Fabry disease is an X-linked recessive inborn error of glycosphingolipid catabolism resulting from the deficient activity of the lysosomal hydrolase α-galactosidase A in tissues and fluids of affected hemizygous males. Most heterozygous female carriers of the gene have an intermediate level of enzymatic activity.
The enzymatic defect leads to the systemic deposition of glycosphingolipids with terminal α-galactosyl moieties, predominantly globotriaosylceramide and, to a lesser extent, galabiosylceramide and blood group B substances. Hemizygous males have extensive deposition of these glycosphingolipid substrates in body fluids and in the lysosomes of endothelial, perithelial, and smooth-muscle cells of blood vessels. Deposition also occurs in ganglion cells, and in many cell types in the heart, kidneys, eyes, and most other tissues.
Clinical manifestations in classically affected hemizygotes who have no detectable α-galactosidase A activity include the onset during childhood or adolescence of pain and paresthesias in the extremities, vessel ectasia (angiokeratoma) in skin and mucous membranes, and hypohidrosis. Corneal and lenticular opacities also are early findings. With increasing age, proteinuria, hyposthenuria, and lymphedema appear. Severe renal impairment leads to hypertension and uremia. Death usually occurs from renal failure or from cardiac or cerebrovascular disease. Atypical hemizygotes with residual α-galactosidase A activity may be asymptomatic or have late-onset, mild disease manifestations primarily limited to the heart (the “cardiac variant”).
Heterozygous females may have an attenuated form of the disease. They usually are asymptomatic, although rarely can be as severely affected as hemizygous males. The most frequent clinical finding in females is the characteristic whorl-like corneal epithelial dystrophy observed by slit-lamp microscopy.
Confirmation of the clinical diagnosis in affected hemizygotes requires the demonstration of deficient α-galactosidase A activity in plasma, leukocytes, or tears, or increased levels of globotriaosylceramide in plasma or urinary sediment. Heterozygous females may have intermediate levels of enzymatic activity and accumulated substrate. More accurate diagnosis of heterozygous females can be accomplished by detection of a molecular lesion in the α-galactosidase A gene or by linkage analysis in families with an affected male.
The disorder is transmitted by the X-linked gene encoding α-galactosidase A, which has been localized to the X-chromosomal region, Xq22.1. The human α-galactosidase A cDNA and genomic sequences have been isolated, characterized, and over 150 mutations have been identified including partial gene rearrangements, splice-junction defects, and point mutations, which emphasize the heterogeneity of the molecular lesions causing this disease.
Prenatal diagnosis can be accomplished by demonstration of deficient α-galactosidase A activity and an XY karyotype, by haplotype linkage analysis, and/or most accurately by demonstration of the specific α-galactosidase A mutation in chorionic villi or cultured amniotic cells.
Low maintenance dosages of diphenylhydantoin or carbamazepine may provide relief of the excruciating pain and constant discomfort. Oral anticoagulants are recommended for stroke-prone patients. Renal dialysis and transplantation are effective in the treatment of end-stage renal disease. Clinical trials of direct enzyme replacement indicate the potential value of this therapeutic approach.