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 60 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. They also reported liver involvement with portal hypertension and coronary artery disease with vascular calcifications as late complications of cystinosis in patients not receiving oral cysteamine therapy. In collaboration with colleagues in the National Eye Institute, the Section described the ophthalmic histopathology of cystinosis, and continues to provide cysteamine eyedrops to patients suffering from photophobia due to corneal cystine crystal accumulation. The collaborative group continues 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 have comprehensively described the musculoskeletal manifestations and progression to disability of alkaptonuria patients. The Section has also successfully enrolled 40 alkaptonuria subjects in 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. An Investigational New Drug (IND) exemption has been obtained from the FDA for this study. 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 such as melanosomes and platelet dense bodies. There are 8 genetic subtypes of this disease, and the Section has cared for more than 160 affected individuals. In basic studies, members of the Section and their collaborators reported a normal contingent of alpha granules in HPS platelets, which are known to lack dense granules. They demonstrated that the HPS3 protein interacts with clathrin; this finding helps explain the function of HPS3 in intracellular trafficking. In clinical studies, the group and collaborators described the first successful lung transplantation in an HPS patient, the ocular pathology of HPS, and the granulomatous colitis of HPS in relation to the particular subtypes. Physicians in the Section have also initiated 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. An IND has been obtained, and enrollment has begun. In parallel with this clinical trial, Section physicians are investigating the etiology of the lung fibrosis through studies of cytokines in HPS pulmonary lavage fluid. 4. The Section is performing linkage studies of Gray Platelet Syndrome, a disorder in which platelet alpha granules are absent and patients suffer from a bleeding diathesis. 5. The Section has also initiated studies to identify 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 to define the natural history and determine outcome parameters for future therapeutic intervention. Approximately 40 patients have been evaluated in this study, and the Section, along with the Office of Rare Diseases, sponsored and published a summary of the proceedings of a workshop on ARPKD/CHF attended by national authorities in the field. Detailed descriptions of the radiographic features of ARPKD/CHF are being prepared for publication. 7. A clinical protocol investigating the natural history of Hutchinson-Gilford Progeria Syndrome has been approved, and 15 patients with this premature aging syndrome have been enrolled. The findings are being compiled. 8. Several patients were seen with Chediak-Higashi disease, a disorder of large intracellular granules and a tendency toward fatal infections. The Section described a severely affected infant and a mildly affected adult, identifying the causative mutations in the CHS1 gene and providing genotype-phenotype correlations on clinical, molecular, and cell biological levels. 9. In collaboration with the Cell Biology of Metabolic Disorders Unit, members of the Section have pursued 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. Sialic acid serves as the terminal sugar on glycoproteins that decorate plasma membranes and modulate cell-cell interactions; muscle proteins such as alpha-dystroglycan are heavily sialylated, and the myopathy of HIBM has been attributed to hyposialylation of alpha-dystroglycan and other muscle proteins. In addition to collaborating on HIBM basic research projects and animal model studies with the Unit, the Section has performed a pilot study of intravenous immune globulin G for treating HIBM, based upon the high sialic acid content of immune globulin. In four treated patients, muscle strength and functional activity improved considerably, prompting further investigations into providing sialic acid or a precursor to HIBM patients.