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. In the past year, members of the Section admitted approximately 60 individuals with nephropathic cystinosis to the NIH Clinical Research Center, largely as outpatients, documenting the beneficial effects of oral cysteamine therapy with respect to growth, renal function, late complications, and ophthalmic abnormalities. In addition, they wrote authoritative reviews on cystinosis, and addressed national and international meetings of pediatric nephrologists and cystinosis advocacy groups. The Section continues to serve as an international authority on the disease, responding to scores of inquiries 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 are writing a clinical protocol for the use of nitisinone, a powerful inhibitor of the enzyme that produces homogentisic acid, and 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. In the past year, members of the Section identified the specific domains of the HPS-1 and HPS-4 proteins that interact with each other to form Biogenesis of Lysosome-related Organelles Complex-3, which functions in the trafficking of intracellular vesicles. They collaborated with European investigators to demonstrate the risk of hemophagocytic lymphohistiocytosis in HPS-2 patients, and described elevated levels of galectin-3 in HPS patients with pulmonary fibrosis. 4. 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 200 patients with ARPKD/CHF and related ciliopathies, now including Alstrom syndrome, have been evaluated in this study. This year, the group wrote the definitive review on Congenital Hepatic Fibrosis, and they continue to serve as the nations authorities on the clinical aspects of ARPKD/CHF and other ciliopathies. 5. Section scientists continue to investigate Chediak-Higashi disease (CHD), recently showing that electron microscopy of platelet dense bodies reflects the efficacy of bone marrow transplantation in this disease. 6. One Section investigator manages a clinical protocol that follows scores of patients with various subtypes of albinism. This year, he provided the authoritative listing of all known mutations causing oculocutaneous albinism, and he serves as the nations authority on this disorder. 7. Section investigators have become world experts in sialic acid synthesis, whose rate-limiting step is catalyzed by GNE, a bifunctional enzyme encoded by the gene GNE. Patients with biallelic GNE mutations develop GNE myopathy, a late-onset neuromuscular disorder. This past year, members of the Section reported elevated glycosphingolipids in cells of GNE myopathy patients, described a new biomarker for the disease based upon hyposialylation of a circulating glycoprotein, established new nomenclature for the disease, and tabulated all the known mutations causing GNE myopathy. 8. Members of the Section also lead the NIH Undiagnosed Diseases Program (UDP), now supported by the Common Fund as a Network of UDPs with 6 Clinical Sites, a Coordinating Center, and two Sequencing Centers. 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. The NIH Intramural Research Programs UDP, located within the Section on Human Biochemical Genetics, is providing guidance to the Undiagnosed Diseases Network (UDN) based upon its 6 years of experience handling more than 9500 inquiries and 3300 medical records from throughout the country and the world. The UDP uses next-generation genetic techniques and serves as a model for bringing personalized medicine to rare disease patients. The Program has accepted more than 800 patients and admitted over 700, providing state-of-the-art clinical investigations in every case, and solving approximately 150 diagnostic dilemmas, most of which represent extremely rare disorders. UDP investigators have also identified candidate genes for approximately 50 new diseases, and are pursuing the basic defects via cellular and biochemical studies. In the past year, publications emanating from the UDP include descriptions of an LMNB1 duplication causing Autosomal Dominant Leukodystrophy, Kearns-Sayre syndrome with isolated growth failure, C19orf12 mutations causing Hereditary Spastic Paraplegia Type 43, a rare case of amyloid myopathy, nephrolithiasis due to defective vitamin D 24-hydroxylase, early-onset myopathy, areflexia, respiratory distress and dysphagia (EMARDD) diagnosed through SNP and exome sequence analysis, GRIN2A mutations causing epileptic encephalopathy treatable with memantine, somatic activating mutations in HRAS and NRAS causing cutaneous and skeletal lesions, hypophosphatemia, and elevated FGF23, the extremely rare occurrence of three disorders in one family (phosphoenolpyruvate carboxykinase deficiency, Smith-Magenis Syndrome, and NMDA receptor glutamate insensitivity due to GRIN2B mutations), and spastic paraplegias due to SPG11 and SPG15. The UDP has also published on the systematic identification of well-characterized exons, cultural differences between the United States and China in the investigation of undiagnosed diseases, and the frequency of incidental findings in NIH UDP patients. UDP leaders have written an editorial on the importance of studying rare diseases and have delivered 25 lectures and seminars on the UDP throughout the world. Section members have contracted for gene function studies of newly identified variants associated with new diseases, have established a training course for the analysis of SNP array and exome sequencing results, and have organized an international conference on rare and undiagnosed diseases. 9. Miscellaneous pursuits of the Section include description of a clinical phenotype due to interaction of a protein, SATB2, with the UPF3B gene, presentation of PET images of a patient with Erdheim-Chester disease, and reporting of novel OPA3 mutations in siblings with 3-methylglutaconic aciduria type III. Section scientists also collaborated on the identification of two new diseases. They characterized a new congenital neutrophil defect syndrome due to biallelic mutations in VPS45, which regulates membrane trafficking through the endosomal system. They also discovered a new type of renal Fanconi Syndrome due to interference with mitochondrial function caused by mistargeting of the peroxisomal protein EHHADH.
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