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Lessard LER, Girard E, Streichenberger N, Petiot P, Acquaviva C, Pagan C, Mulligan P, Bouhour F, Schaeffer L, Jacquier A. Mitochondrial disorders are associated with morphological neuromuscular junction defects. Neuromuscul Disord 2024; 45:105235. [PMID: 39509867 DOI: 10.1016/j.nmd.2024.105235] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2024] [Revised: 10/20/2024] [Accepted: 10/24/2024] [Indexed: 11/15/2024]
Abstract
We aimed to evaluate whether inherited mitochondrial dysfunction is associated with neuromuscular junction remodeling in patients with mitochondrial disorders. Muscle biopsies from 15 patients with mitochondrial disorders and 10 control patients were analyzed through immunostaining for various neuromuscular junction components. The patient group, with a mean age of 49.9 years, exhibited various mitochondrial disorders including chronic progressive external ophthalmoplegia, Kearns-Sayre syndrome, and mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes. Patients with mitochondrial disorders had a high percentage of remodeled (p= 0.0001), neoformed (p= 0.0049) and dilated (p= 0.016) endplates. There was a trend toward an increased proportion of neuromuscular junctions with terminal Schwann cell extension in these patients (p= 0.052). No significant difference was found in myofiber diameter between the groups. The observed neuromuscular junction defects varied widely across different mitochondrial disorder phenotypes and were present even without accompanying muscle weakness or neuropathy. This suggest that mitochondrial disorders are associated with a primary NMJ remodeling independent of muscle structural damage. Pathomechanisms underpinning this remodeling of the neuromuscular junction, as well as clinical factors predictive of this remodeling, remain to be fully characterized.
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Affiliation(s)
- Lola E R Lessard
- Service d'Electroneuromyographie et de pathologies neuromusculaires, Hôpital Neurologique Pierre Wertheimer, Hospices Civils de Lyon, France; INMG-PGNM, UMR CNRS 5261 - INSERM U1315, Université Lyon 1, Lyon, France
| | - Emmanuelle Girard
- INMG-PGNM, UMR CNRS 5261 - INSERM U1315, Université Lyon 1, Lyon, France; Plateforme ANIPHY, UAR CNRS 3453, Inserm US7, Université Lyon 1, SFR Santé Lyon-Est, Lyon, France
| | - Nathalie Streichenberger
- INMG-PGNM, UMR CNRS 5261 - INSERM U1315, Université Lyon 1, Lyon, France; Département d'Anatomo-Pathologie, Groupement Hospitalier Est, Hospices Civils de Lyon, Lyon, France
| | - Philippe Petiot
- Service d'Electroneuromyographie et de pathologies neuromusculaires, Hôpital Neurologique Pierre Wertheimer, Hospices Civils de Lyon, France
| | - Cécile Acquaviva
- Service de Biochimie et Biologie Moléculaire - Unité Pathologies Héréditaires du Métabolisme, Hospices Civils De Lyon, Lyon, France
| | - Cécile Pagan
- Service de Biochimie et Biologie Moléculaire - Unité Pathologies Héréditaires du Métabolisme, Hospices Civils De Lyon, Lyon, France
| | - Peter Mulligan
- INMG-PGNM, UMR CNRS 5261 - INSERM U1315, Université Lyon 1, Lyon, France
| | - Françoise Bouhour
- Service d'Electroneuromyographie et de pathologies neuromusculaires, Hôpital Neurologique Pierre Wertheimer, Hospices Civils de Lyon, France; INMG-PGNM, UMR CNRS 5261 - INSERM U1315, Université Lyon 1, Lyon, France
| | - Laurent Schaeffer
- INMG-PGNM, UMR CNRS 5261 - INSERM U1315, Université Lyon 1, Lyon, France; Centre de Biotechnologie Cellulaire, Hospices Civils De Lyon, Lyon, France.
| | - Arnaud Jacquier
- INMG-PGNM, UMR CNRS 5261 - INSERM U1315, Université Lyon 1, Lyon, France; Centre de Biotechnologie Cellulaire, Hospices Civils De Lyon, Lyon, France
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O'Connor K, Spendiff S, Lochmüller H, Horvath R. Mitochondrial Mutations Can Alter Neuromuscular Transmission in Congenital Myasthenic Syndrome and Mitochondrial Disease. Int J Mol Sci 2023; 24:ijms24108505. [PMID: 37239850 DOI: 10.3390/ijms24108505] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2023] [Revised: 04/28/2023] [Accepted: 05/02/2023] [Indexed: 05/28/2023] Open
Abstract
Congenital myasthenic syndromes (CMS) are a group of rare, neuromuscular disorders that usually present in childhood or infancy. While the phenotypic presentation of these disorders is diverse, the unifying feature is a pathomechanism that disrupts neuromuscular transmission. Recently, two mitochondrial genes-SLC25A1 and TEFM-have been reported in patients with suspected CMS, prompting a discussion about the role of mitochondria at the neuromuscular junction (NMJ). Mitochondrial disease and CMS can present with similar symptoms, and potentially one in four patients with mitochondrial myopathy exhibit NMJ defects. This review highlights research indicating the prominent roles of mitochondria at both the pre- and postsynapse, demonstrating the potential for mitochondrial involvement in neuromuscular transmission defects. We propose the establishment of a novel subcategorization for CMS-mitochondrial CMS, due to unifying clinical features and the potential for mitochondrial defects to impede transmission at the pre- and postsynapse. Finally, we highlight the potential of targeting the neuromuscular transmission in mitochondrial disease to improve patient outcomes.
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Affiliation(s)
- Kaela O'Connor
- Children's Hospital of Eastern Ontario Research Institute, Ottawa, ON K1H 8L1, Canada
- Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada
- Centre for Neuromuscular Disease, University of Ottawa Brain and Mind Research Institute, Ottawa, ON K1H 8M5, Canada
| | - Sally Spendiff
- Children's Hospital of Eastern Ontario Research Institute, Ottawa, ON K1H 8L1, Canada
| | - Hanns Lochmüller
- Children's Hospital of Eastern Ontario Research Institute, Ottawa, ON K1H 8L1, Canada
- Division of Neurology, Department of Medicine, The Ottawa Hospital, Ottawa, ON K1H 8L6, Canada
- Brain and Mind Research Institute, University of Ottawa, Ottawa, ON K1H 8M5, Canada
- Department of Neuropediatrics and Muscle Disorders, Faculty of Medicine, Medical Center-University of Freiburg, 79104 Freiburg, Germany
- Centro Nacional de Análisis Genómico (CNAG-CRG), Center for Genomic Regulation, Barcelona Institute of Science and Technology (BIST), 08028 Barcelona, Catalonia, Spain
| | - Rita Horvath
- Department of Clinical Neurosciences, University of Cambridge, Cambridge CB3 0FD, UK
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Murata D, Grunseich C, Iijima M, Chan D, Corse A, Hoke A, Schindler A, Sesaki H, Roda RH. A Heterozygous Mutation in MFF Associated with a Mild Mitochondrial Phenotype. J Neuromuscul Dis 2023; 10:107-118. [PMID: 36314214 DOI: 10.3233/jnd-221532] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
BACKGROUND The number of mutations in nuclear encoded genes causing mitochondrial disease is ever increasing. Identification of these mutations is particularly important in the diagnosis of neuromuscular disorders as their presentation may mimic other acquired disorders.We present a novel heterozygous variant in mitochondrial fission factor (MFF) which mimics myasthenia gravis. OBJECTIVE To determine if the MFF c.937G>A, p.E313K variant causes a mild mitochondrial phenotype. METHODS We used whole exome sequencing (WES) to identify a novel heterozygous variant in MFF in a patient with ptosis, fatigue and muscle weakness. Using patient derived fibroblasts, we performed assays to evaluate mitochondrial and peroxisome dynamics. RESULTS We show that fibroblasts derived from this patient are defective in mitochondrial fission, despite normal recruitment of Drp1 to the mitochondria. CONCLUSIONS The MFF c.937G>A, p.E313K variant leads to a mild mitochondrial phenotype and is associated with defective mitochondrial fission in patient-derived fibroblasts.
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Affiliation(s)
- Daisuke Murata
- Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Christopher Grunseich
- National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA
| | - Miho Iijima
- Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - David Chan
- Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA
| | - Andrea Corse
- Neuromuscular Medicine, Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Ahmet Hoke
- Neuromuscular Medicine, Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Alice Schindler
- National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA
| | - Hiromi Sesaki
- Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Ricardo H Roda
- Neuromuscular Medicine, Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
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Nagaoka A, Tsujino A, Shiraishi H, Kanamoto T, Shima T, Yoshimura S, Miyazaki T, Tateishi Y, Tsujihata M, Motomura M, Maxwell S, Higuchi O, Beeson D, Vincent A. Motor end-plate analysis to diagnose immune-mediated myasthenia gravis in seronegative patients. J Neurol Sci 2022; 443:120494. [PMID: 36403297 DOI: 10.1016/j.jns.2022.120494] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2022] [Revised: 11/08/2022] [Accepted: 11/10/2022] [Indexed: 11/16/2022]
Abstract
This study aimed to evaluate the diagnostic usefulness of motor end-plate (MEP) analysis along with clustered acetylcholine receptor (AChR) antibody (Ab) assays in patients with myasthenia-like symptoms but negative routine AChR and muscle-specific kinase (MuSK) Ab tests. MEP analysis of muscle biopsies of the biceps brachii was performed in 20 patients to try to differentiate between those with or without immune-mediated myasthenia gravis (MG). Using a quantitative method, complement C3 deposition and AChR densities in MEPs were examined. Independently, cell-based assays were used to detect serum clustered-AChR Abs. Only five of 20 patients had complement deposition at MEPs; four of these patients had reduced AChR densities similar to those in patients with typical AChR Ab positive MG, and distinct from those in the remaining 15 patients. Two of the four serum samples from these patients had clustered-AChR Abs. All complement-positive patients were considered as having immune-mediated MG and improved with appropriate treatments; although one patient presented with MG 3 years later, the remaining patients had other diagnoses during over 10 years of follow-up. These results suggest the usefulness of MEP analysis of muscle biopsies in diagnosing immune-mediated MG in seronegative patients with myasthenia-like symptoms but, due to the invasiveness of the muscle biopsy procedure, clustered AChR Abs should, if possible, be tested first.
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Affiliation(s)
- Atsushi Nagaoka
- Department of Clinical Neuroscience, Unit of Clinical Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki City, Japan.
| | - Akira Tsujino
- Department of Clinical Neuroscience, Unit of Clinical Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki City, Japan.
| | - Hirokazu Shiraishi
- Department of Neurology and Strokology, Nagasaki University Hospital, Nagasaki City, Japan
| | - Tadashi Kanamoto
- Department of Neurology and Strokology, Nagasaki University Hospital, Nagasaki City, Japan
| | - Tomoaki Shima
- Department of Neurology and Strokology, Nagasaki University Hospital, Nagasaki City, Japan.
| | - Shunsuke Yoshimura
- Department of Neurology and Strokology, Nagasaki University Hospital, Nagasaki City, Japan.
| | - Teiichiro Miyazaki
- Department of Neurology and Strokology, Nagasaki University Hospital, Nagasaki City, Japan.
| | - Yohei Tateishi
- Department of Neurology and Strokology, Nagasaki University Hospital, Nagasaki City, Japan.
| | | | - Masakatsu Motomura
- Medical Electronic Course, Nagasaki Institute of Applied Science, Nagasaki City, Japan.
| | - Susan Maxwell
- Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, Oxford, UK.
| | - Osamu Higuchi
- Department of Neurology, Nagasaki Kawatana Medical Center, Nagasaki, Japan.
| | - David Beeson
- Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, Oxford, UK.
| | - Angela Vincent
- Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, Oxford, UK.
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Xu M, Jiang J, He Y, Gu WY, Jin B. Early-onset ophthalmoplegia, cervical dyskinesia, and lower extremity weakness due to partial deletion of chromosome 16: A case report. World J Clin Cases 2022; 10:9332-9339. [PMID: 36159412 PMCID: PMC9477676 DOI: 10.12998/wjcc.v10.i26.9332] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2022] [Revised: 06/08/2022] [Accepted: 07/21/2022] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND We explored the genotype-phenotype correlation of the novel deletion 16p13.2p12.3 in an 8-year-old child with progressive total ophthalmoplegia, cervical dyskinesia, and lower limb weakness by comparing the patient’s clinical features with previously reported data on adjacent copy number variation (CNV) regions.
CASE SUMMARY Specifically, we first performed whole-exome sequencing, CNV-sequencing, and mitochondrial genome sequencing on the patient and his parents, then applied “MitoExome” (the entire mitochondrial genome and exons of nuclear genes encoding the mitochondrial proteome) analysis to screen for genetic mitochondrial diseases. We identified a de novo 7.23 Mb deletion, covering 16p13.2p12.3, by both whole-exome sequencing and CNV sequencing. We also detected 16p13.11 in the deleted region, which is the recurrent distinct region associated with neurodevelopmental disorder. However, the patient only displayed features of progressive total ophthalmoplegia, cervical dyskinesia, and weakness in his lower limbs without neurodevelopmental disorder. The “MitoExome” sequencing was negative. Brain magnetic resonance imaging revealed non-specific sporadic changes in the occipital parietal lobe and basal ganglia.
CONCLUSION Taken together, these results indicated that 16p13.2p12.3 deletion causes a syndrome with the phenotype of early-onset total ophthalmoplegia. The “MitoExome” analysis is powerful for the differential diagnosis of mitochondrial diseases. We report a novel copy number variant in this case, but further confirmation is required.
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Affiliation(s)
- Min Xu
- Department of Neurology, Children’s Hospital of Nanjing Medical University, Nanjing 210008, Jiangsu Province, China
| | - Jiao Jiang
- Department of Neurology, Children’s Hospital of Nanjing Medical University, Nanjing 210008, Jiangsu Province, China
| | - Yan He
- Department of Neurology, Children’s Hospital of Nanjing Medical University, Nanjing 210008, Jiangsu Province, China
| | - Wei-Yue Gu
- Chigene (Beijing), Translational Medical Research Center Co. Ltd, Beijing 101111, China
| | - Bo Jin
- Department of Neurology, Children’s Hospital of Nanjing Medical University, Nanjing 210008, Jiangsu Province, China
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Braz LP, Ng YS, Gorman GS, Schaefer AM, McFarland R, Taylor RW, Turnbull DM, Whittaker RG. Neuromuscular Junction Abnormalities in Mitochondrial Disease: An Observational Cohort Study. Neurol Clin Pract 2019; 11:97-104. [PMID: 33842062 PMCID: PMC8032443 DOI: 10.1212/cpj.0000000000000795] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
Objective To determine the prevalence of neuromuscular junction (NMJ) abnormalities in patients with mitochondrial disease. Methods Eighty patients with genetically proven mitochondrial disease were recruited from a national center for mitochondrial disease in the United Kingdom. Participants underwent detailed clinical and neurophysiologic testing including single-fiber electromyography. Results The overall prevalence of neuromuscular transmission defects was 25.6%. The highest prevalence was in patients with pathogenic dominant RRM2B variants (50%), but abnormalities were found in a wide range of mitochondrial genotypes. The presence of NMJ abnormalities was strongly associated with coexistent myopathy, but not with neuropathy. Furthermore, 15% of patients with NMJ abnormality had no evidence of either myopathy or neuropathy. Conclusions NMJ transmission defects are common in mitochondrial disease. In some patients, NMJ dysfunction occurs in the absence of obvious pre- or post-synaptic pathology, suggesting that the NMJ may be specifically affected.
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Affiliation(s)
- Luis P Braz
- Department of Neurology (LPB), Centro Hospitalar Universitário de São João, Porto, Portugal; and Wellcome Centre for Mitochondrial Research (YSN, GSG, AMS, RM, RWT, DMT), Translational and Clinical Research Institute (RGW), Newcastle University, Newcastle upon Tyne, United Kingdom
| | - Yi Shiau Ng
- Department of Neurology (LPB), Centro Hospitalar Universitário de São João, Porto, Portugal; and Wellcome Centre for Mitochondrial Research (YSN, GSG, AMS, RM, RWT, DMT), Translational and Clinical Research Institute (RGW), Newcastle University, Newcastle upon Tyne, United Kingdom
| | - Gráinne S Gorman
- Department of Neurology (LPB), Centro Hospitalar Universitário de São João, Porto, Portugal; and Wellcome Centre for Mitochondrial Research (YSN, GSG, AMS, RM, RWT, DMT), Translational and Clinical Research Institute (RGW), Newcastle University, Newcastle upon Tyne, United Kingdom
| | - Andrew M Schaefer
- Department of Neurology (LPB), Centro Hospitalar Universitário de São João, Porto, Portugal; and Wellcome Centre for Mitochondrial Research (YSN, GSG, AMS, RM, RWT, DMT), Translational and Clinical Research Institute (RGW), Newcastle University, Newcastle upon Tyne, United Kingdom
| | - Robert McFarland
- Department of Neurology (LPB), Centro Hospitalar Universitário de São João, Porto, Portugal; and Wellcome Centre for Mitochondrial Research (YSN, GSG, AMS, RM, RWT, DMT), Translational and Clinical Research Institute (RGW), Newcastle University, Newcastle upon Tyne, United Kingdom
| | - Robert W Taylor
- Department of Neurology (LPB), Centro Hospitalar Universitário de São João, Porto, Portugal; and Wellcome Centre for Mitochondrial Research (YSN, GSG, AMS, RM, RWT, DMT), Translational and Clinical Research Institute (RGW), Newcastle University, Newcastle upon Tyne, United Kingdom
| | - Doug M Turnbull
- Department of Neurology (LPB), Centro Hospitalar Universitário de São João, Porto, Portugal; and Wellcome Centre for Mitochondrial Research (YSN, GSG, AMS, RM, RWT, DMT), Translational and Clinical Research Institute (RGW), Newcastle University, Newcastle upon Tyne, United Kingdom
| | - Roger G Whittaker
- Department of Neurology (LPB), Centro Hospitalar Universitário de São João, Porto, Portugal; and Wellcome Centre for Mitochondrial Research (YSN, GSG, AMS, RM, RWT, DMT), Translational and Clinical Research Institute (RGW), Newcastle University, Newcastle upon Tyne, United Kingdom
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