Fabry's disease E75.2

X-linked inherited, rare lysosomal storage disease (see lysosome below) with deficiency of the lysosomally localized alpha-galactosidase A, with neurological, nephrological, cardiac and dermatological (small papular angiomas in about 70% of patients) symptoms.

Incidence: 1:40.000

X-linked recessive mutation of the alpha-galactosidase A gene(GLA gene), which is located at gene locus Xq22. The result is a deficiency of alpha-galactosidase A and an accumulation of glycosphingolipids, preferably globotriaosylceramides and galabiosylceramides, in the vascular endothelia, but also in other cells (myocardium).

Umbilical region (leading symptom), gluten, scrotum, trunk, rarely extremities. Rare is an involvement of the oral mucosa and the conjunctiva.

In the first years of life (onset usually in school-age), diffuse pain symptomatology and paresthesias of the extremities, angiokeratomas and hypohidrosis are the main clinical manifestations.

Integument (70% of pat.; angiokeratomas): Multiple, symmetrically distributed, 1-3 mm, purplish-red to blackish-blue, only partially hyperkeratotic papules. The expression may be very discrete or absent. Tufted branching of capillaries of the nail fold as a possible harbinger of angiokeratoma. Hypo- or anhidrosis, therefore temperature increase during physical exertion; increased sensitivity to sudden temperature change.

In the further course, ostensibly symptoms of vascular involvement, e.g., heart failure due to cardiovascular changes(hypertrophic cardiomyopathy due to glycolipid deposition in the myocardium; further in the mitral and aortic valves and in the coronary vessels), progressive renal failure, nephrogenic hypertension, and cerebral insults.

Ocular involvement: Vertebral subepithelial yellow-brown corneal opacities(cornea verticillata in 80% of cases), aneurysms of the retinal vessels, ampullary distension of the conjunctival veins.

Neurological symptoms: paresthesias, temperature-dependent pain crises of the extremities(acroparesthesias) that regress from the 30th LJ, headaches, TIA, pareses, cerebral hemorrhages.

Tinnitus, hearing loss

Progressive renal involvement: asymptomatic microproteinuria, especially in childhood; often progressive loss of renal function to terminal renal failure.

Determination of globotriaosylceramide (Gb3) in blood (standard: < 2.3ug/l) and urine.

Supplementary: Determination of α-galactosidase A activity in leukocytes, serum, tear fluid.

In hemizygotes no or significantly reduced enzyme activity; in heterozygous women possibly no or slightly reduced enzyme activity - nevertheless clinical symptoms cannot be ruled out!

Note: Women represent a genetic mosaic: the functional X chromosome is switched on in one part of the body cells, but switched off in another part. Women can also develop the disease, but later and with significantly less severe symptoms.

Note: There are also GLA polymorphisms without disease significance.

Acanthotic, partially hyperkeratotic epidermis. Hyperkeratosis may be absent. Subepidermal capillary ectasias, often enclosed by the elongated retele ridges. Lipid detection in vessel walls and hair follicle muscles (Sudan black or Sudan red, intense PAS reaction). Electron microscopy: Intracytoplasmic, osmiophilic inclusion bodies in endothelial cells.

Remark: All angiokeratomas due to lysosomal storage diseases are histologically similar.

Enzyme replacement therapy: Agalsidase alpha (Replagal) 0.1 mg/kg bw over 40 minutes or Agalsidase beta (Fabrazyme) 1 mg/kg bw over 2-4 hours at regular (usually 14-day) intervals. Both preparations often cause at least a stagnation of the course of the disease, decrease of acroparaesthesia and improvement of the quality of life. Indications of improvement of heart and kidney insufficiency. Furthermore, symptomatic treatment of cardiovascular, pulmonary and muscular disorders.

Untreated infaust. Lethal outcome between 30 and 50 years of age due to cardio- and renovascular complications (uremia or vascular insults). Under therapy probably significant improvement of the prognosis. With late-onset variants normal life expectancy.

Diagnosis often only in adulthood with progression of the clinical symptoms. In case of suspected disease interdisciplinary approach with molecular genetic analysis, histology, bone marrow biopsy, urine sediment (Maltese crosses: polarization microscopic birefringent ceramide crystals). Eye examination with slit lamp: subepithelial deposited glycosphingolipids.

Capillary microscopy: tufts of some capillaries in 2 to 5 loops and their elongation. Medium plexus visibility (plexus score 2 according to Maricq). Pathological capillaroscopy may be an indication of a systemic vascular change which may occur without lipid deposition in the endothelial cells. The changes are similar to those in systemic collagenosis.

Prenatal diagnosis: chorionic villus sampling in 10th-12th weeks or amnioscentesis in 15th-18th weeks.

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