The Section on Human Biochemical Genetics studies selected inborn errors of metabolism and other genetic disorders to gain insight into cellular mechanisms and to care for neglected groups of rare disease patients. 1. In the past year, the Section evaluated 40 individuals with nephropathic cystinosis, documenting the beneficial effects of oral and topical cysteamine with respect to growth, renal function, late complications, and ophthalmic abnormalities. They addressed national and international meetings of nephrologists and cystinosis advocacy groups and updated the authoritative review on cystinosis for GeneReviews. The Section serves as an international authority on the disease, responding to scores of inquiries every year from patients and physicians throughout the world. 2. The Section also follows patients with alkaptonuria, a disorder of accumulation of homogentisic acid due to deficiency of homogentisate 1,2-dioxygenase. This year, members of the Section reported a new founder mutation in the causative gene, HGD. 3. The Section remains the only center in the world investigating 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. This year, members reported a novel HPS6 mutation and collaborated on a paper that demonstrated abnormalities in HPS mast cells; the basophilic granules of mast cells are lysosome-like organelles. They also characterized an 11 year-old boy with the extremely rare HPS-7 subtype, and described clinical issues associated with lung transplantation for HPS pulmonary fibrosis. Section experts provide advice to physicians and patients throughout the world and contribute to HPS-related meetings of advocacy groups, scientists, and physicians. 4. An ongoing clinical protocol investigates Autosomal Recessive Polycystic Kidney Disease and Congenital Hepatic Fibrosis (ARPKD/CHF) and other ciliopathies, to define the natural history and molecular bases of these disorders; over 200 such patients have been evaluated in this study. This year, the group described a child with overlapping features of two different ciliopathies, Joubert syndrome and Jeune syndrome, due to mutations in KIAA0586. Another case involved cystic cerebellar dysplasia, obsessive-compulsive behavior, and myopia associated with defects in cell adhesion, impaired cellular migration, and biallelic mutations in LAMA1. Finally, a family with Joubert syndrome and Meckel-Gruber syndrome was described that had undergone gene conversion in TMEM231. Members of the Section 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), a disorder of giant intracellular granules. In the classic disease, affected infants succumb to bacterial infections; survivors later suffer from a lymphocytic histiocytosis that is fatal unless treated with a bone marrow transplant. This year, members of the Section collaborated with NIAID investigators to characterize exocytosis of lytic granules and cytokine secretion in natural killer cells of CHD patients. In an extensive clinical investigation, they also described the neurological complications in patients with mild, atypical CHD. 6. One Section investigator manages a clinical protocol that follows scores of patients with albinism; he serves as the nations authority on this disorder. 7. The Unit on Glycosphingolipid Storage Disorders performs clinical and translational studies on Tay-Sachs and Sandhoff diseases and GM1 gangliosidosis. Using cerebral organoids from patient-derived iPS cells as a model system, the Unit is testing gene therapy and small molecules to mitigate these uniformly fatal lysosomal storage diseases. 8. Section investigators remain world experts in disorders of sialic acid metabolism. The rate-limiting step in sialic acid synthesis is catalyzed by GNE, a bifunctional enzyme. Patients with biallelic GNE mutations develop GNE myopathy, a late-onset neuromuscular disorder due to deficiency of sialic acid and, consequently, impaired sialylation of N-linked glycoproteins; one such protein is alpha-dystroglycan. Members of the Section conduct a natural history study to define the progression of muscle disease in GNE myopathy as a baseline for comparison with therapeutic interventions. A second protocol is a clinical trial. Phase 1b determined the optimal dosing schedule and safety of the sialic acid precursor, N-acetylmannosamine (ManNAc) in humans. The second is a placebo-controlled efficacy and safety study using muscle strength as an outcome measure, and a novel Disease Progression Model for data analysis. This work is being performed in collaboration with the National Center for Advancing Translational Sciences and with a company, Escala; there have been two in-person meetings with the FDA to plan a pivotal registration study. The Section Head holds the Investigational New Drug exemption for ManNAc. 9. Members of the Section also lead the NIH Undiagnosed Diseases Program (UDP), now supported by the Common Fund as a Network of UDPs with 7 Clinical Sites, a Coordinating Center, two Sequencing Centers, a biorepository, a model systems core, and a metabolomics core. This initiative, which serves as a model for Precision Medicine, aims to provide answers to patients with mysterious conditions that have long eluded diagnosis, and to advance medical knowledge. The Intramural UDP, directed by members of the Section, provides guidance to the Undiagnosed Diseases Network (UDN) based upon its 8 years of experience reviewing more than 3500 medical records, evaluating more than 1000 patients, and diagnosing approximately 200 rare and novel disorders. Members of the Section serve as Co-Chair of the UDN Steering Committee, chairs of different working groups, and authors of the Manual of Operations. This past year they delivered more than 15 national and international talks on the UDP, organized two international meetings, and created an Undiagnosed Diseases Network International for sharing phenotypic and sequence data. They also contributed to papers describing patients with Ehlers-Danlos syndrome due to CHST14 mutations, X-linked diabetes insipidus due to a novel splice site mutation in AVPR2, neurodegeneration due to PLA2G6 mutations, protein glycosylation defects due to mutations in ALG1, mitotic intragenic recombination as a survival mechanism for Congenital Disorders of Glycosylation, autosomal dominant intellectual disability due to a translocation disrupting TCF4, and spastic paraplegia associated with mutations in UNC80. Process-related publications described the UDPs database for genotypic and phenotypic information (UDPICS), a new software program that harnesses model organism data to help prioritize candidate gene variants in patients with unique phenotypes, and pharmacogenomic findings in UDP patients. The Sections UDP leaders also wrote reviews on the Program and on the national and international Networks in Molecular Genetics and Metabolism, JAMA, and the Nelson Textbook of Pediatrics. 10. The Section also investigates other rare diseases. This year, they collaborated on a report of thyroxine-binding globulin deficiency due to a SERPINA7 mutation in an Iranian patient, protein losing enteropathy due to DGAT1 mutations, somatic mutations in kinase genes associated with histiocytic neoplasms, treatment of hypophosphatemic rickets in a patient with Generalized Arterial Calcification of Infancy, and Smith-Magenis syndrome due to a de novo mutation in RAI1. Finally, Section investigators described the largest group of patients in the world with mutations in NGLY1.
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