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 evaluated and cared for 40 nephropathic cystinosis patients, addressed international meetings of investigators and advocacy groups, and responded to scores of inquiries from throughout the world. The Section also followed 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 evaluated the neurological complications of several patients with mild, atypical CHD. Another Section investigator serves as the countrys authority on albinism, and devised a quantitative grading scale to assess the iris transillumination of albino patients. Yet another Section physician performed and published a comprehensive, prospective natural history study of over 60 patients with Erdheim-Chester Disease, a rare histiocytosis. Members of the Section have now evaluated many patients with ectopic calcification, including Arterial Calcification due to Deficiency of CD73 (ACDC, a disorder of late onset vascular calcification), pseudoxanthoma elasticum (PXE, a disease of vascular fragility), and Generalized Calcification of Infancy (GACI, a vascular disorder generally fatal in infancy). With NHLBI investigators, they demonstrated the role of cellular alkaline phosphatase in promoting the ectopic calcification of ACDC, and they helped elucidate the role of ATP metabolism in PXE. Members of the Section described two patients with platelet alpha-delta storage pool deficiency due to mutations in GFI1B; one patient had a de novo pathogenic variant and the other had biallelic hypomorphic mutations. The Unit on Glycosphingolipid Storage Disorders performs translational studies on Tay-Sachs and Sandhoff diseases and GM1 gangliosidosis. Using cerebral organoids from patient-derived iPS cells, the Unit is testing gene therapy and small molecules to treat these fatal lysosomal storage diseases. 2. The Section remains the only center in the world investigating the clinical and basic aspects of Hermansky-Pudlak syndrome (HPS), a group of 10 rare genetic disorders characterized by oculocutaneous albinism and bleeding due to abnormal formation of intracellular vesicles, including melanosomes in melanocytes and dense bodies in platelets. Types 1, 2, and 4 also have fatal pulmonary fibrosis. This year, members reported mast cell abnormalities in HPS type 1 patients and their possible role in causing pulmonary fibrosis. They also characterized the cellular abnormalities in a HPS-5, demonstrated increased cannabinoid CB1 receptor activity in HPS cells, and wrote a summary of HPS molecular genetics and the definitive online review of HPS. Section experts provide advice to physicians and patients throughout the world and contribute to HPS advocacy group meetings. 3. Autosomal Recessive Polycystic Kidney Disease and Congenital Hepatic Fibrosis (ARPKD/CHF), Joubert Syndrome (JS), and Alstrom Syndrome are ciliopathies, i.e., disorders of the immotile cilia on cells. Section investigators have examined more than 200 ciliopathy patients to define the natural history and molecular bases of these disorders. For JS, the group correlated neuroimaging, molecular defects, and cognitive function in 110 patients and described abnormal glycosylation in JS type 10. They reported mutations in CELSR2, a cell polarity gene, in a JS patient with cortical heterotopia, microophthalmia, and growth hormone deficiency. They identified KIAA0753 mutations in JS patients with growth hormone deficiency, and characterized defective cilia formation in a JS patient with INPP5E mutations. Finally, they summarized the clinical and molecular results on 100 JS patients and the neuropsychological findings of 76 JS patients. For Alstrom Syndrome, Section physicians described the respiratory complications, cardiomyopathy, and auditory profile of 38 individuals in separate publications. The Section is 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, encoding the bifunctional enzyme that catalyzes the rate-limiting steps in sialic acid synthesis; deficient sialylation of alpha-dystroglycan causes GNE myopathy. Section members identified siblings with mutations in the promoter region of GNE, and also conducted a phase 1-2 clinical trial of N-acetylmannosamine (ManNAc), a sialic acid precursor, in patients, showing safety and favorable pharmacokinetics. A pivotal, multicenter, placebo-controlled trial of ManNAc now has IRB approval and funding from the NINDS consortium of neurology centers, NeuroNext; muscle strength and performance are outcome measures. The Section Head holds the IND for ManNAc. 5. In collaborations with Israeli investigators, the Section has described TIMM50 mutations in a family with mitochondrial encephalopathy, seizures, complex V deficiency, and 3-methylglutaconic aciduria. They described progressive leukoencephalopathy and developmental delays in 7 children with biallelic mutations in PLAA, encoding the phospholipase A2-activating protein. A third paper reported a new type of hyperphenylalaninemia associated with dystonia and intellectual disability in 6 individuals from 4 unrelated families with biallelic mutations in DNAJC12, encoding a heat-shock chaperone protein that interacts with the tetrahydrobiopterin-dependent enzymes, phenylalanine, tyrosine, and tryptophan hydroxylase. Finally, Section members and collaborators reported impaired mitochondrial movement and fatal encephalopathy in 6 individuals with homozygous mutations in TRAK1, encoding kinesin proteins essential for mitochondrial trafficking in neurons. 6. Members of the Section also lead the NIH Undiagnosed Diseases Program (UDP), 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, a model for Precision Medicine, provides answers to patients with mysterious conditions that have eluded diagnosis, and advances medical knowledge. The Intramural UDP, directed by members of the Section, provides guidance to the Undiagnosed Diseases Network (UDN) based upon its 9 years of experience reviewing over 4000 medical records, evaluating over 1100 patients, and diagnosing over 200 rare and novel disorders. A member of the Section is Co-Chair of the UDN Steering Committee and chair of a UDN working group. This year, Section members delivered over 20 national and international talks on the UDP, created an Undiagnosed Diseases Network International (UDNI) for sharing phenotypic and sequence data, and organized an international UDNI meeting. They described patients with early-onset dystonia and monoallelic mutations in the histone methyltransferase gene KMT2B, infantile cirrhosis and developmental abnormalities due to compound heterozygous mutations in PP1R15B encoding a protein phosphatase 1 subunit, impaired neurodevelopment due to de novo mutations in EBF3, seizures, encephalopathy, and neuromuscular disease due to biallelic mutations in SCN110A, abnormal bone development associated with a dominant ATP6V1H mutation, Aicardi-Goutieres syndrome due to homozygous mutations in RNASEH2B, and developmental delays related to biallelic mutations in GARS, encoding a tRNA synthetase. The Sections UDP leaders also wrote reviews on the UDNI, with collaborators from Western Australias UDP.
| El-Chemaly, Souheil; Cheung, Foo; Kotliarov, Yuri et al. (2018) The Immunome in Two Inherited Forms of Pulmonary Fibrosis. Front Immunol 9:76 |
| O'Brien, Kevin J; Gahl, William A; Gochuico, Bernadette R (2018) The curse of idiopathic. J Inherit Metab Dis 41:3-4 |
| Florenzano, Pablo; Ferreira, Carlos; Nesterova, Galina et al. (2018) Skeletal Consequences of Nephropathic Cystinosis. J Bone Miner Res 33:1870-1880 |
| Reichold, Markus; Klootwijk, Enriko D; Reinders, Joerg et al. (2018) Glycine Amidinotransferase (GATM), Renal Fanconi Syndrome, and Kidney Failure. J Am Soc Nephrol 29:1849-1858 |
| Zhou, Yang; He, Chuan Hua; Yang, Daniel S et al. (2018) Galectin-3 Interacts with the CHI3L1 Axis and Contributes to Hermansky-Pudlak Syndrome Lung Disease. J Immunol 200:2140-2153 |
| Klein, Christoph; Gahl, William A (2018) Patients with rare diseases: from therapeutic orphans to pioneers of personalized treatments. EMBO Mol Med 10:1-3 |
| Gil-Krzewska, Aleksandra; Saeed, Mezida B; Oszmiana, Anna et al. (2018) An actin cytoskeletal barrier inhibits lytic granule release from natural killer cells in patients with Chediak-Higashi syndrome. J Allergy Clin Immunol 142:914-927.e6 |
| Thumbigere-Math, V; Alqadi, A; Chalmers, N I et al. (2018) Hypercementosis Associated with ENPP1 Mutations and GACI. J Dent Res 97:432-441 |
| Burke, E A; Frucht, S J; Thompson, K et al. (2018) Biallelic mutations in mitochondrial tryptophanyl-tRNA synthetase cause Levodopa-responsive infantile-onset Parkinsonism. Clin Genet 93:712-718 |
| Hall, Patricia L; Lam, Christina; Alexander, John J et al. (2018) Urine oligosaccharide screening by MALDI-TOF for the identification of NGLY1 deficiency. Mol Genet Metab 124:82-86 |
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