Fabry disease

Abstract

Fabry disease (FD) is a progressive, X-linked inherited disorder of glycosphingolipid metabolism due to deficient or absent lysosomal α-galactosidase A activity. FD is pan-ethnic and the reported annual incidence of 1 in 100,000 may underestimate the true prevalence of the disease. Classically affected hemizygous males, with no residual α-galactosidase A activity may display 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 while heterozygous females have symptoms ranging from very mild to severe. Deficient activity of lysosomal α-galactosidase A results in progressive accumulation of globotriaosylceramide within lysosomes, believed to trigger a cascade of cellular events. Demonstration of marked α-galactosidase A deficiency is the definitive method for the diagnosis of hemizygous males. Enzyme analysis may occasionnally help to detect heterozygotes but is often inconclusive due to random X-chromosomal inactivation so that molecular testing (genotyping) of females is 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. The existence of atypical variants and the availability of a specific therapy singularly complicate genetic counseling. A disease-specific therapeutic option - enzyme replacement therapy using recombinant human α-galactosidase A - has been recently introduced and its long term outcome is currently still being investigated. Conventional management consists of pain relief with analgesic drugs, nephroprotection (angiotensin converting enzyme inhibitors and angiotensin receptors blockers) and antiarrhythmic agents, whereas dialysis or renal transplantation are available for patients experiencing end-stage renal failure. With age, progressive damage to vital organ systems develops and at some point, organs may start to fail in functioning. End-stage renal disease and life-threatening cardiovascular or cerebrovascular complications limit life-expectancy of untreated males and females with reductions of 20 and 10 years, respectively, as compared to the general population. While there is increasing evidence that long-term enzyme therapy can halt disease progression, the importance of adjunctive therapies should be emphasized and the possibility of developing an oral therapy drives research forward into active site specific chaperones.

Next generation sequencing‐based copy number analysis reveals low prevalence of deletions and duplications in 46 genes associated with genetic cardiomyopathies

“…2014; Alfares et al. 2015), which was traditionally tested only in patients with clinical diagnosis of Fabry disease, a lysosomal storage disorder that involves acroparesthesias, angiokeratomas, proteinuria, and cardiomyopathy (Germain 2010). Inclusion of GLA in NGS panels revealed a larger than expected fraction of pathogenic GLA variants among individuals with apparently nonsyndromic HCM (Adalsteinsdottir et al.…”

Sleep Disturbance, Obstructive Sleep Apnoea and Abnormal Periodic Leg Movements: Very Common Problems in Fabry Disease

“…Symptoms include dyspnoea in up to 69% of men and 65% of women (Mehta et al 2004), cough, wheeze, reduced exercise tolerance (Lobo et al 2008;Germain 2010) and fatigue (Lobo et al 2008;Franzen et al 2013). Obstructive airway disease has been reported in up to 26% of women and 61% of men (Rosenberg et al 1980;Germain 2010;Franzen et al 2013).…”

Reduction of Plasma Globotriaosylsphingosine Levels After Switching from Agalsidase Alfa to Agalsidase Beta as Enzyme Replacement Therapy for Fabry Disease

“…Fabry disease (FD) is an X-linked disorder that affects both males and females and is caused by deficient activity of the lysosomal enzyme a-galactosidase A (a-Gal A) (Germain 2010). This leads to the accumulation of globotriaosylceramide (GL-3, Gb 3 ), predominantly in the lysosomes of multiple cell types, and the elevation of globotriaosylsphingosine (lyso-GL-3, lyso-Gb 3 ), the more water-soluble deacylated form of GL-3, in the plasma (Aerts et al 2008).…”

“…In vitro studies suggest that these elevations trigger a cascade of pathological processes, including inflammatory and fibrotic responses that cause progressive damage to multiple organs (Germain 2010). In males with classic FD, early signs and symptoms, including neuropathic pain, hypohidrosis, and gastrointestinal dysmotility, usually appear in early childhood (Hopkin et al 2008), and life-threatening renal, cardiac, and cerebrovascular complications typically develop by the fourth or fifth decade of life (Germain 2010).…”