Fabry Disease
Etiology and Pathogenesis [1]Deficiency of the lysosomal enzyme α-galactosidase A leads to progressive accumulation of glycosphingolipids, predominantly globotriaosylceramide (GL-3), in many body tissues, occurring over a period of years or decades. Clinical manifestations include renal failure, cardiomyopathy, and cerebrovascular incidents. Accumulation of GL-3 in renal endothelial cells may play a role in renal failure. Key Symptom Images
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Corneal opacity/whorling |
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Image Credits: Angiokeratomas & Corneal opacity/whorling courtesy of Desnick et al., 2003, with permission from author and publisher.
Clinical Description and Progression/Prognosis
Fabry disease usually presents in childhood with intermittent pain in the hands and feet and episodic crises of pain.
The cardinal presenting features are intermittent acroparesthesia and episodic crises of pain and fever (especially in childhood), angiokeratomas, hypohidrosis, heat/cold intolerance, and a characteristic "whorled" corneal opacity that generally does not affect vision. In these patients, the major causes of mortality include renal failure, cardiomyopathy, and cerebrovascular accidents.
Progressive organ and tissue damage associated may result in substantially decreased life expectancy. Without treatment for uremia, average life expectancy is 41 years[2]; with renal dialysis or transplantation, average life expectancy is about 50 years.[3] Inheritance pattern: X-linked recessive Incidence: pan-ethnic; 1 in 117,000 live births [4] Diagnosis: enzyme assay; gene/mutation analysis for carrier females Conditions with similar presentations: arthritis, rheumatic fever, erythromelalgia, Raynaud’s syndrome, multiple sclerosis, lupus Management: enzyme replacement therapy Other medical care: symptom management
 Acroparesthesia - Burning pain crises of the extremities Onset in childhood May be the initial manifestation of the disease Burning or tingling sensation beginning in the fingers and toes and spreading proximally Crises are: - Periodic and excruciating - May become more frequent and severe with age then lessen in the 2nd or 3rd decades - Precipitated by heat, cold, exercise, humidity, fever, and/or fatigue - Last from several hours to days - Usually associated with a low-grade fever and elevated ESR Hypohidrosis Transient ischemic attacks Early stroke, positive family history of early stroke Muscle weakness Hemiparesis Vertigo/dizziness Hearing loss, tinnitus Nystagmus Head pain Hemiataxia Ataxia of gait Personality changes No mental retardation Back to categories Angiokeratomas - Small dark purple-blue telangiectasia May appear in childhood but usually not noted until after 10 years of age Most dense between the umbilicus and knees with propensity for umbilicus and buttocks Progressive increase in the size and number with age Do not blanch with pressure Hypohidrosis Lymphedema of the legs Corneal and lenticular opacities (seen through slit lamp--generally does not affect vision) Retinal and lenticular abnormalities Cataracts Respiratory Chronic airflow obstruction Dyspnea Cardiovascular Left ventricular hypertrophy Mitral valve prolapse and/or regurgitation Premature coronary artery disease Angina Myocardial infarction Arrhythmias Conduction abnormalities Positive family history of early heart disease Gastrointestinal Episodic diarrhea Post-prandial pain Nausea Vomiting Renal Proteinuria/isosthenuria Tubular dysfunction (polyuria, polydipsia) Symptoms suggesting Fanconi's syndrome (proximal tubular insufficiency, aminoaciduria, glycosuria, renal tubular acidosis) Elevated serum creatinine Progressive and/or unexplained renal insufficiency Back to categories
1. Hauser SL, Longo DL, eds. Harrison’s Principles of Internal Medicine. 14th ed. New York: McGraw-Hill; 1998; p. 2171-4.
2. Colombi A, Kostyal A, Bracher R, Gloor F, Mazzi R, Tholen H. Angiokeratoma corpus diffusum - Fabry's disease. Helv Med Acta. 1967;34:67-83.
3. MacDermot KD, Holmes A, Miners AH. Anderson-Fabry disease: clinical manifestations and impact of disease in a cohort of 98 hemizygous males. J Med Genet. 2001;38:750-760.
4. Meikle PJ, Hopwood JJ, Clague AE, Carey WF. Prevalence of Lysosomal Storage Disorders. JAMA. 1999; 281: 249-254. |
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