Fabry disease (NORD)

Definitions & Key takeaways

Fabry disease is a rare, x-linked lysosomal storage disorder in which an enzyme called alpha-galactosidase A is deficient. This results in the accumulation of ceramide trihexoside in the cells, which causes health problems. People with Fabry disease present with burning pain in the hands and feet, and reduced sweating, and angiokeratomas which appear as hard bumps on the skin. People can also develop heart problems, stroke, and kidney failure.

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Fabry disease is a rare X-linked condition caused by mutations or pathogenic variants in the GLA gene that codes for a lysosomal enzyme called alpha galactosidase A or alpha-gal A.
The alpha-gal enzyme normally breaks down large molecules called globotriaosylceramide or GL3 and other glycosphingolipids, so that small parts of the big molecules can be recycled for the body to use again.
Without alpha-gal, these GL3 molecules build up inside the lysosomes, the recycling centers of the cells, causing a variety of symptoms and health issues.
Fabry disease affects males and females, and it has two forms: classic and nonclassic/later onset. In classic Fabry disease, symptoms start in childhood and include burning, tingling, prickling, and painful neuropathic pain in the hands and feet, frequently triggered by exercise, fatigue, stress, or illness.
There may also be a gradual decrease of sweating in childhood until many teens and adults stop sweating entirely. In some people living with Fabry disease, small reddish-purple rashes called angiokeratomas appear around the lower abdomen and “bathing trunk” region of the body.
There may also be gastrointestinal symptoms like cramps, frequent bowel movements, constipation, and diarrhea. Many patients have a whorl or verticillata in their cornea, that can be found during a split lamp eye exam - but it doesn’t typically affect vision.
Without treatment, Fabry disease complications can include kidney disease, abnormal heart rhythms, heart enlargement, and an increased stroke risk.Nonclassic or later-onset Fabry disease doesn’t cause the earlier symptoms of pain and gastrointestinal issues in childhood, but some adults develop multiple symptoms as young adults.
Others may only show signs of Fabry disease in a specific organ - like the heart or the kidneys. However, these individuals also have a higher risk of Fabry-associated complications.
Fabry disease is diagnosed differently depending on sex. For males at risk to have Fabry disease, blood samples can be tested to see the amount of alpha-gal A.
Low alpha-gal levels prompt analysis of the GLA gene for confirmation. In females, gene analysis should be the first test done, as many affected female have normal levels of alpha-gal A in their blood.
There are two FDA approved treatments for Fabry disease in the United States: enzyme replacement therapy with a synthetic alpha galactosidase A, called agalsidase beta and chaperone therapy with migalastat to help enhance residual enzyme activity.
Otherwise, treatment is aimed at Fabry associated medical issues, like medications to help with neuropathic pain, depression, and decreasing urine protein levels or treatments like pacemakers to help with arrhythmias, or a renal transplant for renal failure.##SummaryAll right, as a quick recap - Fabry disease is an X linked condition, caused by a change in the GLA gene, which leads to a lack of alpha galactosidase A enzyme.
Without this enzyme, large molecules like GL3 build up and cause progressively worsening health issues. Symptoms include burning pain in the hands and feet, angiokeratomas, and decreased sweating.
Left untreated, it may cause heart and kidney failure. Early diagnosis through genetic testing is key, and treatment can be done with synthetic alpha galactosidase A,