|
|||||
|
|
Autosomal Dominant MPAN: Mosaicism Expands the Clinical Spectrum to Atypical Late-Onset Phenotypes |
|
| Authors: | Chloé Angelini MD Christelle Marie Durand PhD Patricia Fergelot MD PhD Julie Deforges MLT Anne Vital MD PhD Patrice Menegon MD Elizabeth Sarrazin MD Rémi Bellance MD Stéphane Mathis MD PhD Victoria Gonzalez MD PhD Mathilde Renaud MD PhD Solène Frismand MD Emmanuelle Schmitt MD Marie Rouanet MD Lydie Burglen MD PhD Brigitte Chabrol MD PhD Béatrice Desnous MD PhD Benoît Arveiler PharmD PhD Giovanni Stevanin PhD Isabelle Coupry PhD Cyril Goizet MD PhD |
| Institution: | 1. Service de Génétique Médicale, Hôpital Pellegrin, CHU Bordeaux, Bordeaux, France
Centre de Référence Maladies Rares «Neurogénétique», Service de Génétique Médicale, CHU Bordeaux, Bordeaux, France University of Bordeaux, CNRS, INCIA, UMR 5287, NRGen Team, Bordeaux, France;2. Service de Génétique Médicale, Hôpital Pellegrin, CHU Bordeaux, Bordeaux, France Centre de Référence Maladies Rares «Neurogénétique», Service de Génétique Médicale, CHU Bordeaux, Bordeaux, France University of Bordeaux, CNRS, INCIA, UMR 5287, NRGen Team, Bordeaux, France MRGM, University of Bordeaux, INSERM U1211, Bordeaux, France;3. Service de Génétique Médicale, Hôpital Pellegrin, CHU Bordeaux, Bordeaux, France MRGM, University of Bordeaux, INSERM U1211, Bordeaux, France;4. Service de Génétique Médicale, Hôpital Pellegrin, CHU Bordeaux, Bordeaux, France;5. Service d'Anatomie Pathologique, Hôpital Pellegrin, CHU Bordeaux, Bordeaux, France;6. Service de Neuroradiologie, Hôpital Pellegrin, CHU Bordeaux, Bordeaux, France Deceased on March 22, 2022.;7. Centre de Référence Maladies Rares Neuromusculaires (AOC), Hôpital Pierre Zobda Quitman, CHU Martinique, Fort de France, Martinique;8. Service de Neurologie (Unité Nerf-Muscle), Centre de Référence Maladies Rares, Neuromusculaires (AOC), Centre SLA, Hôpital Pellegrin, CHU Bordeaux, Bordeaux, France;9. Service de neurologie, Hôpital Gui de Chauliac, CHU Montpellier, Montpellier, France;10. Service de Neurologie, CHRU Nancy, Nancy, France Service de Génétique Clinique, CHRU Nancy, Nancy, France NGERE, INSERM U1256, Faculté de Médecine, Université de Lorraine, Nancy, France;11. Service de Neurologie, CHRU Nancy, Nancy, France;12. Service de Neuroradiologie Diagnostique et Thérapeutique, CHRU Nancy, Nancy, France;13. Service d'explorations Fonctionnelles du Système Nerveux, Hôpital Pellegrin, CHU Bordeaux, Bordeaux, France;14. Laboratoire de Neurogénétique Pédiatrique, Département de Génétique, Hôpital Trousseau, APHP.Sorbonne Université, Paris, France;15. Service de Neuropédiatrie, Hôpital Timone enfants, APHM, Marseille, France;16. University of Bordeaux, CNRS, INCIA, UMR 5287, NRGen Team, Bordeaux, France EPHE, CNRS, INCIA, UMR 5287, PSL Research University, Paris, France;17. University of Bordeaux, CNRS, INCIA, UMR 5287, NRGen Team, Bordeaux, France |
| Abstract: | BackgroundMitochondrial membrane protein-associated neurodegeneration (MPAN) is caused by mutations in the C19orf12 gene. MPAN typically appears in the first two decades of life and presents with progressive dystonia-parkinsonism, lower motor neuron signs, optic atrophy, and abnormal iron deposits predominantly in the basal ganglia. MPAN, initially considered as a strictly autosomal recessive disease (AR), turned out to be also dominantly inherited (AD).ObjectivesOur aim was to better characterize the clinical, molecular, and functional spectra associated with such dominant pathogenic heterozygous C19orf12 variants.MethodsWe collected clinical, imaging, and molecular information of eight individuals from four AD-MPAN families and obtained brain neuropathology results for one. Functional studies, focused on energy and iron metabolism, were conducted on fibroblasts from AD-MPAN patients, AR-MPAN patients, and controls.ResultsWe identified four heterozygous C19orf12 variants in eight AD-MPAN patients. Two of them carrying the familial variant in mosaic displayed an atypical late-onset phenotype. Fibroblasts from AD-MPAN showed more severe alterations of iron storage metabolism and autophagy compared to AR-MPAN cells.ConclusionOur data add strong evidence of the realness of AD-MPAN with identification of novel monoallelic C19orf12 variants, including at the mosaic state. This has implications in diagnosis procedures. We also expand the phenotypic spectrum of MPAN to late onset atypical presentations. Finally, we demonstrate for the first time more drastic abnormalities of iron metabolism and autophagy in AD-MPAN than in AR-MPAN. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. |
| Keywords: | NBIA autosomal dominant MPAN C19orf12 mosaicism late-onset MPAN |