Fabry disease

Fabry disease encompasses a spectrum from severe classic to atypical late-onset forms. In affected males with the classic phenotype, symptoms typically begin in childhood or adolescence with angiokeratomas, episodic acroparesthesia (periodic crises of severe pain in the extremities), hypohidrosis, and characteristic corneal and lenticular opacities. Proteinuria may be detected early, with renal insufficiency typically emerging in the third to fifth decade. Cardiac involvement (left ventricular hypertrophy, , conduction disturbances, and ) and cerebrovascular disease contribute to multisystem morbidity. In the late-onset cardiac and renal variants, affected males and heterozygous females are typically asymptomatic until the sixth to eighth decade. Heterozygous females demonstrate highly variable expressivity, from asymptomatic to clinical features comparable to those in classic affected males, including angiokeratomas, acroparesthesia, and progressive renal or cardiac involvement.

The estimated incidence is 1:50,000 to 1:117,000 males with the classic phenotype. Newborn screening cohorts detect substantially higher rates, including later-onset variants, with reported figures of 1:7,879 in northern Italy and 1:3,000 to 1:4,000 in Hungary, Austria, and Spain.

Fabry disease is caused by germline pathogenic variants in GLA (Xq22.1). GLA encodes the lysosomal exoglycohydrolase alpha-galactosidase A (α-Gal A), and enzyme deficiency drives progressive lysosomal accumulation of globotriaosylceramide (Gb3) and its deacylated derivative, globotriaosylsphingosine (lyso-Gb3), in lysosomes in vascular endothelial cells, kidney epithelial cells, cardiomyocytes, autonomic neurones, and dorsal root ganglia, with secondary effects on cell signalling. Approximately 95% of pathogenic GLA variants are detected by sequence analysis and around 5% by gene-targeted deletion/duplication analysis.

Fabry disease is inherited in an X-linked manner. Affected males transmit the GLA pathogenic variant to all daughters and none of their sons. Heterozygous females have a 50% chance of transmitting the variant to each child. Prenatal molecular testing is technically possible once the familial pathogenic variant has been identified within the family.

In affected males, diagnosis is established by demonstration of deficient alpha-galactosidase A enzyme activity in plasma, leukocytes, or cultured cells using a fluorometric assay. Plasma globotriaosylsphingosine (lyso-Gb3) is a supportive biomarker correlating with disease severity. Identification of a hemizygous pathogenic variant in GLA confirms the diagnosis in males. Enzyme assay is unreliable in heterozygous females, who require molecular genetic testing of GLA.

Main differential diagnoses include:

• : isolated cardiac hypertrophy with normal α-Gal A activity; MYH7, MYBPC3, TNNT2, and others.
• : associated with pain and renal involvement; MEFV.
• Other common misdiagnoses presenting with systemic symptoms include early-onset stroke, multiple sclerosis, rheumatoid arthritis and rheumatic fever.
• Other lysosomal storage disorders presenting with angiokeratomas such as aspartylglucosaminuria (AGA) and fucosidosis (FUCA1)

• Establishing the diagnosis: identification of a disease-associated variant in GLA confirms the diagnosis in males with decreased enzyme activity and establishes the diagnosis in females.
• Initiating individualised surveillance: a confirmed molecular diagnosis is the prerequisite for targeted medical care, including specialist referral and disease-specific monitoring measures that are determined by the treating physicians in consultation with the affected individual.
• Testing of at-risk relatives: once the familial pathogenic variant has been identified, predictive molecular testing of at-risk family members clarifies their variant status and informs reproductive and clinical planning.

Mehta A, Hughes DA. Fabry disease. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2024 [updated 2022 Jan 27]. Available from: