Fabry disease (ORPHA:324)
A rare genetic, multisystemic lysosomal disease characterized by specific cutaneous (angiokeratoma), neurological (pain), renal (proteinuria, chronic kidney failure), cardiovascular (cardiomyopathy, arrhythmia), cochleo-vestibular and cerebrovascular manifestations (transient ischemic attacks, strokes). The phenotypic expression depends on age of onset and, in females, the level of X-inactivation.
Epidemiology
Worldwide, the average prevalence at birth is approximately 1/15,000, but Fabry disease is an underdiagnosed condition and the frequency may be higher.
Clinical description
The clinical picture covers a wide spectrum ranging from mild cases in some heterozygous females, to severe cases in classically affected hemizygous males with no residual alpha-galactosidase A activity. The classical form typically has onset in childhood and may have all the characteristic neurological, cutaneous, renal, cardiovascular, cochleo-vestibular and cerebrovascular signs of the disease. Female patients may have very mild to severe symptoms. Pain is a common early symptom (chronic pain characterized by burning and tingling paresthesia and occasional episodic crises) but may wane in adulthood. Anhidrosis or hypohidrosis may occur causing heat and exercise intolerance. Other signs include angiokeratoma, corneal deposits, tinnitus, hearing loss, fatigue, cardiac and cerebrovascular abnormalities (left ventricular hypertrophy, arrhythmia), dyspnea, and chronic kidney disease. The later-onset form starts in adulthood and in such cases cardiac involvement is the prevailing feature.
Etiology
Fabry disease is a disorder of glycosphingolipid metabolism caused by the functional deficiency of the lysosomal alpha-galactosidase due to pathogenic variants in the GLA gene (Xq21.3-q22). Deficient activity results in accumulation of globotriaosylceramide (Gb3) and its deacylated form, lyso-Gb3, within lysosomes which is then believed to trigger a cascade of cellular events.
Diagnostic methods
The definitive laboratory diagnosis involves demonstration of marked enzyme deficiency in hemizygous males and identification of a pathogenic variant in GLA. Enzyme analysis may occasionally help to detect heterozygotes but is often inconclusive due to X-chromosomal inactivation, making molecular testing (GLA genotyping) of females mandatory.
Differential diagnosis
In childhood, other possible causes of pain such as rheumatoid arthritis and "growing pains" must be ruled out. In adulthood, multiple sclerosis and irritable bowel syndrome (IBS) are occasionally considered.
Antenatal diagnosis
Prenatal diagnosis, available by determination of DNA testing in chorionic villi or cultured amniotic cells is, for ethical reasons, only considered in male fetuses (after non-invasive prenatal testing for fetal sex determination). Pre-implantation genetic diagnosis is possible.
Genetic counseling
The pattern of inheritance is X-linked. The existence of atypical, later-onset, variants and the availability of specific therapies for Fabry disease should be considered when delivering genetic counseling.
Management and treatment
A disease-specific therapeutic option (enzyme replacement therapy using in vitro engineered alpha-galactosidase A) has been available since 2001 and meta-analyses of its long-term efficacy suggest promising outcomes. Enzyme enhancement with a pharmacological chaperone is approved in patients with amenable GLA variants following recent clinical trials. Plant-derived enzyme replacement therapy, substrate reduction therapy (SRT) and gene therapy using adeno-associated viral vectors are currently under investigation in clinical trials. Conventional management consists of pain relief with analgesic drugs, nephroprotection (angiotensin converting enzyme inhibitors or angiotensin receptors blockers), antiarrhythmic agents, pace-maker or implantable cardioverter defibrillator, dialysis, and kidney transplant.
Prognosis
With age, progressive damage to tissues develops, leading to organ failure. End-stage renal disease and life-threatening cardiovascular or cerebrovascular complications limit the life-expectancy of untreated males and females versus the general population.

                            Last update: 
                            March 2022


                            - Expert reviewer(s): 
                            Pr Dominique GERMAIN