Fabry disease is a rare inherited disorder of glycosphingolipid (fat) metabolism resulting from the absent or markedly deficient activity of the lysosomal enzyme, α-galactosidase A (α-Gal A). This disorder belongs to a group of diseases known as lysosomal storage disorders. This enzymatic deficiency is caused by alterations (mutations) in the α-galactosidase A (GLA) gene that instructs cells to make the α-galactosidase A (α-Gal A) enzyme. Lysosomes function as the primary digestive tract of cells. Enzymes within lysosomes break down or digest particular compounds and intracellular structures. α-Gal A functions to break down complex sugar-lipid molecules called glycolipids, specifically, globotriaosylceramide (GL-3 or Gb3), its deacylated form Lyso-GL-3/Gb3 and related glycolipids, by removing the terminal galactose sugar from the end of these glycolipid molecules. The enzyme deficiency causes a continuous build-up of GL-3/Gb3 and related glycolipids in the body’s cells, resulting in the cell abnormalities and organ dysfunction that particularly affect small blood vessels, the heart and kidneys.

The GLA gene is located on the X-chromosome and therefore, Fabry disease is inherited as an X-linked disorder. Males with the type 1 classic and type 2 later-onset phenotypes (see below) are typically significantly more severely affected than their affected female relatives (Arends 2017). Females typically have a more variable course and may be asymptomatic or as severely affected as their male relatives. There are two major disease phenotypes: type 1 “classic” and type 2 “later-onset” subtypes. Both lead to renal failure, and/or cardiac disease, and early death. Type 1 males have little or no functional α-Gal A enzymatic activity (<3% of normal mean activity), and marked accumulation of GL-3/Gb3 and related glycolipids in capillaries and small blood vessels which cause the major symptoms in childhood or adolescence. These include acroparesthesias (excruciating pain in the hands and feet which occur with exercise, fevers, stress, etc.); angiokeratomas (clusters of red to blue rash-like discolorations on the skin); anhidrosis or hypohidrosis (absent or markedly decreased sweating); gastrointestinal symptoms including abdominal pain and cramping, and frequent bowel movements; and a characteristic corneal dystrophy (star-burst pattern of the cornea seen by an slit-lamp ophthalmologic examination) that does not affect vision (Sher 1979, Desnick 2001). With increasing age, the systemic GL-3/Gb3 deposition, especially in the heart leads to arrhythmias, left ventricular hypertrophy (LVH) and then hypertrophic cardiomyopathy (HCM), and in the kidneys to progressive proteinuria, renal insufficiency, and renal failure, and/or to cerebrovascular disease including transient ischemic attacks (TIAs) and strokes. Prior to renal replacement therapy (i.e., dialysis and transplantation) and enzyme replacement therapy (ERT), the average age of death of affected males with the type 1 classic phenotype was ~40 years (Columbi 1967). The incidence of males with the type 1 classic phenotype is about 1 in 40,000 (Desnick 2001), but varies with geographic region and race, ranging from about ~1 in 18,000 to 1 in 95,000 based on newborn screening studies. In contrast, males with the type 2 “later-onset” phenotype (previously called cardiac or renal variants) have residual α-Gal A activity, lack GL-3/Gb3 accumulation in capillaries and small blood vessels, and do not show the early manifestations of type 1 males (i.e., the acroparesthesias, hypohidrosis, angiokeratomas, corneal dystrophy, etc). They experience an essentially normal childhood and adolescence, and typically present with renal and/or cardiac disease in the third to seventh decades of life. Most type 2 later-onset patients have been identified by enzyme screening of patients in cardiac, hemodialysis, renal transplant, and stroke clinics (Doheny 2018), and recently by newborn screening.

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