Fabry disease

Raphael Schiffmann MD (Dr. Schiffmann, Director of the Institute of Metabolic Disease at Baylor Research Institute, received research grants from Amicus Therapeutics, Protalix Biotherapeutics, and Shire.)
Originally released July 5, 1994; last updated November 24, 2016; expires November 24, 2019

This article includes discussion of Fabry disease, alpha-galactosidase A deficiency, Anderson-Fabry disease, angiokeratoma corporis diffusum universale, ceramide trihexosidase deficiency, Fabry's disease, GLA deficiency, and hereditary dystopic lipidosis. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.

Overview

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 possibly soon pharmacological chaperones and substrate synthesis inhibitors. 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 0.5% of all strokes in the young.

 

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

 

• Therapy includes specific intervention, such as enzyme replacement, and other standard medical care, such as newer antiplatelet agents.

 

• Current enzyme replacement therapy for Fabry disease does not lower the risk of stroke.

Historical note and terminology

In 1898, Fabry and Anderson independently described the dermatological features of patients with what is now known as angiokeratoma corporis diffusum. 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” (Fabry 1898). Anderson also diagnosed similar skin lesions in a 39-year-old male as angiokeratoma (Anderson 1898). 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. The disease remained under the purview of dermatologists until 1947, when Pompen and colleagues described the first postmortem pathological examination on 2 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 (Pompen et al 1947). Opitz and colleagues confirmed the X-linked inheritance pattern in 1965. Sweeley and Klionsky first elucidated the biochemical nature of the storage material in Fabry disease (Sweeley and Klionsky 1963). They determined that the accumulating substance consisted primarily of 2 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 (Brady et al 1967). The molecular structure of the gene encoding alpha-galactosidase A, GLA, was first identified as the full-length cDNA clone in 1986 (Bishop et al 1986), and the entire gene organization was determined in 1989 (Kornreich et al 1989). 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.

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