Fabry disease. Alpha-galactosidase A deficiency.
Incidence
It is an X-linked inherited disorder. More than 400 cases reported. Disease is fully expressed in males. Female carriers may have corneal opacities and usually are asymptomatic. Incidence estimations of Fabry disease vary widely from 1:55 000 to 1:3000 male births. The true incidence is likely to be higher than originally thought, owing to the existence of milder variants of the disease.
Clinical Characteristics
Fabry disease is an X-linked lysosomal storage disorder resulting from a deficiency of alpha-galactosidase A (a-Gal A). Fabry disease is a complex, multisystemic and clinically heterogeneous disease with prominent urinary excretion of globotriaosylceramide (Gb3), the principal substrate of the deficient enzyme, a-galactosidase A. Some measure of specific treatment is possible with enzyme replacement therapy, which can be applied safely and effectively to Fabry patients. It may be seen in late childhood or adolescence. There are neurologic and cutaneous symptoms. Recurrent episodes of burning or lancinating pain in limbs, distally, associated with paresthesias and some times edema. During the crisis, there may be fever and high ESR. Abdominal pain and diarrhea may also occur. In between crisis, the neurologic exam is normal. Decreased sweating is reported. On the skin, there are telangiectasias (angiokeratomas) which are small, dark red in color, seen symmetrically often below umbilical area and on the thighs. Also may be seen in the mouth mucosa. There are corneal opacities (seen at times since infancy), and also cataracts of peculiar pattern. Retinal and conjuntival vessels may be tortuous. Renal dysfunction is evident in adolescence but mainly in adulthood. CVA thrombotic may occur in early adulthood producing focal neuro deficits and seizures. Bone lesions are not rare with arthritis of hands. The main complications of Fabry disease are a 100-fold increased risk of ischaemic stroke, cardiac disease including cardiomyopathy, atrio-ventricular conduction defects, a wide variety of arrhythmias, valvular dysfunction (insufficiency or stenosis) and cardiac vascular disease, as well as progressive renal failure usually associated with significant proteinuria. These clinical manifestations are non-specific and may be mistaken for symptoms of other disorders, thus complicating the confirmation of diagnosis. Misdiagnosis of Fabry disease is frequent. Foam cells are found in bone marrow. Lipid-containing cells can be seen in urine sediment. There are typical intralysosomal inclusions (lamellated concentric pattern on EM) on skin, kidney and conjuntival biopsies. There is endothelial cell proliferation in small vessels leading to obstruction and microaneurysms, with multiorgan damage. Tegretol and Dilantin help in controling the incapacitating pain. Aspirin Rx may decrease thrombotic tendency. Antipyretic and hydration help during crisis. The recent improvement of the management of Fabry disease, including the development of enzyme replacement therapy, has made risk factors potentially modifiable by early treatment, hence there is a the need for an effort to identify affected patients as early as possible.
Precipitants
Crisis may be triggered by changes in body temperature due to physical activity, infection or something else.
Provocation Tests
no
Diagnostic Procedures
EB-F, EB-W. There is increased levels of globotriaosylceramide (GL-3) in plasma and urine sediment. In patients with the disease, Gb3 levels in urine are increased to a greater extent than the levels in blood. No other disorder is known to be associated with increased urinary Gb3 excretion, making the analysis of Gb3 a specific screening test for Fabry disease. There is now a rapid and simple liquid chromatography–tandem mass spectrometry (LC-MS/MS) multiplex assay to analyse Gb3/creatinine ratios in urine samples collected on filter paper. Urine samples will be collected on Whatman filter paper no. 903, left to dry overnight and returned by mail to the mass spectrometry laboratory. Abnormal Gb3 excretion in male patients would trigger a-Gal A enzyme assay in plasma, peripheral blood leukocytes, or dried blood spot samples. Patients with marked deficiency of a-Gal A activity would undergo GLA mutation analysis to confirm the diagnosis of Fabry disease. Because a-Gal A enzyme deficiency is often within the normal range in female heterozygotes with Fabry disease, women with abnormal Gb3 excretion would be subjected to GLA mutation analysis to confirm the diagnosis. There are typical intralysosomal inclusions (lamellated concentric pattern on EM) on skin, kidney and conjuntival biopsies. Foam cells are found in bone marrow. Lipid-containing cells can be seen in urine sediment.