This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Gastrointestinal (GI) symptoms are a common but under-recognized manifestation of Fabry disease, a rare, X-linked lysosomal storage disorder resulting from deficiency of enzyme alpha-galactosidase A (alpha-Gal A). Gastrointestinal symptoms, which typically begin in adolescence and worsen with age, are reported by 50-90% of male patients. Classically affected males have an average lifespan of 50 years; in an earlier series before renal dialysis and transplantation were available, average lifespan was 40 years. Clinical manifestations of classic Fabry disease begin in early childhood and include gastrointestinal symptoms, among other symptoms. The most common symptoms are diarrhea and/or constipation. Other symptoms include nausea, vomiting, abdominal pain, early satiety, post-prandial bloating, and food intolerance. Generally, symptoms are more frequent and appear earlier in life in males as compared to females. Most GI symptoms are believed to be the result of GL-3 accumulation in vascular endothelial and perithelial cells and in the cytoplasm of the small unmyelinated neurons and perineurial cells. Smoothing or lack of colonic haustrae in descending and sigmoid colon segments have been reported in some patients who underwent barium enema; delayed gastric emptying has been successfully treated symptomatically to some extent with metoclopramide; small intestine and colon biopsies have shown GL3 accumulation in vegetative neurons of Meissner plexus, small vessels (capillaries, venules and arterioles) and smooth muscle cells. Before the availability of enzyme replacement therapy (ERT), the only treatment options for Fabry disease were palliative and non-specific. In 2003, agalsidase beta (Fabrazyme, Genzyme Corporation, Cambridge MA) became available in the United States, after successful completion of clinical trials showing substantial clearance of GL-3 in plasma, kidney, liver, heart, and skin in patients with classical Fabry disease. Hypothesis: Patients with Fabry disease begin accumulating GL-3 before birth; thus, years of treatment may be necessary to diminish or undo the effects of prior decades without treatment. Gastrointestinal symptoms can have a significant impact on quality of life for patients with Fabry disease. Thus, the major endpoints of clinical trials of agalsidase beta has been demonstration of decreased GL-3 accumulation in the primary organs of pathology, a measure thought to correlate with future clinical benefit. However, the results suggest that resolution of gastrointestinal symptoms could be an early clinical benefit of ERT.
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