SUMMARY Heterozygote detection for angiokeratoma corporis diffusum (Anderson-Fabry disease, ACD), an X-linked disorder of glycosphingolipid metabolism, was examined using a-galactosidase activity, an a-galactosidase/fl-galactosidase activity ratios (a/f ratio) in leucocytes, plasma, and hair follicles. For leucocytes, 22 obligate heterozygotes, 25 suspected heterozygotes, and 47 control subjects were studied, while for plasma, the groups were 17 obligate heterozygotes and 35 controls. The a/fl ratio in plasma and leucocytes was clearly a better discriminator between obligate heterozygotes and controls than a-galactosidase activity alone, but still failed to detect 3 obligates with leucocytes and 2 with plasma. Discrimination was not improved by joint use of plasma and leucocyte a/fl ratios, but was improved by measurement of hair-follicle a/f ratios. The interdecile range of log (a-galactosidase/fl-galactosidase activity) in 20 hair follicles from each of 4 obligate and 7 suspected heterozygotes was clearly different from 11 control subjects. Accordingly, for rapid screening for carriers of ACD, we recommend use of leucocyte or plasma a/f ratios which should detect > 85% of heterozygotes. When results are equivocal, and ancillary information suggests heterozygous status, the more time-consuming measurement of hair-follicle a/f ratios is a useful additional test.

ExtractA 28-month-old Negro male with atypical Sandhoff's disease (GM2 gangliosidosis, type 2) is described. Clinical presentation closely resembled Sandhoff's disease. The appendiceal neuron cytoplasm was distended with periodic acid-Schiff (PAS)-positive material. Hepatic glycolipid N-acetylneuraminic acid was elevated 1.5-fold, chiefly because of increased GM2. Neutral glycolipid hexose was elevated twofold, mainly because of a component with globoside-like chromatographic properties. Unlike patients with Sandhops disease, the child had total 0-D-N-acetylhexosaminidase activity 20-24% of normal in serum and plasma and 7-1 1% of normal in leukocytes and cultured fibroblasts, but activity in liver (<2y0 of normal) was similar to that in Sandhoff's disease. In all tissues examined, >95% of the activity was heat denaturable, corresponding in electrophoretic mobility to the heat-denaturable component of normal tissues. The decrease in heat-denaturable activity with time and the pH optimum were similar in patient and control crude tissue preparations and partially purified preparations of plasma hexosaminidase A. In the child's mother, total hexosaminidase activity was approximately 50y0 of mean control values in serum, plasma, and leukocytes, and serum hexosaminidase A was relatively increased. This finding, together with the death of at least three other children in the kindred from an apparently phenotypically similar illness, indicates the inherited nature of the disorder. SpeculationAppreciable hexosaminidase activity in serum and plasma and its marked deficiency in liver suggest that the active form (or forms) in serum and plasma differ from those in solid tissues, and that the mutation in the case described has altered the hexosaminidases in a manner that virtually abolishes their activity in solid tissues but permits their partial activity in serum and plasma.