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Genetics of Fabry Disease

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

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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Contributor Information and Disclosures
Author

Robert J Desnick, MD, PhD Dean for Genetics and Genomics, Professor and Chairman, Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine

Robert J Desnick, MD, PhD is a member of the following medical societies: American Society for Biochemistry and Molecular Biology, Eastern Society for Pediatric Research, American College of Medical Genetics and Genomics, American Pediatric Society, American Society for Clinical Investigation, American Society for Microbiology, American Society of Human Genetics, Central Society for Clinical and Translational Research, New York Academy of Sciences, Sigma Xi, Society for Experimental Biology and Medicine, Society for Pediatric Research

Disclosure: Received consulting fee from Amicus Therapeutics for consulting; Received consulting fee from Genzyme for consulting; Received grant/research funds from Genzyme for consulting; Received royalty from Genzyme for none; Received scientific advisory board from Genzyme for none; Received consulting fee from Synageva BioPharma for none; Received stock options from Synageva BioPharma for none; Received royalty from Shire HGT for none.

Coauthor(s)

Kenneth H Astrin, PhD Associate Professor of Human Genetics, Department of Human Genetics, Mount Sinai School of Medicine

Kenneth H Astrin, PhD is a member of the following medical societies: American Society of Human Genetics

Disclosure: Nothing to disclose.

Maryam Banikazemi, MD Assistant Professor of Clinical Pediatrics, New York Medical College

Maryam Banikazemi, MD is a member of the following medical societies: American Academy of Pediatrics, American Society of Human Genetics

Disclosure: Nothing to disclose.

Specialty Editor Board

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Chief Editor

Maria Descartes, MD Professor, Department of Human Genetics and Department of Pediatrics, University of Alabama at Birmingham School of Medicine

Maria Descartes, MD is a member of the following medical societies: American Academy of Pediatrics, American College of Medical Genetics and Genomics, American Medical Association, American Society of Human Genetics, Society for Inherited Metabolic Disorders, International Skeletal Dysplasia Society, Southeastern Regional Genetics Group

Disclosure: Nothing to disclose.

Additional Contributors

Robert D Steiner, MD Chief Medical Officer, Acer Therapeutics; Clinical Professor, University of Wisconsin School of Medicine and Public Health

Robert D Steiner, MD is a member of the following medical societies: American Academy of Pediatrics, American Association for the Advancement of Science, American College of Medical Genetics and Genomics, American Society of Human Genetics, Society for Inherited Metabolic Disorders, Society for Pediatric Research, Society for the Study of Inborn Errors of Metabolism

Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: Acer Therapeutics; Retrophin; Raptor Pharma; Veritas Genetics; Censa Pharma<br/>Received income in an amount equal to or greater than $250 from: Acer Therapeutics; Retrophin; Raptor Pharma; Censa Pharma.

David Flannery, MD, FAAP, FACMG Vice Chair of Education, Chief, Section of Medical Genetics, Professor, Department of Pediatrics, Medical College of Georgia

David Flannery, MD, FAAP, FACMG is a member of the following medical societies: American Academy of Pediatrics, American College of Medical Genetics and Genomics

Disclosure: Nothing to disclose.

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