Fabry disease is a progressive disorder of glycosphingolipid metabolism caused by a deficiency or absence of lysosomal α-galactosidase A activity due to mutations in the GLA gene, located on the x-chromosome.
Lack of sufficient α-galactosidase A activity leads to progressive accumulation of the glycosphingolipids globotriaosylceramide (denoted Gl3 or Gb3) and globotriaosylsphingosine (lyso-Gl3 or lyso-Gb3) within lysosomes in a variety of cells types, including vascular endothelium, podocytes, arterial smooth muscle cells, and cardiomyocytes.1,2 Fabry patients are typically classified as Classic or Late-onset (Non-classic) where classic males primarily present in childhood/adolescence with neuropathic pain, angiokeratomas, corneal opacities, hypohidrosis and GI disturbances that progresses to chronic kidney disease, cardiomyopathy, cardiovascular disease, arrhythmias, and stroke/TIA.
Late-onset patients present with variable age of onset and manifestations, and may not have multiple organ involvement. Female Fabry patients have a wide spectrum of disease manifestations from asymptomatic to a severe phenotype similar to classic.7
Males typically exhibit symptoms earlier than females but all patients typically experience a diagnostic delay due to the non-specific disease symptoms that overlap with other diseases7.
Disease presentation is heterogeneous, but the following symptoms may prompt further examination: pain, gastrointestinal symptoms (postprandial abdominal pain, diarrhea, nausea, vomiting), hypohidrosis or anhidrosis, angiokeratomas on the skin, corneal changes, chronic fatigue, and difficulty gaining weight.1
Diagnosis of Fabry disease involves assay of α-galactosidase A activity in males, followed by GLA sequencing. For females, GLA sequencing is the appropriate first test as enzyme activity can be normal. In addition, current evidence suggests globotriaosylsphingosine (denoted Lyso-Gl3 or Lyso-Gb3) can be useful in the diagnostic process. Lyso-Gl3 is significantly increased in classic male and classic female Fabry patients; elevated but less so in non-classic males and may be mildly elevated or normal in non-classic female Fabry patients.6