Phenotypic continuum of NFU1-related disorders

Kaiyrzhanov R. Zaki M.S. Lau T. Sen S. Azizimalamiri R. Zamani M. Sayin G.Y. Hilander T. Efthymiou S. Chelban V. Brown R. Thompson K. Scarano M.I. Ganesh J. Koneev K. Gülaçar I.M. Person R. Sadykova D. Maidyrov Y. Seifi T. Zadagali A. Bernard G. Allis K. Elloumi H.Z. Lindy A. Taghiabadi E. Verma S. Logan R. Kirmse B. Bai R. Khalaf S.M. Abdel-Hamid M.S. Sedaghat A. Shariati G. Issa M. Zeighami J. Elbendary H.M. Brown G. Taylor R.W. Galehdari H. Gleeson J.J. Carroll C.J. Cowan J.A. Moreno-De-Luca A. Houlden H. Maroofian R.
December 2022 John Wiley and Sons Inc

Annals of Clinical and Translational Neurology
2022 #9 Issue 12 2025 - 2035 pp.

Bi-allelic variants in Iron–Sulfur Cluster Scaffold (NFU1) have previously been associated with multiple mitochondrial dysfunctions syndrome 1 (MMDS1) characterized by early-onset rapidly fatal leukoencephalopathy. We report 19 affected individuals from 10 independent families with ultra-rare bi-allelic NFU1 missense variants associated with a spectrum of early-onset pure to complex hereditary spastic paraplegia (HSP) phenotype with a longer survival (16/19) on one end and neurodevelopmental delay with severe hypotonia (3/19) on the other. Reversible or irreversible neurological decompensation after a febrile illness was common in the cohort, and there were invariable white matter abnormalities on neuroimaging. The study suggests that MMDS1 and HSP could be the two ends of the NFU1-related phenotypic continuum.

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Department of Neuromuscular Disorders, UCL Queen Square Institute of Neurology, London, WC1N 3BG, United Kingdom
Human Genetics and Genome Research Division, Clinical Genetics Department, National Research Centre, Cairo, Egypt
Department of Chemistry and Biochemistry, The Ohio State University, 100 West 18th Avenue, Columbus, 43210, OH, United States
Department of Paediatric Neurology, Golestan, Medical, Educational, and Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
Department of Biology, Faculty of Science, Shahid Chamran University of Ahvaz, Ahvaz, Iran
Department of Medical Genetics, Istanbul Faculty of Medicine, Istanbul University, Istanbul, 34098, Turkey
Genetics Section, Molecular and Clinical Sciences, St Georges, University of London, London, United Kingdom
Oxford Medical Genetics Laboratories, The Churchill Hospital, Oxford, OX3 7LJ, United Kingdom
Wellcome Centre for Mitochondrial Research, Translational and Clinical Research Institute, Faculty of Medical Sciences Newcastle University, Newcastle upon Tyne, NE2 4HH, United Kingdom
Division of Genetics, Cooper Health System, Childrens Regional Hospital, Sheridan Pavilion Camden, 08103, New Jersy, United States
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, United States
Department of Neurology and Neurosurgery, Asfendiyarov Kazakh National Medical University, Almaty, 050000, Kazakhstan
Department of Genetics, Institute of Graduate Studies in Health Sciences, Istanbul University, Istanbul, 34098, Turkey
GeneDx, Gaithersburg, 20877, MD, United States
Astana Medical University, Nur-Sultan, Kazakhstan
L.N. Gumilyov Eurasian National University, Nur-Sultan, Kazakhstan
Departments of Neurology and Neurosurgery, Pediatrics and Human Genetics, McGill University, Montreal, Canada
Division of Medical Genetics, Department Specialized Medicine, McGill University Health Centre, Montreal, Canada
Child Health and Human Development Program, Research Institute of the McGill University Health Centre, Montreal, Canada
Skin and Stem Cell Research Center, Tehran University of Medical Sciences, Tehran, Iran
Department of Neurology, Emory University School of Medicine, Atlanta, GA, United States
Division of Neurosciences, Childrens Healthcare of Atlanta, Atlanta, GA, United States
Division of Genetics, University of Mississippi Medical Center, Jackson, MS, United States
Pediatrics Department, Assiut University, Assiut, Egypt
Medical Molecular Genetics Department, Human Genetics and Genome Research Institute, National Research Centre, Cairo, Egypt
Health Research Institute, Diabetes Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
Department of Medical Genetics, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
Narges Medical Genetics and Prenatal Diagnosis Laboratory, East Mihan Ave., Kianpars, Ahvaz, Iran
NHS Highly Specialised Service for Rare Mitochondrial Disorders, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, NE1 4LP, United Kingdom
Department of Neurosciences, University of California, San Diego, La Jolla, 92093, CA, United States
Rady Childrens Institute for Genomic Medicine, San Diego, 92025, CA, United States
Department of Radiology, Autism & Developmental Medicine Institute, Genomic Medicine Institute, Geisinger, Danville, 17822, PA, United States

Department of Neuromuscular Disorders
Human Genetics and Genome Research Division
Department of Chemistry and Biochemistry
Department of Paediatric Neurology
Department of Biology
Department of Medical Genetics
Genetics Section
Oxford Medical Genetics Laboratories
Wellcome Centre for Mitochondrial Research
Division of Genetics
Department of Genetics and Genomic Sciences
Department of Neurology and Neurosurgery
Department of Genetics
GeneDx
Astana Medical University
L.N. Gumilyov Eurasian National University
Departments of Neurology and Neurosurgery
Division of Medical Genetics
Child Health and Human Development Program
Skin and Stem Cell Research Center
Department of Neurology
Division of Neurosciences
Division of Genetics
Pediatrics Department
Medical Molecular Genetics Department
Health Research Institute
Department of Medical Genetics
Narges Medical Genetics and Prenatal Diagnosis Laboratory
NHS Highly Specialised Service for Rare Mitochondrial Disorders
Department of Neurosciences
Rady Childrens Institute for Genomic Medicine
Department of Radiology

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