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:

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

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

4. What is the metabolic abnormality in Fabry disease?

The deficient or absent α-Gal A activity results in the accumulation of glycolipids with terminal α-linked galactose molecules. As noted above, the major accumulated glycolipid is GL-3. In addition, galabiosylceramide, the blood group B glycolipid, and lyso-GL-3 accumulate in the lysosomes of various cell types. The major pathology leading to kidney failure results from the glycosphingolipid accumulation in the kidney microvascular endothelial cells, interstitial, mesangial, tubular cells, and particularly in the podocytes. In the Type 2 Later-Onset patients the kidney pathology results primarily from glycolipid accumulation in the podocytes.

5. What are the clinical findings in males with type 1 classic and type 2 later-onset Fabry disease?

Clinical manifestations in Type 1 Classically affected males begin in childhood or adolescence. Most often, the first symptoms are painful acroparesthesias (especially during febrile illnesses); hypohidrosis; and gastrointestinal symptoms, including postprandial abdominal cramping, bloating, and diarrhea. Small petechial-like angiokeratomas, the classic cutaneous vascular lesions, typically are present in the umbilical and swimsuit regions in childhood. Type 1 Classically affected males also have a distinctive corneal dystrophy observed by slit-lamp microscopy, which does not affect vision. Microvascular involvement of the kidney begins in childhood; progresses to isothenuria, proteinuria, and tubular dysfunction; then, with advancing age, results in progressive kidney disease and ESKD typically by age 35 to 45 years. Dialysis and kidney transplantation are effective in correcting the kidney disease, and kidney transplants are not affected by the disease. All potential family donors should be evaluated to ensure that they are not affected or heterozygotes.

Other manifestations include lower extremity edema in the absence of significant kidney disease, hypoproteinemia, or varices; the lymphedema results from the accumulation of GL-3 in the lymphatic vessels and nodes. Cardiac manifestations include arrhythmias (initially sinus bradycardia), valvular abnormalities, and left ventricular hypertrophy, which may lead to hypertrophic cardiomyopathy. Cerebrovascular disease manifests as transient ischemic attacks and stroke: the strokes often result from the cardiac arrhythmias. Progressive high-frequency hearing loss occurs in Type 1 Classically affected males in the third to fifth decades of life.

In contrast, males with the Type 2 Later-Onset phenotype lack the microvascular endothelial glycolipid deposition that leads to the early manifestations in Type 1 Classic males. Type 2 males develop renal disease and/or heart disease in their third decade of life, or later. The renal disease is characterized by increasing proteinuria due to progressive podocyte glycolipid accumulation, and can progress to renal failure. The heart disease is characterized by progressive cardiomyocyte glycolipid accumulation and typically results in the development of left ventricular hypertrophy (LVH) leading to hypertrophic cardiomyopathy (HCM). Type 2 males also may develop transient ischemic attacks (TIA) and strokes primarily due to cardiac arrhythmias.