Human Biochemical Genetics

National Human Genome Research Institute

Investigators

Linked publications, trials & patents

Abstract

Members of the Section on Human Biochemical Genetics study rare metabolic diseases and other genetic disorders to better understand biochemical pathways and to care for patients with rare and neglected diseases. The Section pursues these goals in various ways. 1. Section experts investigate, diagnose, and treat many specific disorders. In the past year, the Section continued its 40 years of service to patients with nephropathic cystinosis, a lysosomal storage disease whose basic defect Dr. Gahl elucidated in 1982. Gahl provides consultations, presentations, and referrals for US and international patients and promotes newborn screening for cystinosis based upon a collaboration with a program conducted in Germany. Dr. Wendy Introne manages patients with alkaptonuria, a bone and joint disorder due to accumulation of homogentisic acid, an intermediate in the metabolism of tyrosine. She published a definitive editorial on a related disorder within the tyrosine degradative pathway, i.e., hereditary tyrosinemia type I. Dr. Introne is also an international authority on Chediak-Higashi disease (CHD), a disorder of giant intracellular granules, fatal bacterial infections, and lymphocytic histiocytosis. In the past year, Dr. Introne reported the diagnosis of CHD in a 67 year-old woman, by far the oldest person known with this disease. Dr. David Adams continues to serve the albinism community by providing expertise, advice, and collaboration. His group studies the molecular causes of albinism not attributable to known albinism genes, performing in-depth analyses of the worlds largest collection of albinism-related DNA samples. This past year, they defined a structural variant in the OCA2 gene explaining a significant number of previously unsolved cases of albinism. Dr. Juvi Estrada Veras, a Special Volunteer and former Section member, reported abnormalities in the hypothalamic-pituitary-adrenal axis, as well as hypothyroidism, in patients with a rare histiocytosis called Erdheim-Chester Disease (ECD). This year, he and his colleagues described the pituitary imaging and endocrine disorders in ECD. Dr. Meral Gunay-Aygun, also a Special Volunteer and former Section member, collaborated with other Clinical Center physicians to catalog the renal and hepatic involvement of patients with Autosomal Recessive Polycystic Kidney Disease and Congenital Hepatic Fibrosis. Dr. Carlos Ferreira, now in NHGRIs Physician Scientist Development Program, worked with Section investigators to study Generalized Arterial Calcification of Infancy (often fatal in the neonatal period) and Autosomal Recessive Hypophosphatemic Rickets type 2 (ARHR2), due to deficiency of the ectonucleotide pyrophosphatase ENPP1. GACI can also be caused by biallelic mutations in the transporter ABCC6, which is generally associated with pseudoxanthoma elasticum. Ferreiras group reported the long-term effects of GACI on survivors of the neonatal, vascular complications of the disease. They also described the spectrum of disease associated with the GACI/ARHR2 phenotype. 2. The Section also investigates 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 have fatal pulmonary fibrosis. This year, Dr. Bernadette Gochuico and collaborators in NIAAA and NCATS published in vitro and animal model evidence that combined inhibition of inducible nitric oxide synthase and antagonism of the endocannabinoid receptor CB1 can attenuate the pulmonary fibrosis of HPS. The Sections HPS group described the inflammatory bowel disease of HPS, based upon patients seen at the NIH Clinical Center under Dr. Gochuicos HPS natural history protocol. They continue to pursue gene therapy for HPS, and Section clinicians continue to provide advice to HPS physicians, patients, and advocacy groups throughout the world. Dr. Gochuico also published a CT image of pulmonary fibrosis for physicians. 3. Drs. Marjan Huizing, Nuria Carrillo, and Francis Rossignol lead the Sections efforts involving GNE myopathy, a late-onset neuromuscular disorder due to biallelic mutations in GNE, which encodes the rate-limiting enzyme in sialic acid biosynthesis. With Clinical Center collaborators, the group has developed MRI biomarkers of skeletal muscle integrity in GNE patients and has demonstrated increased plasma free sialic acid in individuals with decreased renal function. Dr. Carrillo and NIH collaborators showed that the sialic acid precursor, N-acetylmannosamine (ManNAc), safely increased circulating free sialic acid levels in GNE myopathy patients. Dr. Carrillo also initiated a multicenter, randomized, placebo-controlled, open-label phase 2 clinical trial of ManNAc in GNE myopathy as part of NeuroNext, an NINDS consortium of neurology centers throughout the country. Dr. Rossignol now leads the NHGRI portion of this trial, which has CRADA support from Leadiant Biosciences, Inc. Although Covid has delayed progress, the start of the trial is imminent. Dr. Huizing and Section investigators have also established a consortium to study Salla Disease, a disorder of defective free sialic acid egress from lysosomes, with support from the advocacy group STAR (Salla Treatment And Research). This year, the group published a review of the disease and future plans to investigate its pathobiology and treatment. Dr. Huizing is also planning to study ManNAc for use in renal glomerular diseases. 5. Members of the Section lead the NIH UDP, which is part of the Undiagnosed Diseases Network (UDN) supported by the NIH Common Fund. The UDP investigates patients with mysterious conditions, making diagnoses and describing new disorders and disease mechanisms. Dr. Gahl sits on the UDN Working Group and Dr. Adams co-chairs the Steering Committee of the UDN, a national consortium of 12 clinical sites and supporting cores. This year, Section members assisted in an exposition of the unique contributions of the UDN to science and genetics, and Dr. Gahl spearheaded the publication of a list of medicines essential for rare disease patients throughout the world. Section members continue to provide leadership for the UDN International (UDNI), a consortium of physicians and scientists involved in UDPs all over the world. Section members assisted in coordinating the 9th UDNI conference at the Mayo Clinic and helped the UDNI establish a Working Group for Developing Nations and a Diagnostic Working Group to assist undiagnosed patients obtain consultations and referrals. Dr. May Malicdan in the Section manages the UDPs translational research program. This year, she and her colleagues and collaborators described abnormal transmembrane domain recognition due to GET4 mutations, splicing defects in electron transport chain complex I genes causing mild Leigh syndrome, specific PRUNE1 variants as the cause of a neurodevelopmental disorder with microcephaly, hypotonia and variable brain anomalies (NMIHBA), myoclonic epilepsy due to compound heterozygous variants in KCTD7, and a new autosomal dominant neurological disease of ether lipid synthesis due to de novo variants in FAR1. Dr. Camilo Toro, the UDPs master neurologist, collaborated with Section members to publish a series of patients with KMT2B variants that expands the phenotype and demonstrates the efficacy of deep brain stimulation. Toro and colleagues also described a treatable neuropathy caused by a serine biosynthesis defect, as well as uniparental isodisomy of chromosome 1 causing early-onset Parkinsons disease due to mutations in PARK7. Finally, Section and UDP investigators contributed to the discovery of a new adult-onset autoinflammatory disease called VEXAS and due to X-linked somatic mutations in UBA1.