Fabry Disease

Description

• An X-linked glycolipid storage disease caused by mutation in GLA gene causing a deficiency of the lysosomal enzyme α-galactosidase A
• Also known as angiokeratoma corporis diffusum, ceramide trihexosidosis, α-galactosidase A deficiency, or Anderson-Fabry disease
• Multisystem, progressive disease that can have cutaneous, cardiovascular, cerebrovascular, renal, neurologic, and psychiatric manifestations

Epidemiology

• Second most prevalent lysosomal storage disease (after Gaucher disease)
• Panethnic
• Manifests primarily in men (given that it is X-linked), but female heterozygotes are also affected
• Reported incidence from 1:3,100 to 1:117,000 live male births, although the prevalence is likely underestimated given delays in diagnosis (1). Female prevalence is unclear due to underdiagnosis.
• Underdiagnosed due to rarity of Fabry disease, which is often not considered by clinicians
• Diagnosis may be missed in young patients with stroke or hypertrophic cardiomyopathy of unknown cause.

Pediatric Considerations
Can present in male children around 6 to 8 years and females around 9 years (1), although median age at diagnosis is often later in patients without a known family history. Children often present initially with neurologic or gastrointestinal symptoms (2). The mean age of onset of neurologic symptoms in males is 10 years.

Etiology and Pathophysiology

• X-linked inborn error of the glycosphingolipid metabolic pathway
• Deficiency of α-galactosidase A results in the accumulation of globotriaosylceramide (Gb3) in lysosomes in multiple cell types throughout the body.
• Accumulation of Gb3 is particularly prominent in the vascular endothelium and smooth muscle cells, leading to vascular occlusion, ischemia, and infarct.

Genetics

• GLA gene located on the long arm of the X chromosome, Xq22
• X-linked inheritance pattern
• OMIM #301500
• Men are more commonly affected because they are hemizygous for this (X-linked) gene. Up to 70% of heterozygous females have mild to pronounced features.
• Genetic testing is available. If family history suggests a diagnosis of Fabry disease, genetic testing and counseling should be offered to all family members, regardless of gender.

General Prevention

Fabry disease is a hereditary disorder. Early identification and proper management can prevent or delay complications.