Fabrys Disease

This X-linked lipidosis is characterized biochemically by the accumulation of two glycosphingolipids, globotriaosylceramide and galabiosylceramide. Ihe enzymatic deficiency is alpha-galactosidase A. Ihe molecular structure of the gene encoding the enzyme was first identified as the full-length cDNA clone and is localized to Xq21.33-q22.yi Twenty different mutations have been described for this gene and include deletions or duplications. Ihe majority of the glycosphingolipids are synthesized in the liver or bone marrow and thereafter are transported to cells by lipoproteins. Ihe major substrate burden in Fabry's disease appears to be on cellular membranes that depend on glycosphingolipids for their integrity and function. Organ storage occurs presumably because of permeable membranes that permit accumulation of high levels of circulating lipids.

Ihe clinical symptoms begin in late childhood or adolescence with the development of painful neuropathy, which is most pronounced in the extremities, and corneal and lenticular opacities and characteristic skin lesions, known as angiokeratoma. Ihese dermatological features consist of ectatic blood vessels covered by thin skin and appear as discreet, slightly raised, blue or dark red spots that cluster in the groin, umbilical area, and thighs. Ihe neurological signs are usually vascular in origin and include transient ischemic attacks, ischemic strokes, and cerebral hematomas. Storage of glycolipids in the systemic vascular system leads to progressive cardiac and renal involvements in the subsequent two to three decades, leading to potential metabolic and hypoxic encephalopathy. Pathologically, the CNS shows lipid accumulation in the autonomic nervous system neurons and several other regions including supraoptic, preoptic, and paraventricular nuclei. Ihe nucleus basalis, anterior thalamus, and the hippocampus are also characteristically loaded with glycolipid, and when the cerebral cortex is involved, layers 5 and 6 demonstrate the neuronal lipid storage. In the peripheral nervous system, loss of small myelinated and unmyelinated nerves occurs. y

Because the disease is rare, carrier testing is not routinely performed. In affected pedigrees, however, alpha- galactosidase A analysis identifies affected males and often heterozygous females. Affected males cannot pass the disease to their sons, but all daughters are carriers.

Ihe differential diagnosis includes conditions associated with angiokeratoma, including metabolic disorders such as neuraminidase deficiency, galactosialidosis, fucosidosis, and GM-, gangliosidosis. Drugs that can cause corneal opacification include chloroquine and amiodarone. Ihe treatment of Fabry's disease focuses primarily on abatement of the painful neuropathy, and carbamazepine and diphenylhydantoin, as well as neurotropin have been used with success. W Renal transplantation has also been used in patients with severe renal failure, but whether these allografts can serve as sources of new enzyme for the patient has not been demonstrated.

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