Human Biochemical Genetics

National Human Genome Research Institute

Investigators

Linked publications, trials & patents

Abstract

The Human Biochemical Genetics Section studies genetic diseases to better understand biochemical pathways, care for patients with rare and neglected diseases, and discover new disorders. Our world experts investigate, diagnose, and treat rare disorders via clinical protocols. 1. William Gahl, MD, PhD, continued his 44 years of service to patients with nephropathic cystinosis, a lysosomal storage disease whose basic defect Gahl elucidated in 1982. This year, he evaluated several patients, consulted on U.S. and international cases, and published 3 reviews on the disease, including one with an NHGRI Genetics Fellow and one with postbacc IRTAs. 2. Another protocol investigates Congenital Disorders of Glycosylation (CDGs), i.e., multisystemic disorders due to impaired synthesis of glycoproteins. Lynne Wolfe, CRNP, the Principal Investigator, published papers describing genetic counseling for CDGs, defining the neurodevelopment of individuals with phosphomannomutase deficiency-CDG, and establishing standards for CDG biochemical testing. 3. Wendy Introne, MD, is the world expert in alkaptonuria (AKU), a bone and joint disorder due to accumulation of homogentisic acid (HGA), an intermediate in tyrosine catabolism; she has managed >180 patients. For the past 2 decades, she has worked to demonstrate the safety and efficacy of nitisinone, a drug that we showed lowers HGA production by 95%. Based upon the Section’s clinical data, Dr. Introne demonstrated improvement in patient related outcomes with nitisinone treatment. She then worked with Cycle Pharmaceuticals to apply for New Drug Approval for nitisinone. This involved establishing a CRADA, meeting several times with the FDA, preparing and submitting huge amounts of data, and undergoing a rigorous 7-day FDA site inspection. On June 10, 2025, the FDA approved nitisinone (Harliku), irrevocably improving the future of scores of individuals with this rare disease. 4. 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. Neurological symptoms appear in the second or third decade. Dr. Introne leads a team that created a mouse model of CHD that lacks the Lyst gene and recapitulates the human neurological phenotype. This model can be used to study CHD brain pathology and to test treatments. Dr. Introne also collaborated on a review describing CHD. 5. David Adams, MD, PhD, and Stacie Loftus, PhD, evaluate challenging diagnostic cases within large cohorts of individuals with oculocutaneous albinism (OCA). Both are members of the international ClinGen Variant Expert Panel on albinism. This panel establishes rules and criteria to designate albinism gene variants as benign or pathogenic. This year, they identified complex multi-allele haplotypes in OCA individuals and their impact on gene function. Other research focuses on the development of novel models to assess functional consequences of variants in cell culture. They plan a clinical protocol to evaluate the 30% of persons with albinism whose genetic testing has not revealed a definitive diagnosis. Dr. Loftus has published a review of over 40 genes that, when disrupted, impair melanocyte and melanin function and result in human disease. 6. The Section also investigates Hermansky-Pudlak syndrome (HPS), comprised of 11 genetic disorders with OCA and bleeding due to abnormal formation of intracellular vesicles (e.g., melanosomes in melanocytes and dense bodies in platelets). HPS types 1, 2, and 4 have fatal pulmonary fibrosis. Dr. Introne and Kevin O’Brien, NP, care for HPS patients and work closely with the HPS Network, an advocacy group. Section members have created mouse models of HPS to investigate the delivery of gene therapy and gene editing. This year, they described renal involvement in HPS, showed that Type 2 innate immunity drives HPS pulmonary fibrosis (HPSPF), identified choline, CCL22, and anandamide as biomarkers of HPSPF, and reported on the proteomics of HPS urinary extracellular vesicles. The Section’s HPS clinical team is planning a clinical trial of basimglurant, a glutamate receptor inhibitor with anti-fibrotic properties, for HPSPF. Via a CRADA with CellPhire, May Malicdan, MD, PhD, leads a group testing freeze-dried platelets in HPS mouse models to determine if they reduce bleeding. 7. Marjan Huizing, PhD, and Francis Rossignol, MD, have world class expertise in GNE myopathy, a late-onset neuromuscular disorder due to biallelic mutations in GNE, which encodes the rate-limiting enzyme in sialic acid synthesis. Dr. Rossignol serves as Principal Investigator of a pivotal clinical trial testing the safety and efficacy of the sialic acid precursor, N-acetylmannosamine (ManNAc), for GNE myopathy. This multicenter, randomized, placebo-controlled study is part of NeuroNext, an NINDS consortium of national neurology centers, with funding from NIAMS and CRADA support from Leadiant Biosciences, Inc. The clinical trial visits were completed in June of 2025; NHGRI contributed 18 of the 54 patients. If the ongoing data analysis shows efficacy, Leadiant will apply to the FDA for New Drug Approval of ManNAc for GNE myopathy. Members of the Section also showed that taking ManNAc with food enhanced oral absorption. 8. Another sialic acid initiative involves using ManNAc to treat Focal Segmental Glomerulosclerosis (FSGS), a common cause of kidney failure, since Dr. Huizing has demonstrated hyposialylation of glomerular proteins in these patients. Her preliminary study showed reduction in proteinuria in several patients receiving ManNAc. With two NIDDK nephrologists (Jonathan Bolanos, MD, and Anirban Ganguli, MD), Section members wrote and secured approval of a clinical trial to treat 15 patients with 2g of ManNAc bid for 12 weeks, using reduction in proteinuria as the outcome measure; Dr. Gahl holds the IND. 9. Dr. Huizing created a consortium of 55 investigators from 20 international centers to study Free Sialic Acid Storage Disorders (FSASD), defective in lysosomal sialic acid egress, with support from the advocacy group Salla Treatment and Research (STAR). The Section created a knock-in mouse model and patient-derived iPSC and neural cells to investigate future interventions. Marya Sabir, an Oxford-Cambridge Program PhD Scholar, characterized two of the iPSC lines, analyzed variants in the FSASD causative gene (SLC17A5), elucidated the role of leucocyte sialic acid testing for diagnosis, and described the glycosphingolipid patterns in FSASD plasma, CSF, and iPSC-derived neural cells. Dr. Adams wrote the definitive article on the disease for GeneReviews. 10. The Section made other academic and scientific contributions. Dr. Rossignol wrote articles on phosphoinositide metabolism, congenital dysmorphisms, aminoacidemias and organic acidemias, urea cycle disorders, and glycerophospholipids. Section members worked with Connor Lewis, a postbacc IRTA, to demonstrate the value of differential tractography to follow neurodegeneration. Drs. Adams and Gahl wrote articles on rare and undiagnosed diseases. 11. Section members lead the NIH Undiagnosed Diseases Program (UDP), a signature initiative of the IRP whose contributions are chronicled in Project HG200421 “Undiagnosed Diseases Program.” Drs. Gahl and Adams co-direct the UDP and Dr. Malicdan manages the UDP’s translational research. This past year, Gahl delivered 4 invited national talks on the UDP. 12. For the international rare disease community, Dr. Gahl leads the Undiagnosed Diseases Network International (UDNI), a consortium of ~200 physicians and scientists from 60 nations that he and the Wilhelm Foundation (a rare and undiagnosed diseases advocacy group) established in 2014. Gahl directs the UDNI’s Committees and Working Groups, fosters the Champions Program for the UDNI’s Low and Middle Income Countries, and manages the annual conferences.