Mutations, Genes, and Phenotypes Related to Movement Disorders and Ataxias
Por:
Martínez-Rubio D, Hinarejos I, Sancho P, Gorría-Redondo N, Bernadó-Fonz R, Tello C, Marco-Marín C, Martí-Carrera I, Martínez-González MJ, García-Ribes A, Baviera-Muñoz R, Sastre-Bataller I, Martínez-Torres I, Duat-Rodríguez A, Janeiro P, Moreno E, Pias-Peleteiro LD, O'Callaghan-Gordo M, Ruiz-Gómez Á, Muñoz E, Martí MJ, Sánchez-Monteagudo A, Fuster C, Andrés-Bordería A, Pons RM, Jesús-Maestre S, Mir P, Lupo V, Pérez-Dueñas B, Darling A, Aguilera-Albesa S and Espinós C
Publicada:
1 oct 2022
Resumen:
Our clinical series comprises 124 patients with movement disorders (MDs) and/or ataxia with cerebellar atrophy (CA), many of them showing signs of neurodegeneration with brain iron accumulation (NBIA). Ten NBIA genes are accepted, although isolated cases compatible with abnormal brain iron deposits are known. The patients were evaluated using standardised clinical assessments of ataxia and MDs. First, NBIA genes were analysed by Sanger sequencing and 59 patients achieved a diagnosis, including the detection of the founder mutation PANK2 p.T528M in Romani people. Then, we used a custom panel MovDisord and/or exome sequencing; 29 cases were solved with a great genetic heterogeneity (34 different mutations in 23 genes). Three patients presented brain iron deposits with Fe-sensitive MRI sequences and mutations in FBXO7, GLB1, and KIF1A, suggesting an NBIA-like phenotype. Eleven patients showed very early-onset ataxia and CA with cortical hyperintensities caused by mutations in ITPR1, KIF1A, SPTBN2, PLA2G6, PMPCA, and PRDX3. The novel variants were investigated by structural modelling, luciferase analysis, transcript/minigenes studies, or immunofluorescence assays. Our findings expand the phenotypes and the genetics of MDs and ataxias with early-onset CA and cortical hyperintensities and highlight that the abnormal brain iron accumulation or early cerebellar gliosis may resembling an NBIA phenotype.
Filiaciones:
Martínez-Rubio D:
Rare Neurodegenerative Diseases Laboratory, Centro de Investigación Príncipe Felipe (CIPF), 46012 Valencia, Spain
Joint Unit CIPF-IIS La Fe Rare Diseases, 46012 Valencia, Spain
Hinarejos I:
Rare Neurodegenerative Diseases Laboratory, Centro de Investigación Príncipe Felipe (CIPF), 46012 Valencia, Spain
Joint Unit CIPF-IIS La Fe Rare Diseases, 46012 Valencia, Spain
Sancho P:
Rare Neurodegenerative Diseases Laboratory, Centro de Investigación Príncipe Felipe (CIPF), 46012 Valencia, Spain
Gorría-Redondo N:
Paediatric Neurology Unit, Department of Paediatrics, Hospital Universitario de Navarra, Navarrabiomed, 31008 Pamplona, Spain
Bernadó-Fonz R:
Paediatric Neurology Unit, Department of Paediatrics, Hospital Universitario de Navarra, Navarrabiomed, 31008 Pamplona, Spain
Tello C:
Rare Neurodegenerative Diseases Laboratory, Centro de Investigación Príncipe Felipe (CIPF), 46012 Valencia, Spain
Marco-Marín C:
Structural Enzymopathology Unit, Instituto de Biomedicina de Valencia (IBV), Consejo Superior de Investigaciones Científicas (CSIC), Centro de Investigación Biomédica de Enfermedades Raras (CIBERER-ISCIII), 46010 Valencia, Spain
Martí-Carrera I:
Biodonostia Health Research Institute, Paediatric Group, Donostia University Hospital, Department of Paediatrics, University of the Basque Country UPV/EHU, 20014 San Sebastian, Spain
Martínez-González MJ:
Paediatric Neurology Unit, Hospital Universitario Cruces, 48903 Barakaldo, País Vasco, Spain
García-Ribes A:
Paediatric Neurology Unit, Hospital Universitario Cruces, 48903 Barakaldo, País Vasco, Spain
Baviera-Muñoz R:
Joint Unit CIPF-IIS La Fe Rare Diseases, 46012 Valencia, Spain
Health Research Institute, Hospital Universitari i Politècnic La Fe, 46026 Valencia, Spain
Movement Disorders Unit, Neurology Department, Hospital Universitari i Politècnic La Fe, 46026 Valencia, Spain
Sastre-Bataller I:
Joint Unit CIPF-IIS La Fe Rare Diseases, 46012 Valencia, Spain
Movement Disorders Unit, Neurology Department, Hospital Universitari i Politècnic La Fe, 46026 Valencia, Spain
Martínez-Torres I:
Joint Unit CIPF-IIS La Fe Rare Diseases, 46012 Valencia, Spain
Movement Disorders Unit, Neurology Department, Hospital Universitari i Politècnic La Fe, 46026 Valencia, Spain
Duat-Rodríguez A:
Paediatric Neurology Unit, Hospital Infantil Universitario Niño Jesús, 28009 Madrid, Spain
Janeiro P:
Centro de Referencia de Doenças Hereditarias do Metabolismo, CHULN, Hospital Santa Maria, 1649-035 Lisbon, Portugal
Moreno E:
Department of Paediatrics, Hospital Regional Universitario, 29010 Malaga, Spain
Pias-Peleteiro LD:
Paediatric Neurology Unit, Hospital Sant Joan de Déu, 08950 Barcelona, Spain
O'Callaghan-Gordo M:
Paediatric Neurology Unit, Hospital Sant Joan de Déu, 08950 Barcelona, Spain
Ruiz-Gómez Á:
Department of Paediatrics, Hospital Universitari Son Espases, 07120 Palma de Mallorca, Spain
Muñoz E:
Unit of Parkinson and Movement Disorders, Department of Neurology, Hospital Universitari Clínic, 08036 Barcelona, Spain
Martí MJ:
Unit of Parkinson and Movement Disorders, Department of Neurology, Hospital Universitari Clínic, 08036 Barcelona, Spain
Sánchez-Monteagudo A:
Rare Neurodegenerative Diseases Laboratory, Centro de Investigación Príncipe Felipe (CIPF), 46012 Valencia, Spain
Joint Unit CIPF-IIS La Fe Rare Diseases, 46012 Valencia, Spain
Fuster C:
Rare Neurodegenerative Diseases Laboratory, Centro de Investigación Príncipe Felipe (CIPF), 46012 Valencia, Spain
Andrés-Bordería A:
Rare Neurodegenerative Diseases Laboratory, Centro de Investigación Príncipe Felipe (CIPF), 46012 Valencia, Spain
Pons RM:
Paediatric Neurology, Hospital Agia Sofía, 11527 Athens, Greece
Jesús-Maestre S:
Movement Disorders Unit, Department of Neurology and Clinical Neurophysiology, Instituto de Biomedicina de Sevilla, Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, and Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED-ISCIII), 41013 Seville, Spain
Mir P:
Movement Disorders Unit, Department of Neurology and Clinical Neurophysiology, Instituto de Biomedicina de Sevilla, Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, and Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED-ISCIII), 41013 Seville, Spain
Lupo V:
Rare Neurodegenerative Diseases Laboratory, Centro de Investigación Príncipe Felipe (CIPF), 46012 Valencia, Spain
Pérez-Dueñas B:
Department of Paediatric Neurology, Hospital Universitari Vall d'Hebron, Vall d'Hebron Institut de Recerca, 08035 Barcelona, Spain
Darling A:
Paediatric Neurology Unit, Hospital Sant Joan de Déu, 08950 Barcelona, Spain
Aguilera-Albesa S:
Paediatric Neurology Unit, Department of Paediatrics, Hospital Universitario de Navarra, Navarrabiomed, 31008 Pamplona, Spain
Espinós C:
Rare Neurodegenerative Diseases Laboratory, Centro de Investigación Príncipe Felipe (CIPF), 46012 Valencia, Spain
Joint Unit CIPF-IIS La Fe Rare Diseases, 46012 Valencia, Spain
Department of Biotechnology, Faculty of Veterinary and Experimental Sciences, Universidad Católica de Valencia "San Vicente Mártir", 46001 Valencia, Spain
Green Submitted, gold
|