What is Fabry Disease?
Fabry Disease is a genetic lysosomal storage disorder first described in 1898 by William Anderson and Johannes Fabry. It is caused by a harmful mutation in the GLA gene on the X chromosome, which encodes the enzyme alpha-galactosidase A (αGAL A). This mutation leads to the progressive accumulation of the enzyme’s substrate due to a deficiency (or absence) of the α-galactosidase A enzyme resulting from the X chromosome region Xq22 mutation.
The pathology observed in Fabry disease is primarily attributed to the accumulation of derivatives such as globotriaosylceramide (Gb3) and globotriaosylsphingosine (lysoGb3) in various cell types. Lysosomal Gb3 accumulation is most pronounced in endothelial cells, cardiomyocytes, peripheral neurons, and various renal cell types.
What Are the Subtypes of Fabry Disease?
The disease can be classified into a severe, classic phenotype commonly observed in males with absent enzyme activity and a milder, non-classic phenotype. Classic Fabry patients typically present with characteristic Fabry symptoms such as neuropathic pain, corneal verticillata, and angiokeratomas. Long-term disease manifestations include hypertrophic cardiomyopathy, cardiac arrhythmias, progressive kidney failure, and stroke.
Non-classic Fabry disease, also known as late-onset or atypical Fabry disease, is characterised by a more variable disease course. Patients are generally less severely affected, and symptoms may be limited to a single organ. Males with the non-classic disease typically have residual enzyme activity and lower levels of the deacetylated substrate (globotriaosylsphingosine [lyso-Gb3]).
How is Fabry Disease Diagnosed?
Fabry disease diagnosis involves measuring enzyme activity (alpha-galactosidase A enzyme activity in plasma, leukocytes, dried blood spots on filter paper, or fibroblast cultures is assessed using spectrofluorometric methods), genetic analysis (methods include dot-blot, reverse dot-blot PCR, mutation detection with restriction enzymes, sequence analysis by denaturing high-performance liquid chromatography, denaturing gradient gel electrophoresis, microarray analysis, and DNA sequencing), and measuring accumulated metabolites in blood or tissues. Also, urinalysis, proteinuria measurement, and kidney function tests are informative.
Due to random X chromosome inactivation in female Fabry patients, enzyme levels measured in heterozygous females may be within normal limits. Therefore, GLA gene mutation analysis is requested when Fabry disease is suspected in women.
What are the treatment options for Fabry disease?
- Enzyme Replacement Therapy (ERT)
- Pharmacological Chaperone Therapy
- Preclinical Research Treatments
- Next-Generation Enzyme Replacement Therapy
- Substrate Reduction Therapy
- mRNA and Gene Therapy
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