Clinical and molecular evidence of possible digenic inheritance for MFN2/GDAP1 genes in Charcot-Marie-Tooth disease |
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| Institution: | 1. Human Genetics Department, National Institute of Pediatrics, Mexico City, Mexico;2. Neurology Department, National Institute of Pediatrics, Mexico City, Mexico;3. Genetics Department-Research Unit, Institute of Ophthalmology “Conde de Valenciana”, Mexico City, Mexico;4. Biochemistry Department, Faculty of Medicine, UNAM, Mexico City, Mexico;1. Department of Veterinary Clinical Science, School of Veterinary Medicine and Animal Science, Universidade Estadual Paulista, Botucatu, São Paulo, Brazil. Rua Prof. Dr. Walter Maurício Corrêa, s/n, Botucatu, SP, Brazil;2. School of Veterinary and Animal Science, Universidade Federal de Goiás, Goiânia, Goiás, Brazil. Rodovia Goiânia, km 8 s/n Campus - Samambaia, Goiânia, GO 74001-970, Brazil;3. University Center UNILEAO, Juazeiro do Norte, Ceará, Brazil. Av. Maria Letícia Leite Pereira s/n, Lagoa Seca - Cidade Universitária, Juazeiro do Norte, CE 63040-405, Brazil;4. CALE - Animal Surgery and Specialized Diagnostic Laboratory, Jundiaí, São Paulo, Brazil, Rua Itália, 106 - Jardim Bonfiglioli, Jundiaí, SP 13207-280, Brazil;5. Self-employed Veterinary, Catalão, Goiás, Brazil, Rua Paraná, 330 - Nossa senhora de Fátima, Catalão, GO 75709-240, Brazil;6. School of Veterinary Medicine, Universidade Federal de Uberlândia, Uberlândia, Minas Gerais, Brazil, Av. Mato Grosso, 3289 - Bloco 2S - Umuarama, Uberlândia, MG 38405-314, Brazil;7. Department of Veterinary Clinical Science, School of Veterinary Medicine and Animal Science, Universidade Estadual Paulista, Botucatu, São Paulo, Brazil. Rua Prof. Dr. Walter Maurício Corrêa, s/n, Botucatu, SP 18618-681, Brazil;8. Institute of Biotechnology, Universidade Estadual Paulista, Botucatu, São Paulo, Brazil. Alameda das Tecomarias, s/n - Chácara Capão Bonito, Botucatu, SP 18607-440, Brazil;1. Department of Medicine/Pediatrics, Case Western Reserve University MetroHealth Medical Center, Cleveland, Ohio;2. Division of Hospital Medicine, Department of Medicine, Case Western Reserve University MetroHealth Medical Center, Cleveland, Ohio;1. Dubowitz Neuromuscular Centre, UCL Great Ormond Street Institute of Child Health and Great Ormond Street Hospital for Children, London, UK;2. NIHR Biomedical Research Centre, UCL Great Ormond Street Institute of Child Health and Great Ormond Street Hospital NHS Trust, London, UK;3. Unit of Neuromuscular and Neurodegenerative Disorders, Bambino Gesù Children''s Research Hospital IRCCS, Rome, Italy;4. Dino Ferrari Center, Department of Pathophysiology and Transplantation, University of Milan, Neurology Unit, I.R.C.C.S. Foundation Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy;5. Department of Neuropediatrics and Muscle Disorders, Medical Center-University of Freiburg, Freiburg, Germany;6. Department of Neuropediatrics, University Hospital Bonn, Bonn, Germany;7. Department of Neurology, Medical University of Warsaw, Warsaw, Poland;8. Paediatric Neurology and Nemo Center, Catholic University and Policlinico Gemelli, Rome, Italy;9. Department of Neurology and Neurosurgery, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, the Netherlands;10. Department of Paediatric Physical Medicine and Rehabilitation, Hôpital Femme Mère Enfant, Centre Hospitalier Universitaire de Lyon, France;11. NeuroMyogene Institute, CNRS UMR 5310, INSERM U1217, Université de Lyon, Lyon, France;12. Pharma Development, Safety, F. Hoffmann-La Roche Ltd, Basel, Switzerland;13. Roche Products Limited, Welwyn Garden City, UK;14. Neuroscience Product Development, F. Hoffmann-La Roche Ltd, Basel, Switzerland;15. Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland;1. Pediatric Palliative Care Centre, Department of Pediatrics, University Hospital Carl Gustav Carus, Technische Universität Dresden, Fetscherstr. 74, 01307 Dresden, Germany;2. Department of Pediatrics, University Hospital Carl Gustav Carus, Technische Universität Dresden, Fetscherstr. 74, 01307 Dresden, Germany;3. Friedrich-Baur-Institute, Department of Neurology, Ludwig-Maximilians-University of Munich, Ziemssenstr. 1, 80336 Munich, Germany;4. Social pediatric centre, Stiftung Kreuznacher Diakonie, Ringstraße 58, 55543 Bad Kreuznach, Bad Kreuznach, Germany;5. Department of Neuropediatrics, University Hospital Bonn, Venusberg-Campus 1, 53127 Bonn, Germany;6. Department of Neuropediatrics and Neuromuscular Centre for Children and Adolescents, Children''s Hospital, University of Duisburg-Essen, Hufelandstraße 55, 45147 Essen, Germany;7. Abteilung Neuropädiatrie, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Fetscherstr. 74, 01307 Dresden, Germany |
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| Abstract: | Charcot Marie Tooth disease (CMT) is a progressive motor and sensory polyneuropathy, it is characterized by a very heterogeneous molecular basis and phenotype. MFN2 and GDAP1 participate in mitochondrial energy metabolism and the rare coinheritance of its pathogenic variants has been associated with a cumulative effect in the observed phenotype. We describe a patient with a severe axonal CMT and inherited heterozygous MFN2 (p.Leu741Val) and GDAP1 (p.Gln163*) variants. In accordance with a possible digenic inheritance, none of the heterozygous carriers in his family were symptomatic or exhibited electrophysiological abnormalities. We also review all of the previously reported patients with coinheritance of variants in these two genes; similar to our patient, all exhibit a predominantly axonal severe CMT phenotype. Our findings expand the genotypic spectrum of CMT and further support that digenic inheritance should be considered for analyzing and counseling CMT patients. |
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