Human Biochemical Genetics

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The Section on Human Biochemical Genetics investigates rare and informative inborn errors of metabolism, including Hermansky?Pudlak syndrome, cystinosis, and alkaptonuria. 1. Members of the Section continue to discover mutations in the four known genes causing HPS, and to search for new genes responsible for the disease. In collaboration with other scientists, they have helped develop an assay for detecting serotonin in platelets, evaluated a clotting analyzer for humans with platelet defects, and delineated the radiographic features of HPS patients with pulmonary fibrosis. The Section has examined, cared for,and investigated 120 HPS patients to date. 2. Members of the Section follow approximately 60 patients with cystinosis, some before and some after renal transplantation. They perform mutation analysis on patients new to the protocol, accumulate longitudinal data on treatment regimens, and detect early and late complications of cystinosis. In collaboration with physicians in the National Eye Institute, the Section has helped to describe anterior segment complications of cystinosis and retinal visualization in cystinosis using indocyanine green videoangiography. A study of a new formulation of cysteamine eyedrops was also promulgated by the Section. 3. Alkaptonuria results from accumulation of homogentisic acid, an intermediate in tyrosine degradation, due to deficiency of homogentisate 1,2-dioxygenase. The symptoms include joint and cardiac valve deterioration beginning in mid-life. We have now examined and investigated more than 60 alkaptonuria patients on clinical, biochemical, and molecular grounds. We have identified 90% of the genetic mutations causing alkaptonuria in our patients, and have described a man with alkaptonuria and diabetic nephropathy whose renal disease exacerbated his ochronosis. Two women with alkaptonuria were given low doses of nitisinone, a drug which inhibits the enzyme producing homogentisic acid. Although plasma tyrosine levels rose dramatically, the lowering of homogentisic acid production provides proof of principle for the use of nitisinone in alkaptonuria. 4. The Section also pursues a variety of other rare disorders of human metabolism. Members of the Section have identified the gene and the mutations responsible for type III 3-methylglutaconic aciduria in Iraqi-Jewish and non-Iraqi-Jewish patients. They have described a patient with Griscelli syndrome and neurological involvement caused by mutations in rab27a rather than the expected gene, myosin 5A. In collaboration with other investigators, they have reported patients with lysosomal free sialic acid storage due to mutations in the gene encoding the lysosomal sialic acid transporter. The Section remains the world?s referral laboratory for diagnosing sialuria and other disorders of free sialic acid metabolism.