Fabry Disease Overview

First independently described in 1898 by Drs. William Anderson (England) and Johann Fabry (Germany), Fabry disease is also known as angiokeratoma corporis diffusum, alpha-galactosidase A deficiency,
hereditary dystopic lipidosis, GLA deficiency, ceramide trihexosidase deficiency, and Anderson-Fabry disease.

Fabry disease is one of over 40 known genetic disorders referred to as lysosomal storage disorders. Each of these diseases is caused by an inborn genetic alteration resulting in a deficiency of a particular lysosomal enzyme or enzymes.1 The age of onset, affected organ system(s), and severity of these disorders vary markedly, but all are progressive.

Etiology and pathophysiology

Fabry disease is caused by an alteration in the gene for the lysosomal enzyme α-galactosidase A (α-GAL; also known as α-galactosidase-A, and ceramide trihexosidase). Partial or complete deficiency of α-GAL results in an inability to catabolize lipids with terminal α-galactosyl residues. These lipids, particularly globotriaosylceramide (GL-3; Gb3, ceramide trihexoside, or CTH), accumulate progressively in the vascular endothelium and visceral tissues throughout the body, resulting primarily in progressive multisystemic damage to the kidney, heart, and cerebrovascular system.2

Accumulation of GL-3 in vascular endothelium

Electron micrograph image shows deficiency of cellular accumulation of the substrate GL-3 in the the renal endothelium of a Fabry patient.

Cellular accumulation of the substrate GL-3 in the vascular endothelium and tissues throughout the body. Arrows indicate areas of accumulation in this electron micrograph of the renal capillary endothelium in a Fabry patient. Used with permission from R.J. Desnick, MD, PhD.

Disease progression

In Fabry disease, progressive accumulation of GL-3 starts early in life and continues for decades, and may ultimately result in vascular involvement throughout the body, particularly in the kidneys, heart, and central nervous system. By the third to fifth decade, more serious renal, cardiac, and cerebrovascular complications typically occur.2 

The early clinical course of Fabry disease typically involves symptoms that primarily affect quality of life: chronic pain, angiokeratomas, hypohidrosis, heat and cold intolerance, gastrointestinal symptoms. As the disease progresses, renal, cardiac, and neurological involvement may result in complications that become life-threatening.3

Learn more about the progression of Fabry disease

Molecular basis

Lysosomes are organelles that are responsible for breaking down defunct (dead) organelles, endocytosed particles, and other material that needs to be excreted or recycled. Lysosomes contain numerous acid hydrolases that catabolize macromolecules such as complex proteins, fats, nucleic acids, and carbohydrates that are the result of normal growth and metabolism.

Biosynthesis and trafficking of lysosomal enzymes

Newly synthesized lysosomal enzymes are recognized by the mannose-6-phosphate (M-6-P) receptor at the Golgi, and translocated to lysosomes. A proportion of the enzymes is secreted into circulation and can be recaptured. (TGN: trans-Golgi network)

Each lysosomal enzyme is part of a complex pathway that reduces macromolecules into smaller components, which will be reused by the cell or eventually eliminated from the body. The absence of one enzyme causes a bottleneck in the catabolic pathway, leading to the progressive accumulation of intermediate metabolic products within the lysosome. A primary source of the GL-3 accumulation seen in Fabry disease is postulated to be the membranes of senescent erythrocytes, which contain the glycosphingolipid precursor globoside.2, 4

Clinical presentation and sequelae

The age of presentation of Fabry disease is variable, as are the presenting symptoms and the clinical course.5  The disease usually presents in childhood with pain in the hands and feet, fever, hypohidrosis, fatigue, and exercise intolerance. However, symptoms often go unrecognized until adulthood when organ system damage has occurred. Earlier diagnosis may result in more effective symptom management. 6

The average age of diagnosis is approximately 31 years in females and 24 years in males.7 Delayed diagnosis may be due to the rarity of the disease and/or the nonspecific nature of its early symptoms.

Progressive organ and tissue damage associated with Fabry disease may result in substantially decreased life expectancy. Before the availability of renal dialysis or transplantation, the average age of death among patients with classical Fabry disease was 41 years;8 since then, average life expectancy is still only 50 years.9 Classical Fabry disease is described as having less than 1% enzyme activity and typical manifestations that involve the kidney, heart, and brain.

Learn more about the signs and symptoms of Fabry disease

Atypical variants

Growing evidence indicates there may be a significant number of “atypical variants”: hemizygotes who have few or none of the hallmark symptoms of classical Fabry disease.10-14 Atypical variants have residual plasma α-galactosidase A (α-GAL) levels (1% to 30% of normal) 11-14 and present much later in life than patients with classical Fabry disease. They are often identified serendipitously, and usually have manifestations predominately in one organ system. 15

Learn more about cardiac dysfunction in Fabry disease


1. Meikle PJ, JJ Hopwood, AE Clague, WF Carey. Prevalence of lysosomal storage disorders. Jama. 1999;281:249-254.

2. Desnick R, Ioannou Y, Eng C. α-Galactosidase a deficiency: Fabry disease. In: The Online Metabolic & Molecular Bases of Inherited Disease; 2014.

3. Wanner C., Oliveira J.P., Ortiz A., et al. Prognostic indicators of renal disease progression in adults with fabry disease: Natural history data from the Fabry Registry. Clinical Journal of the American Society of Nephrology 2010 5:12 (2220-2228)

4. Dawson G, CC Sweeley. In vivo studies on glycosphingolipid metabolism in porcine blood. J Biol Chem. 1970;245:410-416.

5. Wilcox WR et al. Mol Genet Metab 2008;93:112-28

6. Shelley ED, WB Shelley, TW Kurczynski. Painful fingers, heat intolerance, and telangiectases of the ear: easily ignored childhood signs of Fabry disease. Pediatr Dermatol. 1995;12:215-219

7.Politei J.M. Cabello J.F. Villalobos J. Valadez G. Loaeza A. Linares A. Martins A.M.Fabry's disease: New concepts about its natural history, evolution and treatment, in relation to the findings of the Fabry Registry Revista de Nefrologia, Dialisis y Trasplante (2009) 29:4 (145-152). 

8. Colombi A, A Kostyal, R Bracher, et al. Angiokeratoma corporis diffusum--Fabry's disease. Helv Med Acta. 1967;34:67-83.

9. Gupta S, M Ries, S Kotsopoulos, R Schiffmann. The relationship of vascular glycolipid storage to clinical manifestations of Fabry disease: a cross-sectional study of a large cohort of clinically affected heterozygous women. Medicine (Baltimore). 2005;84:261-268.

10. Chimineti C, Ricci R, Pieroni M, Natale L, Russo MA, Frustaci A. Cardiac variant of Fabry's disease mimicking hypertrophic cardiomyopathy. Cardiologia. 1999;44:469-473.

11. von Scheidt W, CM Eng, TF Fitzmaurice, et al. An atypical variant of Fabry's disease with manifestations confined to the myocardium. N Engl J Med. 1991;324:395-399.

12. Nakao S, T Takenaka, M Maeda, et al. An atypical variant of Fabry's disease in men with left ventricular hypertrophy. N Engl J Med. 1995;333:288-293.

13. Yoshitama T, S Nakao, T Takenaka, et al. Molecular genetic, biochemical, and clinical studies in three families with cardiac Fabry's disease. Am J Cardiol. 2001;87:71-75.

14. Nagao Y, H Nakashima, Y Fukuhara, et al. Hypertrophic cardiomyopathy in late-onset variant of Fabry disease with high residual activity of α-galactosidase A. Clin Genet. 1991;39:233-237.

15.Wilcox W, Oliveira J, Hopkin R, Ortiz A, Banikazemi M, Feldt-Rasmussen U, et al. Females with Fabry disease frequently have major organ involvement: lessons from the Fabry Registry. Mol Genet Metab 2008;93:112-28.