Human Biochemical Genetics

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Summary: The Section on Human Biochemical Genetics studies selected inborn errors of metabolism to provide insight into cellular mechanisms and care for neglected groups of rare disease patients. 1. Members of the Section admitted approximately 50 individuals with cystinosis as inpatients or outpatients to the NIH Clinical Research Center, documenting the beneficial effects of oral cysteamine therapy with respect to growth, renal function, and ophthalmic abnormalities. In addition, they reviewed the non-renal complications of cystinosis for a pediatric nephrology journal, wrote two book chapters on the disease, addressed an international cystinosis meeting, and continued to work to bring cysteamine eyedrops to New Drug Approval by the FDA. The Section serves as the world authority on cystinosis, responding to scores of inquires every year from patients and physicians throughout the world. 2. The Section continues its investigations into alkaptonuria, a disorder of accumulation of homogentisic acid due to deficiency of homogentisate 1,2-dioxygenase. In collaboration with the Clinical Center's Rehabilitation Medicine Department, members of the Section are conducting a randomized clinical trial of nitisinone, a powerful inhibitor of the enzyme that produces homogentisic acid, using hip range of motion as the primary outcome parameter. Forty subjects are enrolled, and interim analysis at 16 months showed promising results, with minimal adverse effects. Members of the Section also wrote the authoritative chapter on alkaptonuria for the Metabolic and Molecular Bases of Inherited Disease. 3. The Section remains the only center in the world investigating both the clinical and basic aspects of Hermansky-Pudlak syndrome (HPS), a rare disorder of oculocutaneous albinism and bleeding due to abnormal formation of intracellular vesicles, including melanosomes in melanocytes and dense bodies in platelets. There are 8 genetic subtypes of this disease and, by investigating more than 200 affected individuals, members of the Section have determined that the fatal pulmonary fibrosis of HPS occurs only in subtypes 1 and 4. In basic studies, the Section has helped to develop an immunoblotting method to facilitate diagnostic subtyping. Members of he Section also showed that melanocytes of different HPS subtypes display different trafficking of the melanogenic protein TRP1. Physicians in the Section have recruited 31 subjects to a randomized, placebo-controlled clinical trial of the antifibrotic agent, pirfenidone, to combat the fatal pulmonary fibrosis of HPS. The outcome parameter is change in forced vital capacity, and interim analysis is scheduled for spring o 2009. In an ancillary pilot study, patients with severe, fatal pulmonary fibrosis are treated with a 5-drug regimen in an attempt to arrest their disease. In parallel with these clinical trials, Section physicians are investigating the etiology of the lung fibrosis through studies of cytokine markers and surface glycoproteins in blood and pulmonary lavage fluid. Elevations in MCP1, MUC-1, and galectin-3 have been found to signal a decline in pulmonary function. Members of the Section have written four reviews and book chapters on HPS and other disorders of lysosome-related organelles. 4. The Section has mapped the gene for Gray Platelet Syndrome (GPS), a disorder in which platelet alpha granules are absent and patients suffer from a bleeding diathesis. Candidate genes are now being sequenced. The proteome of normal alpha granules has been characterized and compared with that of GPS alpha granules. 5. The Section has also mapped the gene responsible for White Platelet Syndrome, a macrothrombocytopenia associated with multiple Golgi regions in platelets. 6. An ongoing clinical protocol investigates Autosomal Recessive Polycystic Kidney Disease and Congenital Hepatic Fibrosis (ARPKD/CHF) to define the natural history and determine outcome parameters for future therapeutic intervention. Results include rates of progression of kidney growth, liver growth, and decline in renal function, frequency of systemic and portal hypertension, inappropriate elevation of vasopressin, measurements of renal tubular function, and delineation of mutations in the PKHD1 gene. Nearly 100 patients with ARPKD/CHF and related ciliopathies were evaluated in this study. 7. Members of the Section extensively characterized 15 children with the premature aging disorder, Hutchinson-Gilford Progeria Syndrome, and described both the entire phenotype and the oral and craniofacial findings. 8. Members of the Section continue to investigate disorders of vesicle formation and trafficking such as Chediak-Higashi disease (CHD) and Griscelli syndrome. CHD, a disorder characterized by large intracellular granules and a tendency toward fatal infections, is extremely rare, but the Section has now investigated 10 patients and documented a genotype-phenotype correlation. For Griscelli syndrome, the Section demonstrated the pathogenicity of a G43S mutation in the switch I region of the Rab27A gene. The Section continues to investigate patients with CHD, Griscelli syndrome, and related disorders of unknown etiology. 9. In collaboration with the Cell Biology of Metabolic Disorders Unit, members of the Section continue to investigate a rare muscle disease, Hereditary Inclusion Body Myopathy (HIBM). The causative gene is GNE, which encodes the bifunctional enzyme UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase, responsible for catalyzing the first two steps in sialic acid synthesis. Members of the Section and the Unit showed that a mouse model of HIBM exhibited renal glomerular basement membrane disease that was ameliorated by treatment with N-acetylmannosamine (ManNAc), a precursor of sialic acid. Physicians in the Section are now pursuing a clinical protocol to provide ManNAc to HIBM patients to determine if muscle strength can be restored. A Section/Unit collaboration resulted in the demonstration that the dominant allele in sialuria, responsible for uncontrolled synthesis of sialic acid by GNE, can be silenced by allele-specific RNA interference. Members of the Section have also written two review chapters on sialic acid storage diseases. 10. Section investigators examine patients with Congenital Disorders of Glycosylation, and wrote the definitive review on this group of disorders. 11. In collaboration with the Office of Rare disease and the NIH Clinical Center, the Section has spearheaded a new Undiagnosed Diseases Program. This initiative aims to provide answers to patients with mysterious conditions that have long eluded diagnosis, and to advance medical knowledge about rare and common diseases. To date, the Program has received more than 600 inquiries and 200 sets of medical records from throughout the country; it plans to accept 50-100 patients per year.