Fabry disease (also known as Fabry’s disease, Anderson-Fabry disease, angiokeratoma corporis diffusum and alpha-galactosidase A deficiency) is a rare X-linked (inherited) lysosomal storage disease, which can cause a wide range of systemic symptoms. It is a form of sphingolipidosis, as it involves dysfunctional metabolism of sphingolipids.
A deficiency of the enzyme alpha galactosidase A (a-GAL A, encoded by GLA) due to mutation causes a glycolipid known as globotriaosylceramide (abbreviated as Gb3, GL-3, or ceramide trihexoside) to accumulate within the blood vessels, other tissues, and organs. This accumulation leads to an impairment of their proper function.
The DNA mutations which cause the disease are X-linked recessive. The condition affects hemizygous males (i.e. all males), as well as homozygous, and in many cases heterozygous females. While males typically experience severe symptoms, women can range from being asymptomatic to having severe symptoms.
Symptoms are typically first experienced in early childhood and can be very difficult to understand; the rarity of Fabry disease to many clinicians sometimes leads to misdiagnoses. Manifestations of the disease usually increase in number and severity as an individual ages.
- Pain: Full body or localized pain to the extremities (known as acroparesthesia) or GI tract is common in patients with Fabry disease. Acroparesthesia in Fabry disease is believed to be related to the damage of peripheral nerve fibers that transmit pain. GI tract pain is likely caused by accumulation of lipids in the small vasculature of the GI tract which obstructs blood flow and causes pain.
- Renal involvement: Kidney complications are a common and serious effect of the disease; renal insufficiency and renal failure may worsen throughout life. Proteinuria (which causes foamy urine) is often the first sign of kidney involvement. End stage renal failure in fabry patients can typically occur in the third decade of life, and is a common cause of death due to the disease.
- Cardiac manifestations: Cardiac complications occur when glycolipids build up in different heart cells; heart related effects worsen with age and may lead to increased risk of heart disease. Hypertension (high blood pressure) and cardiomyopathy are commonly observed.
- Dermatological manifestations: Angiokeratomas (tiny, painless papules that can appear on any region of the body, but are predominant on the thighs, around the belly-button, buttocks, lower abdomen, and groin) are a common symptom. Anhidrosis (lack of sweating) is a common symptom, and less commonly hyperhidrosis (excessive sweating).Additionally, patients can exhibit Raynaud’s disease-like symptoms with neuropathy (in particular, burning extremity pain).
- Ocular manifestations: Cosmetic ocular involvement may be present showing cornea verticillata (also known as vortex keratopathy), i.e. clouding of the corneas. Keratopathy may be the presenting feature in asymptomatic fabry patients, and must be differentiated from other causes of vortex keratopathy (e.g. drug deposition in the cornea). This clouding does not affect vision. Other ocular findings that can be seen include conjunctival aneurysms, posterior spoke-like cataracts, papilloedema, macular edema, optic atrophy and retinal vascular dilation.
- Other manifestations: Fatigue, neuropathy (in particular, burning extremity pain), cerebrovascular effects leading to an increased risk of stroke, tinnitus (ringing in the ears), vertigo, nausea, inability to gain weight, chemical imbalances, and diarrhea are other common symptoms.
Fabry disease is indicated when associated symptoms are present, and can be diagnosed by a blood test to measure the level of alpha-galactosidase activity, however this may be misleading in female patients due to the random nature of X-inactivation. Chromosomal analysis of the GLA gene is the most accurate method of diagnosis, and many mutations which cause the disease have been noted. Kidney biopsy may also be suggestive of Fabry Disease if excessive lipid buildup is noted. Pediatricians as well as internists commonly misdiagnose Fabry disease.