Ceramide Trihexosidosis (Fabry's Disease) without Skin Lesions

Clarke, Joe T.R.; Knaack, J; Crawhall, J. C.; Wolfe, L. S.

doi:10.1056/nejm197102042840503

Cited by 76 publications

(32 citation statements)

References 11 publications

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“…In Fabry disease, early studies revealed the presence of nonfunctional, immunologically cross-reactive enzyme protein in some classically affected hemizygotes (with essentially no detectable enzymatic activity), while others had no detectable enzyme protein (22,23). Rare, atypical variants with residual a-galactosidase activity and milder phenotypes had enzyme protein (24)(25)(26)(27)(28), however, the amounts were not quantitated. More recent studies of a-galactosidase biosynthesis in fibroblasts from unrelated Fabry hemizygotes demonstrated the occurrence of several types of enzyme defects (21).…”

Section: Introductionmentioning

confidence: 99%

Fabry disease: six gene rearrangements and an exonic point mutation in the alpha-galactosidase gene.

Bernstein¹,

Bishop²,

Astrin³

et al. 1989

J. Clin. Invest.

154

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Fabry disease, an X-linked recessive disorder of glycosphingolipid catabolism, results from the deficient activity of the lysosomal hydrolase, a-galactosidase. Southern hybridization analysis of the a-galactosidase gene in affected hemizygous males from 130 unrelated families with Fabry disease revealed six with different gene rearrangements and one with an exonic point mutation resulting in the obliteration of an Msp I restriction site. Five partial gene deletions were detected ranging in size from 0.4 to > 5.5 kb. Four of these deletions had breakpoints in intron 2, a region in the gene containing multiple Alu repeat sequences. A sixth genomic rearrangement was identified in which a region of about 8 kb, containing exons 2 through 6, was duplicated by a homologous, but unequal crossover event. The Msp I site obliteration, which mapped to exon 7, was detected in an affected hemizygote who had residual enzyme activity. Genomic amplification by the polymerase chain reaction and sequencing revealed that the obliteration resulted from a C to T transition at nucleotide 1066 in the coding sequence. This point mutation, the first identified in Fabry disease, resulted in an arginine356 to tryptophan3% substitution which altered the enzyme's kinetic and stability properties. The detection of these abnormalities provided for the precise identification of Fabry heterozygotes, thereby permitting molecular pedigree analysis in these families which revealed paternity exclusions and the first documented new mutations in this disease.

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Section: Introductionmentioning

confidence: 99%

Fabry disease: six gene rearrangements and an exonic point mutation in the alpha-galactosidase gene.

Bernstein¹,

Bishop²,

Astrin³

et al. 1989

J. Clin. Invest.

154

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show abstract

“…The high Km value found in these four patients was similar to that described for cu-galactosidase B [ 131. In contrast, the fifth patient, besides the B form of a-galactosidase, also had the A form, as shown by the heat inactivation and by the low Km value, similar to that of the controls. Even from a clinical point of view, this patient was unusual since he lacked the skin lesions and had only mild manifestations of his disease [7]. When the activity of trihexosylceramide cu-galactosidase was assayed in this patient, about one-tenth of the activity of the controls was found, whereas in patient no.…”

Section: Discussionmentioning

confidence: 76%

“…4 and no. 5) were recently described as clinical variants of the disease since they had no skin lesions [7]. Fibroblast cultures were initiated from skin biopsies of patients and controls and cells were harvested and sonicated as previously described [4].…”

Section: L Cell Culturementioning

confidence: 99%

“…The specificity of the assay for a-galactosidase, based on the use of synthetic substrates, has been questioned [6,7] because it was thought that the terminal glycosidic bond of the natural substrate had a p-anomeric configuration, but recent studies have shown the terminal galactose of trihexosylceramide to be an ol-anomer [8-l 11. However, the enzymatic assay based on the use of synthetic substrates might measure the activity of more than one cr-galactosidase and, indeed, two forms of the enzyme have been partially purified and characterized from human kidney * Present address: Institute of Genetics, University of Naples, Naples, Italy.…”

Section: Introductionmentioning

confidence: 99%

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Genetic heterogeneity of α‐galactosidase in fabry's disease

1972

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“…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) …”

Section: Introductionmentioning

confidence: 99%