دورية أكاديمية
RTN2 deficiency results in an autosomal recessive distal motor neuropathy with lower limb spasticity.
| العنوان: | RTN2 deficiency results in an autosomal recessive distal motor neuropathy with lower limb spasticity. |
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| المؤلفون: | Maroofian R; Centre for Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London WC1N 3BG, UK., Sarraf P; Department of Neuromuscular Diseases, Iranian Centre of Neurological Research, Neuroscience Institute, Tehran University of Medical Sciences, Tehran 1416753955, Iran.; Department of Neurology, Imam Khomeini Hospital Complex, Tehran University of Medical Sciences, Tehran 1416753955, Iran., O'Brien TJ; Institute of Clinical Sciences, Imperial College London, London SW7 2AZ, UK.; MRC Laboratory of Medical Sciences, London W12 0HS, UK., Kamel M; Department of Pediatrics, Neurology and Metabolic Division, Kasr Alainy Faculty of Medicine, Cairo University, Cairo 4240310, Egypt., Cakar A; Centre for Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London WC1N 3BG, UK.; Neuromuscular Unit, Istanbul Faculty of Medicine, Istanbul University, Istanbul 34093, Turkey., Elkhateeb N; Department of Clinical Genetics, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, UK., Lau T; Centre for Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London WC1N 3BG, UK., Patil SJ; Division of Medical Genetics, Mazumdar Shaw Medical Center, Narayana Hrudayalaya Hospital, Bangalore 560099, India., Record CJ; Centre for Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London WC1N 3BG, UK., Horga A; Centre for Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London WC1N 3BG, UK., Essid M; LR18SP04, Department of Child and Adolescent Neurology, National Institute Mongi Ben Hmida of Neurology, University of Tunis El Manar, Tunis, 1007, Tunisia., Selim L; Department of Pediatrics, Neurology and Metabolic Division, Kasr Alainy Faculty of Medicine, Cairo University, Cairo 4240310, Egypt., Benrhouma H; LR18SP04, Department of Child and Adolescent Neurology, National Institute Mongi Ben Hmida of Neurology, University of Tunis El Manar, Tunis, 1007, Tunisia., Ben Younes T; LR18SP04, Department of Child and Adolescent Neurology, National Institute Mongi Ben Hmida of Neurology, University of Tunis El Manar, Tunis, 1007, Tunisia., Zifarelli G; CENTOGENE GmbH, Rostock 18055, Germany., Pagnamenta AT; NIHR Oxford Biomedical Research Centre, Centre for Human Genetics, University of Oxford, Oxford OX3 9DU, UK., Bauer P; CENTOGENE GmbH, Rostock 18055, Germany., Khundadze M; Institute of Human Genetics, Jena University Hospital, Friedrich Schiller University, Jena 07747, Germany., Mirecki A; Institute of Human Genetics, Jena University Hospital, Friedrich Schiller University, Jena 07747, Germany., Kamel SM; Department of Radiology, Cairo University, Cairo 12613, Egypt., Elmonem MA; Department of Clinical and Chemical Pathology, Kasr Alainy Faculty of Medicine, Cairo University, Cairo 12613, Egypt., Ghayoor Karimiani E; Molecular and Clinical Sciences Institute, St. George's, University of London, London SW17 0RE, UK.; Innovative Medical Research Center, Mashhad Branch, Islamic Azad University, Mashhad 9187147578, Iran., Jamshidi Y; Molecular and Clinical Sciences Institute, St. George's, University of London, London SW17 0RE, UK., Offiah AC; Division of Clinical Medicine, School of Medicine & Population Health, University of Sheffield, Sheffield S10 2RX, UK., Rossor AM; Centre for Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London WC1N 3BG, UK., Youssef-Turki IB; LR18SP04, Department of Child and Adolescent Neurology, National Institute Mongi Ben Hmida of Neurology, University of Tunis El Manar, Tunis, 1007, Tunisia., Hübner CA; Institute of Human Genetics, Jena University Hospital, Friedrich Schiller University, Jena 07747, Germany.; Center for Rare Diseases, Jena University Hospital, Friedrich Schiller Universität, Jena 07747, Germany., Munot P; Dubowitz Neuromuscular Centre, Great Ormond Street Hospital NHS Trust, London WC1N 3JH, UK., Reilly MM; Centre for Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London WC1N 3BG, UK., Brown AEX; Institute of Clinical Sciences, Imperial College London, London SW7 2AZ, UK.; MRC Laboratory of Medical Sciences, London W12 0HS, UK., Nagy S; Centre for Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London WC1N 3BG, UK.; Department of Neurology, University Hospital Basel, University of Basel, Basel 4031, Switzerland., Houlden H; Centre for Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London WC1N 3BG, UK. |
| المصدر: | Brain : a journal of neurology [Brain] 2024 Jul 05; Vol. 147 (7), pp. 2334-2343. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: Oxford University Press Country of Publication: England NLM ID: 0372537 Publication Model: Print Cited Medium: Internet ISSN: 1460-2156 (Electronic) Linking ISSN: 00068950 NLM ISO Abbreviation: Brain Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: Oxford : Oxford University Press Original Publication: London. |
| مواضيع طبية MeSH: | Pedigree*, Humans ; Male ; Female ; Child ; Adult ; Adolescent ; Young Adult ; Middle Aged ; Animals ; Lower Extremity/physiopathology ; Caenorhabditis elegans ; Muscle Spasticity/genetics ; Muscle Spasticity/physiopathology ; Spastic Paraplegia, Hereditary/genetics ; Spastic Paraplegia, Hereditary/physiopathology ; Mutation |
| مستخلص: | Heterozygous RTN2 variants have been previously identified in a limited cohort of families affected by autosomal dominant spastic paraplegia (SPG12-OMIM:604805) with a variable age of onset. Nevertheless, the definitive validity of SPG12 remains to be confidently confirmed due to the scarcity of supporting evidence. In this study, we identified and validated seven novel or ultra-rare homozygous loss-of-function RTN2 variants in 14 individuals from seven consanguineous families with distal hereditary motor neuropathy (dHMN) using exome, genome and Sanger sequencing coupled with deep-phenotyping. All affected individuals (seven males and seven females, aged 9-50 years) exhibited weakness in the distal upper and lower limbs, lower limb spasticity and hyperreflexia, with onset in the first decade of life. Nerve conduction studies revealed axonal motor neuropathy with neurogenic changes in the electromyography. Despite a slowly progressive disease course, all patients remained ambulatory over a mean disease duration of 19.71 ± 13.70 years. Characterization of Caenorhabditis elegans RTN2 homologous loss-of-function variants demonstrated morphological and behavioural differences compared with the parental strain. Treatment of the mutant with an endoplasmic/sarcoplasmic reticulum Ca2+ reuptake inhibitor (2,5-di-tert-butylhydroquinone) rescued key phenotypic differences, suggesting a potential therapeutic benefit for RTN2-disorder. Despite RTN2 being an endoplasmic reticulum (ER)-resident membrane shaping protein, our analysis of patient fibroblast cells did not find significant alterations in ER structure or the response to ER stress. Our findings delineate a distinct form of autosomal recessive dHMN with pyramidal features associated with RTN2 deficiency. This phenotype shares similarities with SIGMAR1-related dHMN and Silver-like syndromes, providing valuable insights into the clinical spectrum and potential therapeutic strategies for RTN2-related dHMN. (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.) |
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| معلومات مُعتمدة: | Michael J Fox Foundation for Parkinson's Research; Charcot-Marie-Tooth Association; Multiple System Atrophy Trust; National Institute for Health Research; HU 800/15-1 Deutsche Forschungsgemeinschaft; MC-A658-5TY30 United Kingdom WT_ Wellcome Trust; MDA510281 Muscular Dystrophy Association; Sparks; Brain Research UK; Great Ormond Street Hospital Charity; International ERC_ European Research Council; U54NS065712 United States NS NINDS NIH HHS; United Kingdom BB_ Biotechnology and Biological Sciences Research Council; 714853 Horizon 2020; UCLH Biomedical Research Centre; Ataxia UK; United Kingdom WT_ Wellcome Trust; MR/S005021/1 United Kingdom MRC_ Medical Research Council; Alzheimer's Research UK; DAAD; Rosetrees Trust |
| فهرسة مساهمة: | Keywords: dHMN; hereditary spastic paraplegia; neurodegeneration; polyneuropathy |
| تواريخ الأحداث: | Date Created: 20240325 Date Completed: 20240705 Latest Revision: 20240707 |
| رمز التحديث: | 20240707 |
| مُعرف محوري في PubMed: | PMC11224604 |
| DOI: | 10.1093/brain/awae091 |
| PMID: | 38527963 |
| قاعدة البيانات: | MEDLINE |
Full Text Finder | تدمد: | 1460-2156 |
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| DOI: | 10.1093/brain/awae091 |