Human Biochemical Genetics

National Human Genome Research Institute

Investigators

Linked publications & trials

Abstract

The Section on Human Biochemical Genetics studies genetic diseases to better understand biochemical pathways and to care for patients with rare and neglected diseases. The Section pursues these goals by investigating, diagnosing, and treating several disorders through clinical protocols managed by world experts. 1. William Gahl, MD, PhD, continued his 42 years of service to patients with nephropathic cystinosis, a lysosomal storage disease whose basic defect Gahl elucidated in 1982. This year, he evaluated several cystinosis patients, consulted on U.S. and international patients, and presented extensively at the Cystinosis Research Networks conference. His collaborative work showing preservation of glomerular and tubular function by early oral cysteamine therapy was published this year, along with elucidation of the role of FGF23 in hyperphosphatemia. Another Section protocol investigates Congenital Disorders of Glycosylation (CDGs, i.e., multisystemic disorders due to impaired synthesis of glycoproteins), with Lynne Wolfe, CRNP, as principal investigator. This year, she and her collaborators described genotype/phenotype correlations in Fryns syndrome due to biallelic mutations in PIGN (a GPI anchor protein) and reported specific lipid elevations in CDGs. Wendy Introne, MD, manages the Sections patients with alkaptonuria, a bone and joint disorder due to accumulation of homogentisic acid (HGA), an intermediate in tyrosine catabolism. She has enrolled >100 patients in her clinical protocol and is pursuing New Drug Approval by the FDA for nitisinone, a drug that we demonstrated lowers HGA production by 95%. Dr. Introne is also an international authority on Chediak-Higashi disease (CHD), a disorder of giant intracellular granules, fatal bacterial infections, and lymphocytic histiocytosis due to biallelic mutations in the LYST gene. In the past year, Dr. Introne and colleagues pursued the mechanism of neurological impairment in CHD, demonstrating defective autophagic lysosome reformation in CHD neurons. They also advanced CHD molecular diagnostics by using cDNA sequencing and wrote a review on the disease. Dr. Introne has continued the Sections studies of Smith-Magenis syndrome, describing Birt-Hogg-Dube syndrome in a patient. David Adams, MD, PhD, continues to provide the albinism community with expertise and advice, bolstered by the transfer of Stacie Loftus, PhD, to the Section from Dr. Pavans lab. They reported the cause of missing heritability in a large number of oculocutaneous albinism (OCA) type 1B patients. Adams and NEI collaborators also employed artificial intelligence to evaluate visual acuity in patients with foveal hypoplasia. Bernadette Gochuico, MD, a pulmonologist in the Section, and collaborators described structural and functional pulmonary abnormalities in osteogenesis imperfecta and cystic lung disease in Proteus Syndrome. 2. The Section also investigates Hermansky-Pudlak syndrome (HPS), comprised of 11 genetic disorders with OCA and bleeding due to abnormal formation of intracellular vesicles. Types 1, 2, and 4 have fatal pulmonary fibrosis. Before Dr. Gochuico, left the NIH and transferred her HPS clinical protocol to Dr. Introne, she and colleagues described the Sections pursuit of gene therapy for HPS pulmonary fibrosis and reported increased cell motility in HPS lung fibroblasts due to dysregulated myosin. Dr. Gochuico also collaborated with extramural researchers to elucidate elements of abnormal immunity and inflammation in HPS-1. Other Section members reported a unique, disease-causing deletion in the HPS3 gene and wrote online reviews on HPS for GeneReviews and for the National Organization for Rare Disorders (NORD). Section members continue to work with NIAAA scientists on a dual inhibitor of endocannabinoid receptor 1 and inducible nitric oxide synthase that can potentially slow the progression of HPS pulmonary fibrosis. Members of the Section continue to care for HPS patients in association with the HPS Network. 3. The Section has a longstanding interest in sialic acid disorders. One such disease is GNE myopathy, a late-onset neuromuscular disorder due to biallelic mutations in GNE, which encodes the rate-limiting enzyme in sialic acid synthesis. Francis Rossignol, MD, is principal investigator of a pivotal clinical trial testing the safety and efficacy of the sialic acid precursor, N-acetylmannosamine (ManNAc), for patients with GNE myopathy. This multicenter, randomized, placebo-controlled study is part of NeuroNext, an NINDS consortium of national neurology centers, with CRADA support from Leadiant Biosciences, Inc. In May of 2023, he completed enrollment of the NHGRI contingent of 18 patients. Marjan Huizing, PhD, and other Section members are now preparing a clinical protocol to study ManNAc in renal glomerular diseases. Section members also investigate various aspects of Free Sialic Acid Storage Disorders (FSASD) and have created a consortium of 18 international investigators studying disorders of sialic acid egress from lysosomes, with support from the advocacy group STAR (Salla Treatment And Research). The consortium meets regularly to coordinate research and includes an Oxford-Cambridge Program PhD student, Marya Sabir. In 2023, Dr. Huizing wrote an online review of FSASD for NORD. 4. Section members lead the NIH Undiagnosed Diseases Program (UDP), the founding member of the Undiagnosed Diseases Network (UDN), a national consortium of 12 clinical sites and supporting cores. The UDP investigates patients with mysterious conditions, making diagnoses and describing new disorders and disease mechanisms. Drs. Gahl and Adams co-direct the UDP and May Malicdan, MD, PhD, manages the UDPs translational research program. This year, she and her colleagues and collaborators discovered a new neurodevelopmental disease due to biallelic mutations in ATG4D and a new disorder of spasticity and neuroregression associated with generalized splicing defects resulting from SNAPC4 loss-of-function variants. Dr. Malicdan also reported a unique, atypical presentation of a tubulinopathy due to a TUBB4B mutation. Camilo Toro, MD, is the master neurologist who directs the adult portion of the UDP. This year, he collaborated with Section, IRP, and extramural investigators to describe the molecular basis of ROSAH syndrome (gain-of-function ALPK1 variants), publish a broad characterization of African Nodding Syndrome, report a de novo HK1 (hexokinase 1) variant as a cause of Boucher-Neuhauser syndrome, describe a myopathy due to a splice variant in MYH2, write an article on pituitary hypersecretion due to-loss of-function PAM variants, and summarize the genetic bases of UDP patients with intracerebral calcifications. Section and UDP investigators collaborated with immunologists to describe a new autoinflammatory disease due to pathogenic variants in STAT4. Other Section members reported the mechanism of haploinsufficiency of KMT5B in impairing murine and human neurodevelopment. 5. For the international rare disease community, Dr. Gahl leads the Undiagnosed Diseases Network International (UDNI), a consortium of >130 physicians and scientists from >40 nations; with the Wilhelm Foundation (a rare and undiagnosed diseases advocacy group), he established the UDNI in 2014. In 2022, Gahl coordinated the 11th UDNI conference in Vienna, established a Champions Initiative to foster UDPs in developing nations, and published papers on the value of clinical networks for rare diseases and the unmet needs of undiagnosed patients in various countries. With colleagues, he wrote articles on the UDN, insights gleaned from the UDP, and the relationship between the UDNI and a new journal entitled Rare. Gahl also delivered 7 invited national and international talks, including the Roscoe Brady Award lecture for WORLDSymposium.