The Section on Human Biochemical Genetics studies selected inborn errors of metabolism and other genetic disorders to provide insight into cellular mechanisms and to 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 wrote a nephrology book chapter on cystinosis and described the craniofacial and dental findings of the disease, collaborated on an investigation of mitochondrial autophagy in cystinotic cells, addressed national meetings of cystinosis advocacy groups, and assisted in the submission of a New Drug Approval application to the FDA for cysteamine eyedrops. 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 continued its investigations into alkaptonuria, a disorder of accumulation of homogentisic acid due to deficiency of homogentisate 1,2-dioxygenase. Members of the group described the mutation spectrum in homogentisic acid oxygenase (HGD), the gene involved in alkaptonuria. Members of the Section are writing a paper on the results of a randomized clinical trial of nitisinone, a powerful inhibitor of the enzyme that produces homogentisic acid, and they continue to provide their expertise for patients and physicians throughout the world. 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 270 affected individuals, members of the Section have determined that the fatal pulmonary fibrosis of HPS occurs only in subtypes 1, 2 and 4. The Sections work has identified novel HPS1 mutations in Puerto Rican, Indian, and African American patients, and has described the clinical characteristics of HPS-6. Members of the group also identified the promoter regions of HPS genes and described abnormal cytokine patterns in HPS alveolar macrophages. Physicians in the group are writing a report on their randomized, placebo-controlled clinical trial of the antifibrotic agent, pirfenidone, to combat the fatal pulmonary fibrosis of HPS. In an ancillary pilot study, patients with severe, fatal pulmonary fibrosis are being treated with a 5-drug regimen in an attempt to arrest their disease;three patients have been enrolled. 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. Finally, members of the Section have written a GeneReviews summary of 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 continue to be sequenced. Members of the Section have also elucidated the proteome of the alpha granules of platelets, and have provided data that demonstrate that Gray Platelet Syndrome platelets have ghost membranes that lack certain endogenously derived proteins. 5. An ongoing clinical protocol investigates Autosomal Recessive Polycystic Kidney Disease and Congenital Hepatic Fibrosis (ARPKD/CHF), along with other ciliopathies, to define the natural history and molecular bases of these disorders. More than 100 patients with ARPKD/CHF and related ciliopathies have been evaluated in this study. The group has published papers describing the radiologic features of ARPKD/CHF, correlations of cyst size and renal function in ARPKD/CHF, MKS3 gene mutations in patients with clinical features of other ciliopathies, and PKHD1 sequence variations in 78 patients with ARPKD/CHF. Members of the Section serve as the nations authorities on the clinical aspects of ARPKD/CHF and other ciliopathies. 6. Members of the Section characterized the oral and craniofacial findings in children with Hutchinson-Gilford Progeria Syndrome. 7. 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 described paternal heterodisomy in one affected child, as well as classical CHD in an African American infant. They have also identified a novel deletion in the RAB27A gene resulting in Griscelli Syndrome type 2. 8. Section investigators have contributed to the description of a new genetic disorder of epilepsy, ataxia, sensorineural deafness and renal tubulopathy due to mutations in KCNJ10, to the use of glyceryl triacetate for Canavans disease, to the mitochondrial localization of the OPA3 protein in cells of patients with 3-methylglutaconic aciduria, to the use of gene therapy with GNE delivered by Lipoplex particles for Hereditary Inclusion Body Myopathy, to the demonstration that polyphosphates within platelet dense granules promote inflammation and coagulation, and to the discovery that secreted RAB27B, small GTPase associated with vesicle membranes, promotes breast cancer cell invasion. 9. In collaboration with the Office of Rare Disease Research and the NIH Clinical Center, the Section has spearheaded a new NIH 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 3400 inquiries and 1200 sets of medical records from throughout the country. The Program has accepted more than 330 patients and admitted approximately 220, providing state-of-the-art clinical investigations in every case, and solving approximately 30 diagnostic dilemmas. One new disease has been discovered, involving arterial joint calcifications due to deficiency of the vascular endothelial cell enzyme that converts AMP to adenosine and inorganic phosphate. This disease reveals the critical role of adenosine in inhibiting default calcification in vascular cells.
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