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 neglected groups of patients. 1. Members of the Section admitted approximately 85 individuals with cystinosis as inpatients to the NIH Clinical Research Center, documenting the beneficial effects of oral cysteamine therapy with respect to growth, renal function, swallowing ability, and abnormalities of the posterior segment of the eye. They also reported idiopathic intracranial hypertension as a complication of cystinosis and, in collaboration with colleagues in the National Eye Institute, provided cysteamine eyedrops to patients suffering from photophobia due to corneal crystal accumulation. The group continues to work to bring cysteamine eyedrops to New Drug Approval by the FDA. 2. The Section has intensified its investigations into alkaptonuria, a disorder of accumulation of homogentisic acid due to deficiency of homogentisate 1,2-dioxygenase. In a pilot study, seven patients achieved a reduction of approximately 95% of their homogentisic acid production by taking 2 mg per day of the drug nitisinone, a powerful inhibitor of the enzyme that produces homogentisic acid. The Section has now initiated a randomized clinical trial of nitisinone in alkaptonuria, using hip range of motion as the primary outcome parameter. An Investigational New Drug (IND) exemption has been granted by the FDA for this study. 3. The Section has become a center for investigating the clinical and basic aspects of Hermansky-Pudlak syndrome (HPS), 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, and the Section has cared for more than 140 affected individuals. In basic studies, members of the Section and their collaborators described abnormal protein trafficking in HPS-1, HPS-2, and HPS-3 melanocytes and an HPS-like disease in mice due to deficiency of a transporter regulating pheomelanin production. The Section also reported a quantitative real-time PCR method to detect hemizygosity in an HPS-1 patient, and demonstrated that the HPS3 protein interacts with clathrin; this important finding explains the function of HPS3 in intracellular trafficking. In clinical studies, the group and colleagues described the first successful lung transplantation in an HPS patient, the specific eye movement abnormalities associated with HPS, and the granulomatous colitis of HPS in relation to particular subtypes. Physicians in the Section have 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 is underway. The group continues to define the natural history of clinical involvement in HPS, and to perform cell biological studies of the movement of intracellular vesicles. 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. 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. Twenty-five patients have been evaluated in this study, and the Section, along with the Office of Rare Diseases, sponsored a workshop on ARPKD/CHF attended by national authorities in the field. 6. A new clinical protocol investigates the natural history of Hutchinson-Gilford Progeria syndrome. To date, 10 patients with this premature aging syndrome have been enrolled, and therapeutic trials are under consideration. 7. Several patients were seen with Chediak-Higashi disease, a disorder of large intracellular granules and a tendency toward fatal infections. The Section described one affected child in detail, identifying the causative mutations in the LYST gene and providing genotype-phenotype correlation.