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 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. In addition, they collaborated on publications describing the use of a sedoheptulose assay for cystinosis newborn screening, the genetic basis of cystinosis in Turkish patients, and on the toxic side effects of oral cysteamine therapy. They also wrote the definitive review on cystinosis for GeneReviews, addressed national meetings of cystinosis advocacy groups, and continued to assist the National Eye Institute in the provision of cysteamine eyedrops to the cystinosis community. 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 Section published an article on the results of a randomized clinical trial of nitisinone, a powerful inhibitor of the enzyme that produces homogentisic acid, showing safety and biochemical, but not clinical, efficacy. They are involved in plans for a second international trial of nitisinone dealing with prophylaxis, and continue to provide their expertise for patients and physicians throughout the world. As evidence, they wrote the most authoritative review on alkaptonuria for GeneReviews. 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 were 8 genetic subtypes of this disease, but members of the Section reported a ninth subtype in a single male infant due to bi-allelic mutations in the gene pallidin. The gene product encodes a component of a protein complex responsible for intracellular vesicle formation. Members of the Section also collaborated on papers describing the importance of HPS subtyping, novel HPS1 mutations in Puerto Rican patients, and the clinical and molecular manifestations of HPS in non-Puerto Rican Hispanic individuals. Having studied approximately 300 HPS patients, physicians in the group described a scoring system for assessing the pulmonary fibrosis of HPS using high-resolution CT scans, and reported on their randomized, placebo-controlled clinical trial of the antifibrotic agent, pirfenidone, showing safety but not efficacy in combating the fatal pulmonary fibrosis of HPS. One member of the group treats patients with severe, fatal pulmonary fibrosis using a 5-drug regimen in an attempt to arrest their disease;three patients have been enrolled. Section investigators continue to pursue the etiology of the lung fibrosis of HPS, through studies of cytokine markers and surface glycoproteins (MCP1, MUC-1, and galectin-3) in blood and pulmonary lavage fluid. They also described alveolar epithelial cell dysfunction in an HPS mouse model, and pulmonary fibrosis in two non-HPS patients with telomerase mutations. 4. Gray Platelet Syndrome (GPS) is a disorder in which platelet alpha granules are absent and patients suffer from a bleeding diathesis. The Section followed up its GPS mapping study by identifying the causative gene, NBEAL2, involved in the biogenesis of platelet alpha granules. Members of the Section also published the normal alpha granule proteome and the differences manifested by Gray Platelet Syndrome platelets. 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. Approximately 200 patients with ARPKD/CHF and related ciliopathies have been evaluated in this study. The group recently published papers describing liver and pancreas involvement in the X-linked ciliopathy, Oral-Facial-Digital syndrome, and hepatic fibrosis in Autosomal Dominant Polycystic Kidney Disease. Members of the Section serve as the nations authorities on the clinical aspects of ARPKD/CHF and other ciliopathies. 6. Investigators within the Section characterized the otologic and audiologic manifestations of Hutchinson-Gilford Progeria Syndrome. 7. Section scientists continue to investigate disorders of vesicle formation and trafficking such as Chediak-Higashi disease (CHD) and Griscelli syndrome, providing molecular diagnoses for patients throughout the world and investigating atypical, mildly affected individuals with the neurological manifestations of CHD. 8. One Section investigator has established a clinical protocol following scores of patients with various subtypes of albinism. The clinical and molecular investigations provided by this study make him the United States authority on this disorder. In related studies, scientists in the Section have used homozygosity mapping and whole exome sequencing to identify mutations in two genes (SLC45A2 and G6PC3) in a single patient with consanguineous parents. They also showed that nitisinone improves ocular and skin pigmentation abnormalities in a mouse model of oculocutaneous albinism, paving the way for possible treatment in humans. 9. Section investigators and collaborators have reported that glyceryl triacetate improves the phenotype of a mouse model of Canavan disease and has been used safely in humans, that the LPHN3 gene is associated with susceptibility to ADHD, and that the PTPRF gene is disrupted in amastia. They have described a mouse model of Lowe syndrome/Dent disease renal tubulopathy and have performed extensive molecular analysis of the RAI1 gene in Smith-Magenis syndrome patients. 10. In collaboration with the Office of Rare Diseases Research and the NIH Clinical Center, Members of the Section lead the NIH Undiagnosed Diseases Program (UDP). 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 5500 inquiries and 2000 sets of medical records from throughout the country. The Program has accepted more than 450 patients and admitted over 380, providing state-of-the-art clinical investigations in every case, and solving approximately 70 diagnostic dilemmas. UDP investigators have described a new disorder, Arterial Calcifications due to CD73 Deficiency (ACDC), resulting from NT5E mutations, and have also reported the associated vascular pathology. They have discovered a second new disease, an autosomal dominant myopathy due to a specific gene defect, and have published papers on ultra-rare diseases such as infantile-onset Spinal Muscular Atrophy with Respiratory Distress type 1 and a spastic ataxia-neuropathy syndrome due to AFG3L2 mutations. The Program uses next-generation genetic techniques and serves as a model for bringing personalized medicine to rare disease patients. Section leaders have published a review of the Programs first two years accomplishments, and a Commentary in front-line journals.
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