Sphingolipidoses: molecular manifestations and biochemical strategies.

Among the estimated 20,000 to 40,000 human gene pairs (1) approximately 2000 single-gene alterations are now recognized (2). A specific protein alteration has been established or suggested for about 10% of these mutations (3). Most lysosomal storage disorders fall into this class of inherited metabolic disorders. The sphingolipidoses represent those lysosomal storage disorders in which the predominating storage product is a specific sphingolipid. The diseases have been classified according to the lipid that accumulates (Table 1). Chemical identification of the accumulated product led to the description of the specific enzymatic lesion in Gaucher's disease (4), metachromatic leuko-dystrophy (5), and Niemann-Pick disease (6). However , as was predicted by Hers (7), the storage material of certain lysosomal storage disorders can be very heterogeneous, resulting sometimes in an ambiguous classification of lipidoses. Although we have chosen to include a-fucosidosis in the sphingolipi-doses, it has been argued, with some justification, that the complex nature of the numerous products accumulating in this particular disorder make such a designation restrictive (8). In Krabbe's disease, it is not product heterogeneity but rather lack of overt lysosomal storage that has limited its unequivocal classification as a sphingolipidosis; however, the primary enzyme deficiency in this disorder has clearly been established as being lysosomal (9-11). The prevalence of the sphingolipidoses is similar to that of other common inborn errors of metabolism. In Ashkenazi Jews the gene frequency of Gaucher's disease has been estimated to be 1 :50 (12), that of Tay-Sachs disease 1 :30 (13), that of type A Niemann-Pick disease 1:200 (14). In the Swedish population, the estimates of gene frequencies of metachromatic leukodystrophy and Krabbe's disease have been placed at 1:200 (15) and 1:230 (16), respectively. In comparison , the gene frequency of sickle cell anemia in blacks is 1:25 (17), of cystic fibrosis in Europeans is 1:50 (18), and of phenylketonuria in Europeans is 1:125 (19). All genetic disorders are by definition characterized by aberrant biochemical processes. However, pheno-typic expression often is observed at some metabolic point distant from the primary genetic lesion. The lysosomal storage disorders offer the unique opportunity of studying phenotypic expression (lysosomal storage) in close proximity to the altered gene product (enzyme deficiency). Scientists have not overlooked this advantage and remarkable progress has been made in the study of the sphingolipidoses. The popularity of this field can be judged by the 4,395 publications that have appeared during the last 5 years on …