• X-linked recessive lysosomal storage disease.
  
• Males.
  
  
  
  • –Deficient plasma and/or leukocyte α-galactosidase A (in classic phenotype <1% of normal mean activity; in later-onset variants >1% of normal mean activity).
    
  • –Certain α-galactosidase A gene mutations provide genotype/phenotype correlations.
    
  • –Accumulation of globotriaosylceramide (GL-3).
    
  • –Presence of angiokeratomas, acroparesthesias, hypohidrosis, corneal and lenticular changes, renal failure, cardiac disease, and cerbrovascular disease.
  
  
• Females.
  
  
  
  • –Due to random X-chromosome inactivation, commonly females may have plasma and leukocyte α-galactosidase A activity varying from severely deficient to normal.
    
  • –α-Galactosidase A mutation analysis required for definitive diagnosis.
    
  • –Females vary in clinical symptoms from asymptomatic to as severe as classically affected males. Symptoms may appear at later ages than in affected males.

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). This enzymatic defect results in the progressive accumulation of GL-3 and related glycosphingolipids with terminal α-galactosyl moieties in the lysosomes of endothelial, epithelial, perithelial, and smooth muscle cells throughout the body. 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 clinical manifestations of the disease, including angiokeratomas, acroparesthesias, and hypohidrosis. With advancing age, the progressive vascular glycosphingolipid accumulation leads to renal failure, cardiac and cerebrovascular disease, and early death. Based on the United States and European dialysis and transplantation registries, most classically affected males go into 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. The incidence of classical Fabry disease is estimated to be ˜1 in 40,000–60,000 males.

In addition to the classic Fabry disease phenotype, later-onset variants have been identified that do not include the classic manifestations of Fabry disease, the acroparesthesias, angiokeratoma, hypohidrosis, or corneal and lenticular lesions (Table 48–1). Cardiac variants who present in the fifth to eighth decades of life have left ventricular hypertrophy, mitral insufficiency and/or cardiomyopathy, and mild to moderate proteinuria with normal renal function for age. Residual α-Gal A activity and primarily cardiomyocyte glycosphingolipid deposition are present. Renal variants also lack the classic manifestations of Fabry disease but renal insufficiency develops. Screening of patients with end-stage renal disease (ESRD) of unknown causes has identified mutation-positive patients with Fabry disease. The incidence of the later-onset phenotypes has been estimated at 1 in 4000 males.

Because of random X-chromosome inactivation, heterozygous females may have clinical symptoms of Fabry disease that range from asymptomatic to as severe as in affected males. Heterozygous females are generally less severely affected than males and their symptoms may occur later in life than in affected males.

Enzyme replacement therapy for Fabry disease has recently become available and has been shown to be effective (see Treatment section).

Affected males with the classic and later-onset phenotypes can be reliably diagnosed by the demonstration of deficient α-Gal A activity in plasma, isolated leukocytes, and/or cultured cells. Classically affected males have essentially no α-Gal A activity, while later-onset cardiac and renal variants exhibit residual activity (>1% of normal). Identification of a mutation in the patient’s α-Gal A gene confirms the diagnosis of Fabry disease.

Heterozygous females have markedly variable α-Gal A activities because of random X-chromosomal inactivation and, therefore, measurement of plasma and/or leukocyte α-Gal A activity may be misleading. For example, some obligate heterozygotes (daughters of affected males) may have α-Gal A levels ranging from normal to very low activities similar to those of affected males. Many females (˜90%) have the characteristic corneal dystrophy of Fabry disease. Accurate diagnosis of heterozygous females requires demonstration of the specific mutation in the α-Gal A gene. Such testing is recommended for all at-risk females.