Genetics of Fabry Disease

Updated: Feb 24, 2016
  • Author: Robert J Desnick, MD, PhD; Chief Editor: Maria Descartes, MD  more...
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Overview

Background

Fabry disease is an X-linked lysosomal storage disease that is caused by deficient activity of lysosomal enzyme α -galactosidase A (α -Gal A). Most males with no α -Gal A activity develop the classic phenotype of Fabry disease, which affects multiple organ systems. The first clinical manifestations of the disease, which consist of episodes of severe pain in the extremities (acroparesthesias), hypohidrosis, corneal and lenticular changes, and skin lesions (angiokeratoma) develop in childhood. See the images below.

Angiokeratoma is the small punctate reddish-to-blu Angiokeratoma is the small punctate reddish-to-bluish angiectases on the umbilicus.
Angiokeratomas are commonly observed as dense clus Angiokeratomas are commonly observed as dense cluster of lesions on the flank and private areas.
Corneal verticillata, commonly seen in patients wi Corneal verticillata, commonly seen in patients with Fabry disease, detectable by slit lamp examination.

The rate of disease progression and specific organ damage demonstrate intrafamilial and interfamilial variability. Renal failure, cardiovascular disease, and stroke are the major causes of morbidity and mortality, occurring in the fourth or fifth decade of life.

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Pathophysiology

Glycosphingolipids, predominantly globotriaosylceramide (GL-3) and galabiosylceramide, accumulate in the lysosomes of various cells (eg, in the vascular endothelium of multiple organs) owing to α -Gal A deficiency. The accumulation of GL-3 in the lysosomes causes lysosomal and cellular dysfunction; this, in turn, triggers the cascade of cells and tissue ischemia and fibrosis.

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Epidemiology

Frequency

United States

Fabry disease is one of the more common lysosomal storage disorders, affecting approximately 1 in 40,000-60,000 males.

Mortality/Morbidity

Prior to the availability of renal transplant, dialysis, and, more recently, enzyme replacement therapy (ERT), the average age at death in men with classic Fabry disease was 41 years. Renal failure, heart failure and/or myocardial infarction, and stroke were among the most likely causes of death.

Race

Although most patients with Fabry disease are white, the disorder has been described in patients in many ethnic groups, including those with Hispanic, African, Asian, and Middle Eastern ancestry.

Sex

As is expected in X-linked disorders, males with deleterious mutations have little to no residual α -Gal A activity. Therefore, these patients experience the full spectrum of disease symptoms. Because of random X inactivation (lyonization), the disease presentation in female carriers is more variable and depends on the normal-to-mutant ratio of α -Gal A in the different tissues. A significant number of female carriers may develop Fabry disease–related symptoms, including acroparesthesias, GI symptoms, renal and cardiac disease, and/or stroke.

Age

Most males with classic Fabry disease first manifest symptoms in childhood or early adolescence. The earliest manifestations include acroparesthesias, angiokeratomas, hypohidrosis, and lenticular and corneal changes. Proteinuria usually becomes evident in the second decade of life, and renal insufficiency is typically present in the third decade of life. Cardiovascular and cerebrovascular diseases usually develop in the fourth decade of life.

Individuals with atypical renal or cardiac variants usually do not have signs or symptoms in childhood. Many of these patients remain asymptomatic well into adulthood, when patients with classic symptoms are severely affected or have died from the disease.

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