Biochemical and Genetic Studies in Two Families With Fabry Disease

Abstract

Genetic, biochemical, and enzymatic studies were performed in two families with Fabry disease. The urinary glycolipids and the leukocyte \g=a\-galactosidase, \g=b\-galactosidase,N-acetyl-\g=b\-glucosaminidase, and N-acetyl-\g=b\-galactosaminidase activities were determined in members of these families. Seven male members of both families had the typical symptoms of classic Fabry disease with abnormally low levels of \g=a\-galactosidase and increased urinary excretion of glycolipids.Female carriers who had moderately low levels of \g=a\-galactosidasewith excessive urinary glycolipid excretion showed typical clinical symptoms except for one subject. Our results suggest that there is a correlation between the urinary glycolipid excretion, the level of leukocyte \g=a\-galactosidase activity, and the clinical picture in hemizygous male patients with Fabry disease and heterozygous female carriers.(Arch Neurol 31: [45][46][47][48][49][50] 1974) Fabry disease is characterized clini¬ cally by episodes of severe fleet¬ ing pains in the extremities, crises of fever, hypohidrosis, tortuosity and di¬ lation of the conjunctival and retinal vessels, clouding of the cornea, and proteinuria.The disease is an inborn error of glycolipid metabolism, transmitted as a sex-linked recessive trait,1 5 and is manifested by the sequelae of deposi¬ tion of glycolipids, eg, ceramide trihexoside (CTH) and ceramide dihexoside (CDH), in blood vessels, nerves, ganglion cells, the cornea, kidneys, heart, and other tissues.11-10 Brady et al11 reported that the ac¬ cumulation of glycolipid is due to a deficiency of ceramide trihexosidase. Recently, using artificial substrates, Kint12 has shown that a-galactosidase is deficient in the leukocytes of pa¬ tients with Fabry disease.However, few systematic clinicobiochemical studies including the ge¬ netic aspects in pedigrees of Fabry disease have been reported. The pur¬ pose of this communication is to pre¬ sent information on the biochemical and enzymatic changes, as well as the clinical manifestations, of patients and carriers in two families with Fabry disease. Materials and MethodsThe urinary glycolipids and leukocyte agalactosidase, /3-galactosidase, N-acetyl-ß-glucosaminidase, and N-acetyl-/J-galactosaminidase activities were determined in 10 members of family A and 17 members of family B. Clinical and ophthalmologic examinations were also performed on all members. The leukocyte a-galactosidase, /8-galactosidase, N-acetyl-ß-glucosaminidase, and N-acetyl-ß-galactosaminidase activities were also measured in 23 healthy adult controls.Urinary Glycolipid Detection.-When available, a 24-hour urine collection was used for the test. Urine was filtered on sol¬ vent-washed filter papers that were air dried for a few hours. The filter papers were extracted in 40 ml of chloroformmethanol (2:1 v/v) for one hour. The ex¬ tract was washed with 8 ml of distilled wa¬ ter. The upper phase was discarded, and the lower phase was dried at 55 C. An ali¬ quot of the total lipid extract was chromatographed on plates ...

Lysosomal Enzyme Activities Among Chinese: Leukocyte α-Galactosidase and β-Galactosidase

“…Heat inactivation studies also showed low levels of a-galactosidase A, consistent with car rier status. We have not carried out hair root [6] or urine glycolipid [7] analyses to confirm the diagnosis. However, since the number of individuals with low activity was so high, there is also the possibility that some of them are low-activity variants and are not carriers of Fabry's disease.…”

Increased glycosphingolipid excretion associated with proteinuria.

“…In addition, it has been proposed that analysis of glycosphingolipids in the urinary sediment can be a usefuil adjunct in the diagnosis of a wide variety of glycosphingolipidoses including: Krabbe's leukodystrophy, Gaucher's, Fabry's, Sandhoff's diseases, and metachromatic leukodystrophy (5). Analysis of urinary sediment for trihexosylceramide and digalactosylceramide has been used to screen for hemizygotes and heterozygotes with Fabry's disease (5)(6)(7)(8)(9)(10)(11)(12) …”