MOLECULAR-GENETICS OF METACHROMATIC LEUKODYSTROPHY

Metachromatic leukodystrophy is an autosomal recessive inherited lysos omal storage disease. It can be caused by mutations in two different g enes, the arylsulfatase A and the prosaposin gene. These genes encode two proteins that are needed for the proper degradation of cerebroside sulfate, a glycolipid mainly found in the myelin membranes; Deficienc y of arylsulfatase A or of a proteolytic product of prosaposin leads t o the accumulation of cerebroside sulfate, which causes a lethal progr essive demy elination. Mutations in the arylsulfatase A gene are far m ore frequent than those of the prosaposin gene. So far 31 amino acid s ubstitutions, one nonsense mutation, three small deletions, three spli ce donor site mutations, and one combined missense/splice donor site m utation have been identified in the arylsulfatase A gene. Two of these mutant alleles are frequent, accounting for about one-half of all mut ant alleles, whereas the remainder are heterogeneous. Amino acid subst itutions cluster in exons 2 and 3, a region that shows a high degree o f conservation among sulfatases of different function and origin. Diff erent mutations are associated with phenotypes of different severity, but there is a remarkable variability of severity when patients with i dentical genotypes are compared. Demonstration of an arylsulfatase A d eficiency is not a proof of metachromatic leukodystrophy, since a subs tantial deficiency without any clinical consequences is frequent in th e general population. This deficiency is caused by an arylsulfatase A allele, which due to certain mutations encodes greatly reduced amounts of functional enzyme. However, these amounts are sufficient to sustai n a normal phenotype. In the diagnosis and genetic counseling, these d eficiencies must be differentiated from those causing meta chromatic l eukodystrophy. So far only six patients with mutations in the prosapos in gene have been described, in which three defective alleles two with amino acid substitutions and one with a 33-bp insertion have been ide ntified. (C) 1994 Wiley-Liss, Inc.