Fabry disease (NORD)

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Fabry disease (NORD)




Fabry disease (NORD)


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Fabry disease (NORD)

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USMLE® Step 1 style questions USMLE

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A 5-year-old boy is brought to the clinic with skin lesions that his parent noticed last week while they were out swimming. His parent notes that while his siblings typically sweat while playing outside, he rarely sweats, and his shirts are almost always dry, even after strenuous exercise. The patient has also complained of pain in his arms and legs, particularly in the heat, over the past month. He occasionally complains of intermittent, severe abdominal pain. His birth was unremarkable and he has attained all his developmental milestones. His family is of Ashkenazi Jewish descent. Vitals are within normal limits. Skin examination reveals erythematous macules around the umbilicus and groin area.

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Neurological examination reveals symmetric peripheral neuropathy with diminished sensation to touch and temperature. Abdominal examination is unremarkable. Complete blood count is normal. A genetic disorder is suspected. If further testing is performed, which of the following enzymes is most likely to be deficient in this patient?  

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α-galactosidase A

Fabry disease p. 86

Fabry disease p. 58, 86

Heart disease

Fabry disease p. 86

Peripheral neuropathy

Fabry disease p. 86

Renal failure

Fabry disease p. 86


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 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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