Underlying pathology

Fabry disease is one of over fifty known rare inherited disorders called lysosomal storage disorders. Each of these diseases are caused by an inborn genetic defect resulting in a deficiency of a particular lysosomal enzyme or enzymes Germain, DP. Fabry Disease. Orphanet J Rare Dis. 2010 Nov 22;5:30. doi: 10.1186/1750-1172-5-30. . The age of onset, affected organ system(s), and severity of these disorders vary markedly, but all are progressive.

Fabry disease is caused by a mutation in the GLA gene, which encodes lysosomal α-galactosidase A (also known as α-GAL; α-Gal-A, and ceramide trihexosidase) Desnick R.J., Ioannou Y.A., Eng C.M. (2014). α-Galactosidase A Deficiency: Fabry Disease. In Valle D, Beaudet A.L., Vogelstein B, Kinzler K.W., Antonarakis S.E., Ballabio A, Gibson K, Mitchell G (Eds). . Partial or complete deficiency of α-GAL activity results in a reduced ability to catabolize lipids with terminal α-galactosyl residues. These lipids, particularly globotriaosylceramide (also known as GL-3; Gb3, ceramide trihexoside, or CTH), accumulate within the lysosomes of multiple cell types throughout the body, including the capillary endothelial cells, renal, cardiac and nerve cells with resultant progressive multisystemic damage. Over time, this can lead to end-organ damage of the kidneys, heart, and/or cerebrovascular system.

Accumulation of GL-3 in capillary endothelium

Arrows indicate areas of GL-3 accumulation in this electron micrograph of the renal capillary endothelium in a patient with Fabry disease.

Image used with permission from Sanofi Genzyme gallery.

Disease presentation

Fabry disease has a wide variety of heterogeneously progressive clinical phenotypes. Previously, only the ‘classic’ phenotype of Fabry disease had been documented. Nowadays, also non-classical phenotypes have been reported. Because of this broad spectrum of phenotypes, clinical manifestations can vary significantly between patients. Clinical manifestations for patients can include neuropathic pain, pain crises, heat/cold intolerance, dermatological problems (angiokeratomas), ocular manifestations, gastrointestinal problems,  cardiac problems (e.g. arrhythmias and left ventricular hypertrophy (LVH)) and renal problems. This wide variety of clinical manifestations can make diagnosing Fabry disease challenging.