 3 nonallelic forms:
arylsulfatase A deficiency (MIM.250100 at 22q13) with 5 allelic forms
- late infantile
- adult form
- partial cerebroside sulfate deficiency
- pseudo-arylsulfatase A deficiency
cerebroside sulfatase activator deficiency (MIM.249900) (saposin B deficiency) (MIM.176801)
multiple sulfatase deficiency or juvenile sulfatidosis (MIM.272200), a disorder that combines features of a mucopolysaccharidosis with those of metachromatic leukodystrophy.
Recognized clinical subtypes of the disorder include a late infantile form (the most common), a juvenile form, and an adult form. The two forms with childhood onset often present with motor symptoms and progress gradually, leading to death in 5 to 10 years.
In the adult form, psychiatric or cognitive symptoms are the usual initial complaint, with motor symptoms coming later, and the disease has a slower course than in the infantile form.
Five allelic and two nonallelic forms are now recognized, with onset from childhood to adulthood corresponding to mutations that lead to decreased synthesis or activity of the enzyme. Although there is no known cure, promising results have recently been achieved with bone marrow transplantation.
The most striking histologic finding is demyelination with resulting gliosis. Macrophages with vacuolated cytoplasm are scattered throughout the white matter. The membrane-bound vacuoles contain complex crystalloid structures composed of sulfatides; when bound to certain dyes such as toluidine blue, sulfatides shift the absorbance spectrum of the dye, a property called metachromasia.
Similar changes in peripheral nerve are observed. The detection of metachromatic material in the urine is also a sensitive method of establishing the diagnosis.
genetic metabolic diseases