Autosomal dominant HK1-related neurodevelopmental disorder with visual defects and brain anomalies (NEDVIBA): An emerging mitochondrial disorder
Purpose: Hexokinase 1 (HK1) encodes a ubiquitously expressed hexokinase, which is responsible for the first step of glycolysis, phosphorylation of glucose to glucose-6-phosphate. Both autosomal recessive and dominant variants in this gene have previously been shown to cause human disease, and presen...
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2025-01-01
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| author | Bobby G. Ng Erik A. Eklund Jill A. Rosenfeld Abdallah F. Elias Aya Abu-El-Haija Celine Bris Magalie Barth Jong-Hee Chae Murim Choi Holly A. Dubbs Carl Fratter Nicola Foulds Candace Gamble Ralitza H. Gavrilova Jaclyn Haven Trevor L. Hoffman Jill V. Hunter Austin Larson Timothy Edward Lotze Pilar Magoulas Emily C. Magness Debra M. Bootin Eric D. Marsh Victoria Nesbitt Matthew T. Pastore Joanna Poulton Shamima Rahman Fernando Scaglia Chaya Murali Jennifer Posey Joshua Rotenberg Betsy Schmalz Deepali N. Shinde Zöe Powis Rivka Sukenik-Halevy Kristen V. Truxal Tami Uster Matheus Vernet Machado Bressan Wilke Erik Klee Hyewon Woo Donald Younkin Jianhua Zhao Jorge Granadillo Seema Lalani David Chitayat Wendy K. Chung Hudson H. Freeze Volkan Okur |
| author_facet | Bobby G. Ng Erik A. Eklund Jill A. Rosenfeld Abdallah F. Elias Aya Abu-El-Haija Celine Bris Magalie Barth Jong-Hee Chae Murim Choi Holly A. Dubbs Carl Fratter Nicola Foulds Candace Gamble Ralitza H. Gavrilova Jaclyn Haven Trevor L. Hoffman Jill V. Hunter Austin Larson Timothy Edward Lotze Pilar Magoulas Emily C. Magness Debra M. Bootin Eric D. Marsh Victoria Nesbitt Matthew T. Pastore Joanna Poulton Shamima Rahman Fernando Scaglia Chaya Murali Jennifer Posey Joshua Rotenberg Betsy Schmalz Deepali N. Shinde Zöe Powis Rivka Sukenik-Halevy Kristen V. Truxal Tami Uster Matheus Vernet Machado Bressan Wilke Erik Klee Hyewon Woo Donald Younkin Jianhua Zhao Jorge Granadillo Seema Lalani David Chitayat Wendy K. Chung Hudson H. Freeze Volkan Okur |
| author_sort | Bobby G. Ng |
| collection | DOAJ |
| description | Purpose: Hexokinase 1 (HK1) encodes a ubiquitously expressed hexokinase, which is responsible for the first step of glycolysis, phosphorylation of glucose to glucose-6-phosphate. Both autosomal recessive and dominant variants in this gene have previously been shown to cause human disease, and presently, there are clinical data available for 27 individuals with the monoallelic neurodevelopmental disorder with visual defects and brain anomalies. Delineation of the entire phenotypic spectrum and genotype-phenotype relations will aid in management and counseling decisions. Methods: We present molecular and clinical data on 22 additional individuals with heterozygous, mostly de novo, variants in HK1. We also reviewed data from the published literature. Results: The clinical manifestations of neurodevelopmental disorder with visual defects and brain anomalies include varying degrees of intellectual disability/developmental delay, hypotonia, epileptic encephalopathy, visual deficits, a Leigh syndrome spectrum pattern on brain magnetic resonance imaging, and elevated lactate in blood and cerebrospinal fluid, suggesting mitochondrial dysfunction. Based on severity, individuals can be classified into mild, moderate, severe, or lethal forms. In terms of genotype-phenotype correlation, we find that all individuals carrying a missense variant at the threonine 457 residue have severe clinical features. Conclusion: HK1 should be included in mitochondrial disorder gene sequencing panels. |
| format | Article |
| id | doaj-art-bb64b0f8ca264e96b65e6cdc89e1e08e |
| institution | OA Journals |
| issn | 2949-7744 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Genetics in Medicine Open |
| spelling | doaj-art-bb64b0f8ca264e96b65e6cdc89e1e08e2025-08-20T02:16:12ZengElsevierGenetics in Medicine Open2949-77442025-01-01310342510.1016/j.gimo.2025.103425Autosomal dominant HK1-related neurodevelopmental disorder with visual defects and brain anomalies (NEDVIBA): An emerging mitochondrial disorderBobby G. Ng0Erik A. Eklund1Jill A. Rosenfeld2Abdallah F. Elias3Aya Abu-El-Haija4Celine Bris5Magalie Barth6Jong-Hee Chae7Murim Choi8Holly A. Dubbs9Carl Fratter10Nicola Foulds11Candace Gamble12Ralitza H. Gavrilova13Jaclyn Haven14Trevor L. Hoffman15Jill V. Hunter16Austin Larson17Timothy Edward Lotze18Pilar Magoulas19Emily C. Magness20Debra M. Bootin21Eric D. Marsh22Victoria Nesbitt23Matthew T. Pastore24Joanna Poulton25Shamima Rahman26Fernando Scaglia27Chaya Murali28Jennifer Posey29Joshua Rotenberg30Betsy Schmalz31Deepali N. Shinde32Zöe Powis33Rivka Sukenik-Halevy34Kristen V. Truxal35Tami Uster36Matheus Vernet Machado Bressan Wilke37Erik Klee38Hyewon Woo39Donald Younkin40Jianhua Zhao41Jorge Granadillo42Seema Lalani43David Chitayat44Wendy K. Chung45Hudson H. Freeze46Volkan Okur47Human Genetics Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CAPediatrics, Clinical Sciences Lund, Lund University, Lund, SwedenBaylor Genetics Laboratories, Houston, TX; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TXDepartment of Medical Genetics, Shodair Children's Hospital, Helena, MTDivision of Genetics and Genomics, Harvard Medical School, Boston, MADepartment of Biochemistry and Genetics, MitoVasc Institute, UMR CNRS 6015-INSERM U1083, Angers, FranceDepartment of Biochemistry and Genetics, Angers University Hospital Center, Angers, FranceDepartment of Genomic Medicine, Seoul National University Hospital, Seoul, Republic of Korea; Department of Pediatrics, Seoul National University College of Medicine, Seoul, Republic of KoreaDepartment of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of KoreaDivision of Neurology, Children’s Hospital of Philadelphia, Philadelphia, PAOxford Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust, Oxford, United KingdomWessex Clinical Genetics Services, University Hospital Southampton NHS Foundation Trust, Southampton, United KingdomCook Children's Clinical Genetics, Fort Worth, TXDepartment of Neurology, Mayo Clinic, Rochester, MNDepartment of Medical Genetics, Shodair Children's Hospital, Helena, MTSouthern California Kaiser Permanente Medical Group, Department of Regional Genetics, Anaheim, CADepartment of Pediatric Radiology, Texas Children’s Hospital, Baylor College of Medicine, Houston, TXDepartment of Pediatrics, Section of Genetics, University of Colorado School of Medicine, Aurora, CODepartment of Molecular and Human Genetics, Baylor College of Medicine, Houston, TXDepartment of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX; Texas Children’s Hospital, Houston, TXDepartment of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX; Texas Children’s Hospital, Houston, TXThe Woman's Hospital of Texas, Houston, TXDivision of Neurology, Children’s Hospital of Philadelphia, Philadelphia, PANHS Highly Specialized Services for Rare Mitochondrial Disorders-Oxford Centre, Oxford University Hospitals NHS Foundation Trust, Oxford, United KingdomDivision of Genetic and Genomic Medicine, Nationwide Children’s Hospital, Columbus, OHNuffield Department of Women's and Reproductive Health, The Women's Centre, University of Oxford, Oxford, United KingdomMitochondrial Research Group, UCL Great Ormond Street Institute of Child Health, London, United Kingdom; Metabolic Unit, Great Ormond Street Hospital for Children NHS Foundation Trust, London, United KingdomDepartment of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX; Texas Children’s Hospital, Houston, TX; Joint BCM-CHUK Center of Medical Genetics, Prince of Wales Hospital, Shatin, Hong Kong SARDepartment of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX; Texas Children’s Hospital, Houston, TXDepartment of Molecular and Human Genetics, Baylor College of Medicine, Houston, TXHouston Specialty Clinic, Houston, TXDivision of Genetic and Genomic Medicine, Nationwide Children’s Hospital, Columbus, OHAmbry Genetics, Aliso Viejo, CAQuest Diagnostics, Marlborough, MAGenetic Institute, Meir Medical Center, Kfar Saba, Israel; School of Medicine, Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv, IsraelDivision of Genetic and Genomic Medicine, Nationwide Children’s Hospital, Columbus, OHDivision of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, CanadaCenter for Individualized Medicine, Mayo Clinic, Rochester, MNCenter for Individualized Medicine, Mayo Clinic, Rochester, MNDepartment of Pediatrics, Chungbuk National University Hospital, Cheongju, Republic of KoreaDivision of Neurology, Children’s Hospital of Philadelphia, Philadelphia, PACancer Metabolism and Microenvironment Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CAGenetics and Genomic Medicine, Washington University School of Medicine, St. Louis Children’s Hospital, St. Louis, MODepartment of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX; Texas Children’s Hospital, Houston, TXDivision of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, CanadaDepartment of Pediatrics, Boston Children’s Hospital and Harvard Medical School, Boston, MA; Correspondence and requests for materials should be addressed to Wendy K. Chung, Harvard Medical School, 300 Longwood Avenue Mailstop #BCH3218, Boston, MA 02115Human Genetics Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA; Hudson H. Freeze, Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037Molecular Diagnostics, New York Genome Center, New York, NY; Volkan Okur, New York Geonome Center, 101 Avenue of the Americas, New York, NY 10013Purpose: Hexokinase 1 (HK1) encodes a ubiquitously expressed hexokinase, which is responsible for the first step of glycolysis, phosphorylation of glucose to glucose-6-phosphate. Both autosomal recessive and dominant variants in this gene have previously been shown to cause human disease, and presently, there are clinical data available for 27 individuals with the monoallelic neurodevelopmental disorder with visual defects and brain anomalies. Delineation of the entire phenotypic spectrum and genotype-phenotype relations will aid in management and counseling decisions. Methods: We present molecular and clinical data on 22 additional individuals with heterozygous, mostly de novo, variants in HK1. We also reviewed data from the published literature. Results: The clinical manifestations of neurodevelopmental disorder with visual defects and brain anomalies include varying degrees of intellectual disability/developmental delay, hypotonia, epileptic encephalopathy, visual deficits, a Leigh syndrome spectrum pattern on brain magnetic resonance imaging, and elevated lactate in blood and cerebrospinal fluid, suggesting mitochondrial dysfunction. Based on severity, individuals can be classified into mild, moderate, severe, or lethal forms. In terms of genotype-phenotype correlation, we find that all individuals carrying a missense variant at the threonine 457 residue have severe clinical features. Conclusion: HK1 should be included in mitochondrial disorder gene sequencing panels.http://www.sciencedirect.com/science/article/pii/S2949774425014645HexokinaseHK1Leigh syndrome spectrumMitochondrial disorderNEDVIBA |
| spellingShingle | Bobby G. Ng Erik A. Eklund Jill A. Rosenfeld Abdallah F. Elias Aya Abu-El-Haija Celine Bris Magalie Barth Jong-Hee Chae Murim Choi Holly A. Dubbs Carl Fratter Nicola Foulds Candace Gamble Ralitza H. Gavrilova Jaclyn Haven Trevor L. Hoffman Jill V. Hunter Austin Larson Timothy Edward Lotze Pilar Magoulas Emily C. Magness Debra M. Bootin Eric D. Marsh Victoria Nesbitt Matthew T. Pastore Joanna Poulton Shamima Rahman Fernando Scaglia Chaya Murali Jennifer Posey Joshua Rotenberg Betsy Schmalz Deepali N. Shinde Zöe Powis Rivka Sukenik-Halevy Kristen V. Truxal Tami Uster Matheus Vernet Machado Bressan Wilke Erik Klee Hyewon Woo Donald Younkin Jianhua Zhao Jorge Granadillo Seema Lalani David Chitayat Wendy K. Chung Hudson H. Freeze Volkan Okur Autosomal dominant HK1-related neurodevelopmental disorder with visual defects and brain anomalies (NEDVIBA): An emerging mitochondrial disorder Genetics in Medicine Open Hexokinase HK1 Leigh syndrome spectrum Mitochondrial disorder NEDVIBA |
| title | Autosomal dominant HK1-related neurodevelopmental disorder with visual defects and brain anomalies (NEDVIBA): An emerging mitochondrial disorder |
| title_full | Autosomal dominant HK1-related neurodevelopmental disorder with visual defects and brain anomalies (NEDVIBA): An emerging mitochondrial disorder |
| title_fullStr | Autosomal dominant HK1-related neurodevelopmental disorder with visual defects and brain anomalies (NEDVIBA): An emerging mitochondrial disorder |
| title_full_unstemmed | Autosomal dominant HK1-related neurodevelopmental disorder with visual defects and brain anomalies (NEDVIBA): An emerging mitochondrial disorder |
| title_short | Autosomal dominant HK1-related neurodevelopmental disorder with visual defects and brain anomalies (NEDVIBA): An emerging mitochondrial disorder |
| title_sort | autosomal dominant hk1 related neurodevelopmental disorder with visual defects and brain anomalies nedviba an emerging mitochondrial disorder |
| topic | Hexokinase HK1 Leigh syndrome spectrum Mitochondrial disorder NEDVIBA |
| url | http://www.sciencedirect.com/science/article/pii/S2949774425014645 |
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