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Essentials of Diagnosis

  • Early clinical manifestations in classically affected males include angiokeratomas, acroparesthesias, hypohidrosis, and a characteristic bilateral corneal dystrophy. With advancing age, classic and later-onset males develop renal failure, cardiac disease, and strokes.

  • The clinical diagnosis is confirmed in males by markedly deficient leukocyte α-galactosidase A (α-Gal A) activity and/or identification of a pathologic α-galactosidase gene (GLA) mutation.

  • Female heterozygotes from classic and later-onset families may be asymptomatic or as severe as their affected male relatives. They are diagnosed by demonstration of the family’s pathologic GLA mutation.


Fabry disease is an X-linked inborn error of glycosphingolipid catabolism caused by the deficient activity of the lysosomal enzyme, α-galactosidase A (α-Gal A; Figure 47–1). This enzymatic defect results primarily in the progressive accumulation of globotriaosylceramide (Gb3 or GL-3) and related glycosphingolipids with terminal α-galactosyl moieties in the lysosomes of endothelial, epithelial, perithelial, and smooth muscle cells throughout the body.

Figure 47–1.

The metabolic defect in Fabry disease. The deficient activity of α-galactosidase A (α-Gal A) results in the accumulation of globotriaosylceramide (Gb3 or GL-3) and other glycoconjugates with terminal α-galactosyl moieties.

There are two major clinical subtypes, the classic and later-onset phenotypes (Figure 47–2). Table 47–1 compares the signs and symptoms in males with the two phenotypic subtypes. In classically affected males who have little, if any, α-Gal A activity, the glycosphingolipid deposition in the vascular endothelium is responsible for the major early clinical manifestations of the disease, including angiokeratomas, acroparesthesias, and hypohidrosis (Figure 47–3). With advancing age, the progressive vascular, cardiomyocyte, and podocyte glycosphingolipid accumulation leads to renal failure, cardiac disease, strokes, and premature demise. Based on the United States and European dialysis, and transplantation registries, most classically affected males develop renal failure between the ages of 35 and 45 years. Prior to the advent of renal transplantation and dialysis, the average age of death for classically affected males in one series was 41 years. Affected males and heterozygotes are normal intellectually. Neurologic involvement in classically affected males and symptomatic heterozygotes is primarily neuropathic pain (ie, acroparesthesias). The incidence of classical Fabry disease is estimated to be approximately 1 in 25,000–40,000 males based on recent newborn screening studies.

Figure 47–2.

The phenotypic spectrum of Fabry disease in affected males. There are two major phenotypic subtypes, the early-onset “classic” phenotype, which typically manifests in childhood, and the “later-onset” phenotype that presents with renal and/or cardiac disease in adulthood. There are two subtypes of the later-onset phenotype, as patients may present with primarily cardiac or renal disease, see Table 47–1 for signs and symptoms of males with the two phenotypes.

Figure 47–3.

Photomicrograph and electron micrographs showing the microvascular endothelial glycosphingolipid deposition. Left: Note the ...

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