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 rare disease patients. 1. In the past year, the Section followed 40 nephropathic cystinosis patients, addressed international meetings of investigators and advocacy groups, responded to scores of inquiries from throughout the world, and described the skeletal complications of nephropathic cystinosis. The Section also cared for several patients with alkaptonuria, a disorder of accumulation of homogentisic acid due to deficiency of homogentisate 1,2-dioxygenase. Section scientists investigated Chediak-Higashi disease (CHD), a disorder of giant intracellular granules, fatal bacterial infections, and lymphocytic histiocytosis. They determined the basis of impaired lytic granule release from CHD natural killer cells, i.e., an actin cytoskeletal barrier. A Section investigator, the countrys authority on albinism, devised a quantitative grading scale to assess the iris transillumination of albino patients. Yet another Section physician, having evaluated over 60 patients with a rare histiocytosis called Erdheim-Chester Disease, described their MRI and CT imaging findings and reported several cases of interstitial lung disease. Members of the Section continue to evaluate patients with ectopic calcification, including pseudoxanthoma elasticum (PXE, a disease of vascular fragility), and Generalized Calcification of Infancy (GACI, a vascular disorder generally fatal in infancy). They characterized the role of alkaline phosphatase inhibition in preventing calcification in PXE, described hypercementosis in the teeth of GACI patients with ENPP1 mutations, and wrote a review on mechanisms of ectopic calcification. 2. The Section remains the only center in the world investigating the clinical and basic aspects of Hermansky-Pudlak syndrome (HPS), comprised of 10 rare genetic disorders of oculocutaneous albinism and bleeding due to abnormal formation of intracellular vesicles. Types 1, 2, and 4 also have fatal pulmonary fibrosis. This year, Section investigators collaborated on basic studies of the pathogenesis of idiopathic pulmonary fibrosis. One project involved cannabinoid CB1 receptor activity, another investigated interactions between galectin-3 and the CHI3L1 axis, and another pursued the immunone in inherited forms of pulmonary fibrosis. Two other studies dealt with the management of lung transplantation and with the outcome of long-term pirfenidone therapy for HPS pulmonary fibrosis. Members of the Section also described unusual cases of HPS-1 and HPS-6, wrote reviews on HPS for GeneReviews and eLS, and opined on the problem that many HPS patients cannot obtain pirfenidone therapy because it is approved only for idiopathic pulmonary fibrosis. Section experts provide advice to physicians and patients throughout the world and contribute to HPS advocacy group conferences. 3. Research into ciliopathies, i.e., disorders of immotile cilia on cells, continues to be a focus of the Section. Section investigators have examined more than 200 ciliopathy patients to define the natural history and molecular bases of these disorders. For Joubert Syndrome (JS), the group has catalogued the molecular and clinical characteristics of 100 patients, correlated the neuroimaging findings of 110 patients with their cognitive function and genetic mutation, described the neuropsychological phenotypes of 76 affected individuals, reported the ciliogenesis defect in JS due to INPP5E mutations, documented the renal disease associated with JS, and correlated the ophthalmic findings with genetic mutations and hepatorenal disease in 99 patients. For Alstrom Syndrome, Section investigators have characterized the myopathy, auditory findings, and endocrine, renal and metabolic complications of a cohort of 38 patients. The Section remains an international referral center for ciliopathies. 4. Section investigators remain world experts in GNE myopathy, a late-onset neuromuscular disorder of sialic acid metabolism due to biallelic mutations in GNE. GNE encodes the bifunctional enzyme that catalyzes the rate-limiting steps in sialic acid synthesis; deficient sialylation of alpha-dystroglycan causes GNE myopathy. This year, Section members described a method for quantifying terminal sugar residues on muscle biopsies using lectin fluorescence. They also reported the pharmacokinetics of sialic acid generation after oral administration of the sialic acid precursor, N-acetylmannosamine (ManNAc), in patients with GNE myopathy. This work, part of a phase 1-2 clinical trial of ManNAc for GNE myopathy, provides the basis for dosing in a future, pivotal clinical study. That multicenter, placebo-controlled trial has secured funding from NIAMS as part of NeuroNext, an NINDS consortium of neurology centers throughout the country. The trial also has CRADA support from Leadiant Bioscience, Inc., a company that has purchased the license for ManNAc and will soon receive the IND for ManNAc from the Section Head. 5. Collaborations with international investigators have resulted in descriptions of two new diseases. One involves cerebellar ataxia and encephalopathy due to mutations in CoQ5 C-methyltransferase, and the other manifests renal failure due to a monoallelic mutation in glycine aminotransferase. Other shared projects led to reports of cortical atrophy and hypofibrinogenemia in a family with mutations in the FGG and TBCD genes, urine oligosaccharide profiling in a congenital disorder of de-glycosylation (NGLY1 deficiency), oculogyric crisis in a patient with PLA2G6 disease, and abnormal sphingolipid metabolites in patients with impaired serine metabolism. 6. Members of the Section also lead the NIH Undiagnosed Diseases Program (UDP), supported by the NIH Common Fund. This initiative, a model for Precision Medicine, provides answers to patients with mysterious conditions that have eluded diagnosis, and advances medical knowledge. Two Section members sit on the UDN Working Group. The Intramural UDP is part of the Undiagnosed Diseases Network (UDN), a national consortium of 12 clinical sites, a coordinating center, sequencing center, biorepository, two model systems cores, and a metabolomics core. Over the past 10 years, the NIH UDP reviewed over 4000 medical records, evaluated over 1200 patients, and diagnosing over 200 rare and novel disorders. This year, Section members delivered over 20 national and international talks on the UDP, fostered expansion of the Undiagnosed Diseases Network International (UDNI) for sharing phenotypic and sequence data, and organized the 6th international UDNI meeting in Naples. They described separate patients with biallelic glycyl-tRNA synthetase mutations and developmental delays, biallelic mutations in tryptophanyl-tRNA synthetase and infantile parkinsonism, and biallelic mutations in valyl-tRNA synthetase and microcephaly, seizures, and cerebral atrophy. The group also reported a patient with Aicardi-Goutieres Syndrome and atypical brain imaging, another with spermine synthase deficiency causing Snyder-Robinson Syndrome, two children with SPTAN1 mutations causing encephalopathy without epilepsy, a boy with autism spectrum disorder having a de novo ATP1A3 mutation and biallelic mutations in NLRP3, two adults with neurodegeneration and xeroderma pigmentosum due to ERCC4 mutations, and several individuals with developmental neuroregression due to de novo mutations in UBTF. Finally, the Sections UDP leaders wrote reviews on the Italy-US collaboration over rare and undiagnosed diseases, the medical impact of the UDN, the diagnosis and care of rare disease patients in Western Australia, and the role of rare disease therapies in personalized medicine.
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