Fabry disease

1. What is Fabry disease?

Fabry disease is a systemic, X-linked, lysosomal storage disorder that results from the deficient activity of the enzyme α-galactosidase A (α-Gal A) and the lysosomal accumulation of its primary glycolipid substrate, globotriaosylceramide (GL-3). The progressive GL-3 accumulation, particularly in vascular endothelial lysosomes, leads to ischemia and occlusion of small vessels throughout the body. Clinical onset in affected males with the Type 1 Classic phenotype occurs in childhood or adolescence and is characterized by painful acroparesthesias, gastrointestinal dysfunction, corneal dystrophy, absent or decreased sweat (anhidrosis or hypohidrosis), and cutaneous lesions (angiokeratomas). With advancing age, the progressive glycolipid accumulation, especially in podocytes and cardiomyocytes, leads to kidney failure, cardiac disease, ischemic strokes, and early demise. Patients typically develop end-stage kidney disease (ESKD) in the third to fifth decades of life. Female heterozygotes from Type 1 Classically affected families can be as severely affected as Type 1 Classically affected males, or may be asymptomatic throughout life, primarily as a result of random X-chromosomal inactivation. Patients with the Type 2 Later-Onset phenotype lack the childhood manifestations of the Type 1 Classic early-onset phenotype and often are unrecognized. Previously undiagnosed males with both Types 1 and 2 Fabry disease have been identified in hemodialysis, cardiac, and stroke clinics by screening patients for markedly deficient plasma α-Gal A activity. Such studies have identified that ∼0.2% of males on hemodialysis have unrecognized Fabry disease. Since the disease is X-linked, at-risk family members should be screened, and affected patients should receive genetic counseling, medical evaluations, and early therapeutic intervention, especially in males with the Type 1 Classic phenotype.

2. What are the two major subtypes of Fabry disease?

The two major subtypes of Fabry disease are the Type 1 Classic and Type 2 Later-Onset phenotypes. The phenotypic subtypes are determined by the specific α-Gal A mutation; thus, all affected family members will have the same phenotypic subtype. Affected males with the Type 1 Classic phenotype have little, if any, α-Gal A enzyme activity (<1% of mean normal), whereas males with the Type 2 Later-Onset phenotype have residual enzymatic activity, typically >1% of mean normal activity. Heterozygous females from Type 1 Classic Fabry families have a wide range of clinical manifestations from asymptomatic to severely affected, whereas heterozygous females from Type 2 Later-Onset families may have symptoms later in life, including cardiac and kidney manifestations. Heterozygotes from Type 2 Later-Onset families are likely to be less involved clinically, but can have as severe manifestations as their affected male relatives. Newborn screening studies have revealed that the Type 2 Later-Onset patients are more commonplace than patients with the Type 1 Classic phenotype.

3. What is the genetic basis of Fabry disease?

All cases of Fabry disease are caused by mutations in the gene GLA encoding the lysosomal hydrolase α-Gal A. The GLA gene is located on the X-chromosome, and the disease is inherited as an X-linked disorder. To date, more than 950 GLA gene mutations have been described. Type 1 Classically affected males have mutations that result in essentially no enzymatic activity, whereas patients with the Type 2 Later-Onset phenotype have mutations that retain low levels of residual enzyme activity. There are no common GLA mutations, and most GLA gene mutations are private, occurring in only one or a few families. For both phenotypes, the sons of affected males will not have the disease, whereas all daughters will be heterozygotes. For heterozygous females, there is a 50% risk of passing the GLA gene mutation onto their children with each pregnancy:

• 50% of sons will be affected and 50% will not inherit the disease

• 50% of daughters will be heterozygotes and 50% will not inherit the disease gene