Human Biochemical Genetics

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The Section on Human Biochemical Genetics studies selected inborn errors of metabolism to provide insight into cellular mechanisms and care for abandoned populations of patients. 1. Hermansky-Pudlak syndrome (HPS) is a rare disorder of oculocutaneous albinism and bleeding due to abnormal formation of melanosomes and platelet dense bodies. There are 7 genetic subtypes of this disease. Members of the Section described 6 new, non-Puerto Rican HPS-1 patients along with 4 novel HPS1 mutations, and 7 new, non-Puerto Rican HPS-4 patients having 3 novel HPS4 mutations. We continue to define the natural history of clinical involvement in the subtypes of HPS, and to perform cell biological studies of the movement of intracellular vesicles in these disorders. 2. This year members of the Section admitted more than 70 cystinosis patients to the Clinical Center, following their treatment with cysteamine and documenting the presence or absence of nonrenal complications of the disorder. One 25-year old man had coronary artery disease, and this is now being reported as a late complication of cystinosis. One woman carrying the diagnosis of ocular cystinosis was diagnosed instead with multiple myeloma. Two siblings treated well with cysteamine were reported to have excellent kidney function and growth at ages 14 and 8. In collaboration with the National Eye Institute, members of the Section continue to investigate cysteamine eyedrops for the treatment of corneal cystine crystals. 3. The Section has expanded its expertise in alkaptonuria, a disorder of accumulation of homogentisic acid due to deficiency of homogentisate 1,2-dioxygenase. The Section documented the natural history of the disease with respect to joints, kidney stones, and cardiac valves, and began therapy in 5 patients with nitisinone, which reduced the toxic homogentisic acid by 95%. Mutation analysis was also performed in patients enrolled in the Section?s studies. 4. Members of the Section diagnosed and described three different patients with disorders of free sialic acid metabolism, i.e., Salla disease and Infantile Free Sialic Acid Storage Disease. These disorders results from defective sialin, the lysosomal membrane transport protein which carries free sialic acid out of lysosomes. 5. The Section also studied selected rare disease patients, including two with Gray Platelet Syndrome and three with Hereditary Inclusion Body Myopathy. The deficient enzyme in this latter disease, UDP-GlcNAc 2-epimerase, was assayed in cultured fibroblasts. Mutation analysis was also performed on the patients? DNA. Protocols were initiated to find the gene causing Gray Platelet Syndrome and to document the natural history of Autosomal Recessive Polycystic Kidney Disease and Congenital Hepatic Fibrosis.