Search for a rare disease
Fabry disease (FD) is a progressive, inherited, multisystemic lysosomal storage disease characterized by specific neurological, cutaneous, renal, cardiovascular, cochleo-vestibular and cerebrovascular manifestations.
Annual incidence is reported to be 1 in 80,000 live births but this figure may underestimate disease prevalence. When late-onset variants of the disease are considered, a prevalence of approximately 1 in 3,000 has been suggested. FD is pan-ethnic.
The clinical picture covers a wide spectrum ranging from mild cases in heterozygous females, to severe cases in classically affected hemizygous males with no residual alpha-galactosidase A activity. These patients may have all the characteristic neurological (pain), cutaneous (angiokeratoma), renal (proteinuria, kidney failure), cardiovascular (cardiomyopathy, arrhythmia), cochleo-vestibular and cerebrovascular (transient ischemic attacks, strokes) signs of the disease. Female patients may have very mild to severe symptoms. Pain is a common early symptom of FD (chronic pain characterized by burning and tingling paresthesia and occasional episodic crises characterized by agonizing burning pain). Pain may resolve in adulthood. Anhidrosis or hypohidrosis may occur causing heat and exercise intolerance. Other signs include angiokeratoma, corneal changes, tinnitus, chronic fatigue, cardiac and cerebrovascular abnormalities (left ventricular hypertrophy, arrhythmia, angina), dyspnea, and nephropathy.
Fabry disease is a disorder of glycosphingolipid metabolism caused by deficient or absent lysosomal alpha-galactosidase A activity related to mutations in the GLA gene (Xq21.3-q22) encoding the alpha-galactosidase A enzyme. Deficient activity results in accumulation of globotriaosylceramide (Gb3) within lysosomes, believed to trigger a cascade of cellular events.
Definitive laboratory diagnosis involves demonstration of marked enzyme deficiency in hemizygous males. Enzyme analysis may occasionally help to detect heterozygotes but is often inconclusive due to random X-chromosomal inactivation, making molecular testing (genotyping) of females mandatory.
In childhood, other possible causes of pain such as rheumatoid arthritis and "growing pains" must be ruled out. In adulthood, multiple sclerosis is sometimes considered.
Prenatal diagnosis, available by determination of enzyme activity or DNA testing in chorionic villi or cultured amniotic cells is, for ethical reasons, only considered in male fetuses. Pre-implantation diagnosis is possible.
FD is transmitted as an X-linked trait. The existence of atypical, late-onset, variants and the availability of specific therapy complicate genetic counseling.
Management and treatment
A disease-specific therapeutic option (enzyme replacement therapy using in vitro engineered alpha-galactosidase A) has recently been introduced and its long-term outcome is under investigation for both preparations available, but is promising. Enzyme enhancement with pharmacological chaperones is currently under investigation in clinical trials. Conventional management consists of pain relief with analgesic drugs, nephroprotection (angiotensin converting enzyme inhibitors and angiotensin receptors blockers), antiarrhythmic agents, pace-maker or implantable cardioverter defibrillator, dialysis and kidney transplant.
With age, progressive damage to vital organ systems develops, possibly leading to organ failure. End-stage renal disease and life-threatening cardiovascular or cerebrovascular complications limit the life-expectancy of untreated males and females with reductions of 20 and 10 years, respectively, versus the general population.
- Review article
- English (2010)
- Guidance for genetic testing
- English (2011, pdf)
- Clinical genetics review
- English (2017)