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  • Updated 06.22.2023
  • Released 07.05.1994
  • Expires For CME 06.22.2026

Fabry disease



Fabry disease is an X-linked disorder of glycosphingolipid metabolism that is caused by deficiency of alpha-galactosidase A. As a result, patients have a markedly increased risk of developing common-looking small-fiber peripheral neuropathy, ischemic stroke, myriad cardiac manifestations, and chronic renal disease. Some studies have found that about 0.5% of patients with stroke have GLA gene mutations. Specific therapy for Fabry disease now exists, including enzyme replacement and pharmacological chaperones. Modified enzyme replacement therapy with a long circulation half-life and substrate synthesis inhibitors is being tested. Current enzyme replacement therapy does not lower the risk of stroke. Clinical experience suggests that antiplatelet agents that are ADP-receptor blockers markedly reduce the risk of stroke in Fabry disease patients.

Key points

• Fabry disease is a genetic risk factor for stroke, small fiber neuropathy, heart, and kidney disease.

• It is X-linked, but heterozygote women may be symptomatic too.

• Fabry disease may explain approximately 0.13% of all strokes.

• The main complications of Fabry disease are nonspecific in character and, therefore, the disease is likely to be overlooked.

• Therapy includes specific intervention, such as enzyme replacement, and pharmacological chaperones.

• Current enzyme replacement therapy for Fabry disease, if initiated in adulthood, does not lower the risk of stroke and may not reduce the risk of cardiac death.

Historical note and terminology

In 1898, German dermatologist Johannes Fabry (1860–1930) and English surgeon William Anderson (1842–1900) independently described the dermatological features of patients with what is now known as angiokeratoma corporis diffusum (51; 05).

Fabry reported skin lesions in a 13-year-old boy that initially were thought to represent purpura nodularis. After further study of this patient, the lesions were found to contain small-vessel aneurysms. Fabry classified this disease as “angiokeratoma corporis diffusum” (51). Fabry reported a follow-up on his original patient in 1916.

Anderson also diagnosed similar skin lesions in a 39-year-old male as angiokeratoma (05). This patient had albuminuria in addition to other clinical features that Anderson argued might be due to a systemic process rather than a disease limited to the skin. In 2016, Gaggl and colleagues published an extended pedigree in which Anderson's original case was the propositus; the pedigree spans seven generations and includes six affected males and seven obligate female carriers (56). The pedigree is consistent with an X-linked recessive trait.

The disease remained under the purview of dermatologists until 1947, when Pompen and colleagues described the first postmortem pathological examination on two affected brothers. This report documented the existence of abnormal storage vacuoles in blood vessels throughout the body and established that Fabry disease was a generalized storage disorder (105).

Various studies in the 1960s documented pedigrees consistent with an X-linked recessive inheritance pattern, most notably a study from the University of Wisconsin by German-American medical geneticist John M Opitz (b 1935) and colleagues (30; 152; 34; 99; 82).

Sweeley and Klionsky first elucidated the biochemical nature of the storage material in Fabry disease (138). They determined that the accumulating substance consisted primarily of two glycosphingolipids, globotriaosylceramide and galabiosylceramide. Brady and colleagues showed that Fabry disease was caused by a deficiency of the enzyme alpha-galactosidase A, resulting in the storage of glycolipids containing a terminal alpha-galactosyl residue such as globotriaosylceramide (17).

The molecular structure of the gene encoding alpha-galactosidase A, GLA, was first identified as the full-length cDNA clone in 1986 (13), and the entire gene organization was determined in 1989 (79).

Following the development of enzyme replacement therapy for Gaucher disease, the production of glucocerebrosidase and the mechanisms of lysosomal targeting were used as a blueprint to produce recombinant human alpha-galactosidase, which received regulatory approval from the European Union in 2002 and FDA approval in 2003.