Human Biochemical Genetics

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The Section on Human Biochemical Genetics studies inborn errors of metabolism and other genetic disorders to gain insight into cellular mechanisms and to care for neglected rare disease patients. 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 nephropathic cystinosis, providing consultations to patients, physicians, and advocacy groups throughout the world. Dr. Gahl helped formulate an international consensus statement on the management of cystinotic bone disease and contributed to new insights into the role of FGF23 in the regulation of bone mineralization in cystinosis. He also collaborated on the first newborn screening program for cystinosis in the world, conducted in Germany. Dr. Wendy Introne cared for patients with alkaptonuria (a connective tissue disorder due to accumulation of homogentisic acid), describing impaired aortic distensibility and thyroid function. Dr. Introne is also an international authority on Chediak-Higashi disease (CHD), a disorder of giant intracellular granules, fatal bacterial infections, and lymphocytic histiocytosis. She described the neuropsychological aspects of CHD, wrote a definitive review, and contributed to the creation of 4 CHD induced pluripotent stem cell lines. Dr. David Adams continued to serve the albinism community by providing expertise, advice, and collaborations. Dr. Juvi Estrada Veras, a Special Volunteer and former Section member, reported the neurological, oral, thyroid, and adrenal manifestations of a rare histiocytosis called Erdheim-Chester Disease. Dr. Meral Gunay-Aygun, a Special Volunteer, analyzed ciliopathy data that she had collected over the past decade as a member of the Section. Ciliopathies, disorders of immotile cilia on cells, include Joubert Syndrome (JS), Alstrom syndrome, and polycystic kidney diseases. Dr. Gunay and colleagues discovered a genetic modifier of JS (barttin) using a mouse model and rescued the ciliary protein defect of JS cells using exon skipping. They described the organ-specific manifestations of ciliopathies, wrote the definitive review on Alstrom Syndrome, and provided management recommendations for JS. Dr. Carlos Ferreira, now in the Physician Scientist Development Program, initiated a clinical protocol to study ENPP1 enzyme replacement therapy in individuals with deficiency of that enzyme; the associated disorders include Generalized Arterial Calcification of Infancy (often fatal in the neonatal period) and Autosomal Recessive Hypophosphatemic Rickets type 2. 2. Congenital Disorders of Glycosylation (CDGs) are biochemical defects that result in abnormal glycosylation of proteins. By virtue of the Sections involvement in a CDG Consortium, its close interactions with the NIH Undiagnosed Diseases Program (UDP), and the interest of Lynne Wolfe, PNP, Section members have collaborated to describe 30 patients with mutations in SLC25A2, which encodes a UDP-galactose transporter. With NIAID scientists, they reported glycosylation defects in X-linked Immunodeficiency with Magnesium Defect (XMEN) disease due to mutations in MAGT1, a magnesium transporter required for enzymes that synthesize activated glycan precursors. Other CDGs result from defects in phosphatidylinositol glycans, which form GPI anchors on the surface of cells. Section members collaborated to report patients with a PIGM protomer mutation and neurological findings, GPI anchor deficiency due to ARV1 mutations, and 40 patients with PIGA mutations. Lynne Wolfe helped describe individuals with carbomoylphosphate synthetase 2 deficiency who may benefit from supplementation with uridine and Dr. Carlos Ferreira described the clinical characteristics of Saul-Wilson Syndrome, whose glycoprotein defects result from morphological abnormalities in the Golgi network due to mutations in COG4 (Component of Oligomeric Golgi Complex 4). 3. 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. Dr. Bernadette Gochuico leads a collaboration with NIAAA and NCATS investigating a molecule that combines inhibition of inducible nitric oxide synthase and antagonism of the endocannabinoid receptor CB1 to treat HPS pulmonary fibrosis. Using mouse models developed by Dr. May Malicdan, Section collaborators demonstrated that the fibrosis-inducing drug bleomycin also causes drug efflux from lung cells. Dr. Marjan Huizing, along with May Malicdan, wrote reviews on the mutations causing HPS, and Section clinicians provided advice to HPS physicians, patients and advocacy groups throughout the world. 4. Drs. Huizing and Nuria Carrillo, with collaborators, developed an LC-MS/MS method to measure cytidine-5-monophospho-N-acetylneuraminic acid in human leukocytes and demonstrated increased plasma sialic acid levels due to reduced kidney function in humans. Huizing and Section investigators established a working group 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). A major thrust of the Section involves GNE myopathy, a late-onset neuromuscular disorder due to biallelic mutations in GNE, which encodes the rate-limiting enzyme in sialic acid biosynthesis. Dr. Carrillo initiated a multicenter, randomized, placebo-controlled clinical trial of the sialic acid precursor, N-acetylmannosamine (ManNAc) in GNE myopathy as part of NeuroNext, an NINDS consortium of neurology centers throughout the country. The trial has CRADA support from Leadiant Biosciences, Inc., and will start in the fall of 2020. This year, Dr. Huizing described the rationale for using ManNAc in renal glomerular diseases. 5. Members of the Section also lead the NIH UDP, which is part of the Undiagnosed Diseases Network (UDN) supported by the NIH Common Fund. The UDN, a model for Precision Medicine, strives to diagnose patients with mysterious conditions and to discover 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. In the past year, the Section has helped the UDP develop a powerful sequence analysis pipeline, enhance ontological vocabularies for craniofacial and oral phenotypes, document the unique contributions of the UDN to the biomedical sciences, identify clinical terms using machine learning, and describe new diagnostic approaches to rare undiagnosed diseases. International contributions included a call to action for rare diseases in Africa, a plea for open science in the investigation of rare diseases, and the 5-year follow-up on the Undiagnosed Diseases Network International (UDNI), established by the UDP in 2014. In 2020, Section members organized the 8th international UDNI meeting in Nijmegen, the Netherlands. Dr. Malicdan has spearheaded the translational research performed within the Section on UDP patients. She and her colleagues and collaborators have described a developmental disorder due to mutations in ypel3, renal and craniofacial abnormalities associated with deficiency of the adaptor protein PHETA1/2, and syndromic hearing loss due to deletion of SLC12A2. Other Section investigators have published cases of hypomagnesemia due to deletion of HNF1B, chronic panencephalitis due to dengue virus, developmental impairment due to ARH3 mutations, atypical Waardenburg syndrome due to a novel SOX10 mutation, clinical characteristics of KMT2B-related disorders, and cognitive change related to an extremely rare disorder called Facial Onset Sensory and Motor Neuropathy.