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. Members of the Section have expertise in several specific disorders. 1. In the past year, the Section evaluated 35 nephropathic cystinosis patients, addressed international meetings of investigators and advocacy groups, responded to inquiries from throughout the world, and described the bone abnormalities of the disease. The Section also cared for patients with alkaptonuria (a connective tissue disorder due to accumulation of homogentisic acid) and Chediak-Higashi disease (a disorder of giant intracellular granules, fatal bacterial infections, and lymphocytic histiocytosis). One Section investigator, an international authority on albinism, reported increased melanin pigment in albinotic individuals with low tyrosinase activity treated with nitisinone, an inhibitor of tyrosine degradation. Other Section members reported the pulmonary complications and dental manifestations of a rare histiocytosis, Erdheim-Chester Disease. The Section continued to evaluate patients with ectopic calcification due to biallelic mutations in ABCC6 causing a disease of vascular fragility (pseudoxanthoma elasticum) or ENPP1, causing fatal vascular stenosis (Generalized Calcification of Infancy). The Section remains an international referral center for individuals with ciliopathies, i.e., disorders of immotile cilia on cells; these include Joubert syndrome, Alstrom syndrome, and polycystic kidney disease. The Section has also begun studying sialic acid storage disorders. 2. The Section remains the worlds foremost center investigating 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. In a major collaboration with NIAAA and NCATS, Section investigators are studying the effects of a molecule that combines inhibition of inducible nitric oxide synthase and antagonism of the endocannabinoid receptor CB1 on an HPS mouse model with pulmonary fibrosis. Section clinicians reported HPS and albinism in several Chinese children, and basic researchers characterized the effects of bleomycin on mouse models of HPS pulmonary fibrosis. Section experts continue to provide advice to physicians and patients throughout the world and contribute to HPS advocacy group conferences. 3. Section investigators remain world experts in GNE myopathy, a late-onset neuromuscular disorder due to biallelic mutations in GNE, which encodes the rate-limiting enzyme in sialic acid biosynthesis. Section members previously reported that the sialic acid precursor, N-acetylmannosamine (ManNAc), treats the sialic acid deficiency of a GNE mouse model. They also demonstrated safety and efficacy of ManNAc in phase I and II studies of patients with GNE myopathy. A member of the Section is now Principal Investigator of a pivotal clinical trial of ManNAc in GNE myopathy to begin October 1, 2019; that multicenter, randomized, placebo-controlled trial is funded by NIAMS as part of NeuroNext, an NINDS consortium of neurology centers throughout the country. The trial also has CRADA support from Leadiant Biosciences, Inc. The Section has published a statistical method of measuring disease progression in GNE myopathy and has proposed the use of ManNAc in renal glomerular disease. 4. Members of the Section also lead the NIH Undiagnosed Diseases Program (UDP), which is part of the Undiagnosed Diseases Network (UDN) supported by the NIH Common Fund. This initiative, a model for Precision Medicine, provides answers to patients with mysterious conditions, and advances medical knowledge. Section members sit on the UDN Working Group, which oversees a national consortium of 12 clinical sites, a coordinating center, sequencing center, biorepository, two model organism cores, and a metabolomics core. Over the past 10 years, the NIH UDP reviewed over 4000 medical records, evaluated over 1300 patients, and diagnosing over 300 rare and novel disorders. The Section contributed to a groundbreaking New England Journal of Medicine article on the impact of a genetic diagnosis upon individuals previously undiagnosed. Section members also demonstrated the value of urinary glycome analysis in reaching a diagnosis, and developed a sophisticated pipeline of automated sequence analysis programs that illustrated the genetic burden carried by UDP probands. Finally, Section members delivered more than 15 national and international talks on the UDP in 2018, wrote a chapter on rare and undiagnosed diseases for Nelsons textbook of pediatrics, fostered expansion of the Undiagnosed Diseases Network International (UDNI) to share phenotypic and sequence data, and organized the 7th international UDNI meeting in Delhi. 5. Evaluating UDP patients has fostered new disease discovery and expansion of known genetic phenotypes. Members of the Section have spearheaded projects that revealed the genetic bases of 6 diseases; 5 investigations were published in the American Journal of Human Genetics in the past year and one in Plos Genetics. Specifically, Saul-Wilson Syndrome was shown to be caused by a monoallelic mutation in COG4, which encodes a protein in the Conserved Oligomeric Golgi complex responsible for retrograde vesicle trafficking within the Golgi. Another study described a new disorder of developmental delay, liver abnormalities, dysmorphic features, and woolly hair associated with biallelic variants in CCDC47. A third new disease, characterized by facial dysmorphisms, congenital heart defects, and neurodevelopmental abnormalities, was associated with biallelic mutations in TMEM94. A fourth disorder described by the Section was a combination of albinism, developmental delay, and organ storage caused by dysfunction of lysosomes and lysosome-related organelles. This occurred because of increased lysosomal acidity created by a gain-of-function mutation in CLCN7, encoding a chloride transporter that determines the influx of protons into lysosomes. Another case involved a boy with kinky hair reminiscent of Menkes disease, a copper deficiency disorder. The child had biallelic mutations in HEPHL1, whose function was determined by the Section to include oxidation of ferrous to ferric iron, allowing this metal to be incorporated into its apoenzymes. Finally, members of the Section described a new disorder of epilepsy, colobomas, dysmorphisms, developmental delay, and cerebellar hypoplasia due to monoallelic mutations in WDR37, which encodes a protein whose WD repeats facilitate the formation of multiprotein complexes. Section members also assisted in the description of a new disease of developmental delay, microcephaly, and brittle nails and hair due to biallelic mutations in cysteinyl tRNA synthetase. They revealed the molecular, clinical, and biochemical bases of SLC25A2 Congenital Disorder of Glycosylation, characterizing 30 previously unreported cases of this disease, and expanded the known phenotypes of COPA syndrome, a pulmonary disorder, and late infantile ceroid lipofuscinosis, a neurodevelopmental disorder due to CLN6 mutations. Section members reported a case of Early Infantile-onset Epileptic Encephalopathy 28 due to deletion of the WWOX gene related to uniparental disomy. One family had motor delays, coloboma and corneal defects associated with a novel TENM3 mutation, and another had dysarthria, ataxia, and sensory neuropathy related to COX20 variants. The Section collaborated with world experts in describing atypical autosomal dominant leukodystrophy due to an upstream deletion of lamin B1; previously reported cases were due to lamin B1 duplications.
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