Progress in the understanding and treatment of Fabry disease

Abstract

Background: Fabry disease is caused by α-galactosidase A deficiency. Substrates of this lysosomal enzyme accumulate, resulting in cellular dysfunction. Patients experience neuropathic pain, kidney failure, heart disease, and strokes. Scope of review:The clinical picture and molecular features of Fabry disease are described, along with updates on disease mechanisms, animal models, and therapies.Major conclusions: How the accumulation of α-galactosidase A substrates, mainly glycosphingolipids, leads to organ damage is incompletely understood. Enzyme replacement and chaperone therapies are clinically available to patients, while substrate reduction, mRNA-based, and gene therapies are on the horizon. Animal models exist to optimize these therapies and elucidate disease mechanisms for novel treatments.General significance: Recent newborn screening studies demonstrate that Fabry disease is the most common lysosomal storage disease. As many countries now include Fabry disease in their screening panels, the number of identified patients is expected to increase significantly. Better knowledge of disease pathogenesis is needed to improve treatment options.

Gb3‐cSrc complex in glycosphingolipid‐enriched microdomains contributes to the expression of p53 mutant protein and cancer drug resistance via β‐catenin–activated RNA methylation

“…In addition to upregulated expression of GCS in cells under stress, hereditary deficiency of glucosylceramidase (also known as glucocerebrosidase) results in accumulation of GlcCer in cells and causes Gaucher's disease 59,60 . In Fabry disease, one of the lysosomal storage diseases, GLA mutations defect α‐galactosidase A (α‐GALA) in hydrolyzing the terminal α‐galactosyl moieties from GSLs, and bring about accumulation of Gb3 in cells, particularly in kidneys, heart and skin 61,62 . Aberrant elevation of these GSLs in GEMs can alter membrane fluidity, membrane protein trafficking and assembly of signaling molecules 8,12 .…”

Lysosomal Ceramide Metabolism Disorders: Implications in Parkinson’s Disease

“…Mutations in GLA gene cause deficiency of α-GLA activity and lead to develop Fabry disease. Fabry disease was described for the first time in 1898 [53], it is characterized by the progressive accumulation of globotriaosylceramide, globotriaosylsphingosine, and digalactosylceramide in cells, which alters the normal function of several cellular organelles and causes multi-systemic effects with neuronal, renal, cardiac, and cerebrovascular involvement [54]. To date, around 967 different GLA mutations have been described (listed on the Human Gene Mutation Database, http://www.hgmd.cf.ac.uk/); most of them have been identified only in individual families.…”

“…In adulthood, people develop also lymphedema, proteinuria, and the first signs of renal, cardiac, or CNS/cerebrovascular disease, all symptoms that worsen over the time. The late onset forms of Fabry disease may present as a stroke, left ventricular hypertrophy, or renal failure [54].…”

“…Although Fabry disease was defined "rare" (with a prevalence of 1:50,000 [55]), recent newborn screenings revealed that this disorder is more common than expected (the incidence ranges from 1:1250 to 1:8454) [56][57][58][59]. The discrepancy among these data can be explained by the heterogeneity of the symptoms and the late onset of the disease (patients develop symptoms at their teenage or adulthood years), thus the use of the newborn screening for the diagnosis allowed to better identify people affected [54].…”

Novel imaging technologies for genetic diagnoses in the inborn errors of metabolism

“…Fabry disease (FD) is an X-linked lysosomal storage disorder, characterized by decreased or absent activity of the lysosomal enzyme alpha galactosidase A due to mutation of the alpha galactosidase A gene at Xq22.1. Clinical symptoms as a result of this accumulation include renal and cardiac failure, painful acroparaesthesias, angiokeratomas, hypohydrosis, corneal dystrophy, and stroke [71][72][73][74][75][76][77] . Strokes are seen in 25% of males and 21% of manifesting female carriers.…”