Human Biochemical Genetics

National Human Genome Research Institute

Investigators

Linked publications & trials

Abstract

The Section on Human Biochemical Genetics studies metabolic and 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 many specific disorders through longitudinal clinical protocols managed by world experts. 1. William Gahl, MD, PhD, continued his 41 years of service to patients with nephropathic cystinosis, a lysosomal storage disease whose basic defect Gahl elucidated in 1982. Gahl evaluated several cystinosis patients this year and provided consultations, presentations, and referrals for U.S. and international patients. He collaborated with Dr. Katharina Hohenfellner to perform statistical analyses demonstrating the direct relationship between early initiation of cysteamine therapy, good adherence to cysteamine treatment, and preservation of renal glomerular function. This collaboration also showed that oral cysteamine therapy begun in the first 2 weeks of life can prevent or attenuate the renal tubular Fanconi syndrome of cystinosis. This milestone finding provides a rationale for instituting molecular-based newborn screening for cystinosis. Lynne Wolfe, NP, investigates Congenital Disorders of Glycosylation (CDGs), multisystemic disorders due to impaired synthesis of glycoproteins. She and her collaborators reported the liver damage associated with CDGs, described the EEG findings of PIGN (a GPI anchor protein disorder of development with congenital anomalies), and reported the clinical, biochemical, and molecular findings of patients with MOGS-CDG (a disorder of hypotonia, dysmorphisms, seizures, and hypogammaglobulinemia due to glucosidase I deficiency). Wendy Introne, MD, manages patients with alkaptonuria, a bone and joint disorder due to accumulation of homogentisic acid (HGA), an intermediate in tyrosine catabolism. This year she compiled data for the FDA demonstrating the drastic reduction in HGA production due to nitisinone, an inhibitor of the enzyme that produces HGA. 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 has collaborated on the delineation of pathogenic variants in the disease-causing gene, LYST. Dr. David Adams continues to provide the albinism community with expertise, advice, and collaboration, investigating the molecular bases of hypopigmentation using the worlds largest collection of albinism-related DNA samples. With his colleagues, he identified disease-causing structural variants in the OCA2 gene using a custom capture sequencing technique. Dr. Juvi Estrada Veras is a former Section member and the world expert in Erdheim-Chester Disease (ECD), a rare histiocytosis with multisystem involvement, largely due to somatic mutations in BRAF. Estrada Veras and colleagues described the issues surrounding living with ECD and provided consultations and advice for ECD patients throughout the world. Dr. Meral Gunay-Aygun, also a former Section member, collaborated to investigate Joubert Syndrome (JS), a rare ciliopathy with abnormal cerebellar development. Her group correlated growth measurements with kidney disease, liver involvement, and genotype in JS patients and documented the clinical findings of 94 patients. 2. The Section also investigates Hermansky-Pudlak syndrome (HPS), comprised of 10 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 demonstrated that endocannabinoid receptor 1 and inducible nitric oxide synthase each promotes HPS pulmonary fibrosis; a dual inhibitor of these two molecules is being studied to prevent or slow the progression of HPS pulmonary fibrosis. Section investigators created a new mouse model of HPS and demonstrated that it exhibits progressive pulmonary fibrosis; this model is being employed to test the inhibitor as treatment and to pursue gene therapy using Adeno Associate Virus vectors. Dr. Gochuico continues to provide advice to HPS physicians, patients, and advocacy groups throughout the world. 3. Drs. Marjan Huizing, Nuria Carrillo, and Francis Rossignol lead studies of GNE myopathy, a late-onset neuromuscular disorder due to biallelic mutations in GNE, which encodes the rate-limiting enzyme in sialic acid biosynthesis. Carrillo and collaborators showed in a clinical trial the safety and efficacy of the sialic acid precursor, N-acetylmannosamine (ManNAc), for patients with GNE myopathy. This modified sugar increased circulating free sialic acid levels, a finding that led to a multicenter, randomized, placebo-controlled, phase 2 clinical trial of ManNAc in GNE myopathy as part of NeuroNext, an NINDS consortium of national neurology centers. Dr. Rossignol leads the NHGRI portion of this trial, which has CRADA support from Leadiant Biosciences, Inc.; he enrolled the first patient in May of 2022. Dr. Huizing is also preparing a clinical protocol to study ManNAc for use in renal glomerular diseases. She and other Section members continue to manage a consortium of approximately 15 international investigators studying Salla Disease, a disorder of defective free sialic acid egress from lysosomes, with support from the advocacy group STAR (Salla Treatment And Research). The group meets twice a year to coordinate research. The Section is also engaged in training an Oxford-Cambridge Program PhD student, Marya Sabir; her thesis involves the natural history and treatment of Salla Disease. 4. Members of the Section lead the NIH Undiagnosed Diseases Program (UDP), which is part 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. Dr. Gahl sits on the UDN Working Group and Dr. Adams co-chairs the UDN Steering Committee. Dr. May Malicdan in the Section manages the UDPs translational research program. This year, she and her colleagues and collaborators described the regulatory function of the FOXR1 gene product for brain development, the mechanism of a CUL3 mutation causing hyperkalemic hypertension through dysregulation of ubiquitin ligase, and the effects on neurodevelopment of a de novo variant in the epilepsy gene NBEA. Dr. Camilo Toro, the UDPs master neurologist, helped to identify a new neurodevelopmental disorder with myoclonus due to de novo CHDDS variants, described the treatment of a patient with osteopetrosis due to an LRP5 mutation, characterized the clinical, genomic, and immunological aspects of African Nodding Disease, and described a new disorder of facial palsy, joint contractures, and peripheral neuropathy due to a TUBB3 mutation. Dr. Toro, with Cynthia Tifft, MD, PhD (Director of the Pediatric UDP), collaborated on a review of GM2 gangliosidosis and, with Changrui Xiao, MD, documented several adult cases of lysosomal storage disorders in the UDP cohort. Thomas Markello, MD, PhD, used UDP data to help create an innovative pedigree-based workflow to analyze rare disease variants. Section members also continue to lead the Undiagnosed Diseases Network International (UDNI), a consortium of physicians and scientists involved in UDPs all over the world. They helped coordinate the 10th UDNI conference in Torino, Italy, and the 11th UDNI conference to be held in Vienna in November of 2022. Dr. Gahl is also working with the UDNI and the Wilhelm Foundation (a rare and undiagnosed diseases advocacy group) to establish a special Champions Initiative that will foster the creation of UDPs in developing nations.