International Journal of Molecular Sciences (Oct 2022)
Mutations, Genes, and Phenotypes Related to Movement Disorders and Ataxias
- Dolores Martínez-Rubio,
- Isabel Hinarejos,
- Paula Sancho,
- Nerea Gorría-Redondo,
- Raquel Bernadó-Fonz,
- Cristina Tello,
- Clara Marco-Marín,
- Itxaso Martí-Carrera,
- María Jesús Martínez-González,
- Ainhoa García-Ribes,
- Raquel Baviera-Muñoz,
- Isabel Sastre-Bataller,
- Irene Martínez-Torres,
- Anna Duat-Rodríguez,
- Patrícia Janeiro,
- Esther Moreno,
- Leticia Pías-Peleteiro,
- Mar O’Callaghan Gordo,
- Ángeles Ruiz-Gómez,
- Esteban Muñoz,
- Maria Josep Martí,
- Ana Sánchez-Monteagudo,
- Candela Fuster,
- Amparo Andrés-Bordería,
- Roser Maria Pons,
- Silvia Jesús-Maestre,
- Pablo Mir,
- Vincenzo Lupo,
- Belén Pérez-Dueñas,
- Alejandra Darling,
- Sergio Aguilera-Albesa,
- Carmen Espinós
Affiliations
- Dolores Martínez-Rubio
- Rare Neurodegenerative Diseases Laboratory, Centro de Investigación Príncipe Felipe (CIPF), 46012 Valencia, Spain
- Isabel Hinarejos
- Rare Neurodegenerative Diseases Laboratory, Centro de Investigación Príncipe Felipe (CIPF), 46012 Valencia, Spain
- Paula Sancho
- Rare Neurodegenerative Diseases Laboratory, Centro de Investigación Príncipe Felipe (CIPF), 46012 Valencia, Spain
- Nerea Gorría-Redondo
- Paediatric Neurology Unit, Department of Paediatrics, Hospital Universitario de Navarra, Navarrabiomed, 31008 Pamplona, Spain
- Raquel Bernadó-Fonz
- Paediatric Neurology Unit, Department of Paediatrics, Hospital Universitario de Navarra, Navarrabiomed, 31008 Pamplona, Spain
- Cristina Tello
- Rare Neurodegenerative Diseases Laboratory, Centro de Investigación Príncipe Felipe (CIPF), 46012 Valencia, Spain
- Clara Marco-Marín
- 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
- Itxaso Martí-Carrera
- Biodonostia Health Research Institute, Paediatric Group, Donostia University Hospital, Department of Paediatrics, University of the Basque Country UPV/EHU, 20014 San Sebastian, Spain
- María Jesús Martínez-González
- Paediatric Neurology Unit, Hospital Universitario Cruces, 48903 Barakaldo, País Vasco, Spain
- Ainhoa García-Ribes
- Paediatric Neurology Unit, Hospital Universitario Cruces, 48903 Barakaldo, País Vasco, Spain
- Raquel Baviera-Muñoz
- Joint Unit CIPF-IIS La Fe Rare Diseases, 46012 Valencia, Spain
- Isabel Sastre-Bataller
- Joint Unit CIPF-IIS La Fe Rare Diseases, 46012 Valencia, Spain
- Irene Martínez-Torres
- Joint Unit CIPF-IIS La Fe Rare Diseases, 46012 Valencia, Spain
- Anna Duat-Rodríguez
- Paediatric Neurology Unit, Hospital Infantil Universitario Niño Jesús, 28009 Madrid, Spain
- Patrícia Janeiro
- Centro de Referencia de Doenças Hereditarias do Metabolismo, CHULN, Hospital Santa Maria, 1649-035 Lisbon, Portugal
- Esther Moreno
- Department of Paediatrics, Hospital Regional Universitario, 29010 Malaga, Spain
- Leticia Pías-Peleteiro
- Paediatric Neurology Unit, Hospital Sant Joan de Déu, 08950 Barcelona, Spain
- Mar O’Callaghan Gordo
- Paediatric Neurology Unit, Hospital Sant Joan de Déu, 08950 Barcelona, Spain
- Ángeles Ruiz-Gómez
- Department of Paediatrics, Hospital Universitari Son Espases, 07120 Palma de Mallorca, Spain
- Esteban Muñoz
- Unit of Parkinson and Movement Disorders, Department of Neurology, Hospital Universitari Clínic, 08036 Barcelona, Spain
- Maria Josep Martí
- Unit of Parkinson and Movement Disorders, Department of Neurology, Hospital Universitari Clínic, 08036 Barcelona, Spain
- Ana Sánchez-Monteagudo
- Rare Neurodegenerative Diseases Laboratory, Centro de Investigación Príncipe Felipe (CIPF), 46012 Valencia, Spain
- Candela Fuster
- Rare Neurodegenerative Diseases Laboratory, Centro de Investigación Príncipe Felipe (CIPF), 46012 Valencia, Spain
- Amparo Andrés-Bordería
- Rare Neurodegenerative Diseases Laboratory, Centro de Investigación Príncipe Felipe (CIPF), 46012 Valencia, Spain
- Roser Maria Pons
- Paediatric Neurology, Hospital Agia Sofía, 11527 Athens, Greece
- Silvia Jesús-Maestre
- 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
- Pablo Mir
- 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
- Vincenzo Lupo
- Rare Neurodegenerative Diseases Laboratory, Centro de Investigación Príncipe Felipe (CIPF), 46012 Valencia, Spain
- Belén Pérez-Dueñas
- Department of Paediatric Neurology, Hospital Universitari Vall d’Hebron, Vall d’Hebron Institut de Recerca, 08035 Barcelona, Spain
- Alejandra Darling
- Paediatric Neurology Unit, Hospital Sant Joan de Déu, 08950 Barcelona, Spain
- Sergio Aguilera-Albesa
- Paediatric Neurology Unit, Department of Paediatrics, Hospital Universitario de Navarra, Navarrabiomed, 31008 Pamplona, Spain
- Carmen Espinós
- Rare Neurodegenerative Diseases Laboratory, Centro de Investigación Príncipe Felipe (CIPF), 46012 Valencia, Spain
- DOI
- https://doi.org/10.3390/ijms231911847
- Journal volume & issue
-
Vol. 23,
no. 19
p. 11847
Abstract
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.
Keywords
- movement disorders
- ataxia
- cerebellar atrophy
- neurodegeneration with brain iron accumulation (NBIA)
- gene panel
- exome sequencing