Mutations, Genes, and Phenotypes Related to Movement Disorders and Ataxias.

Leticia Pías-Peleteiro, Carmen Espinós, Sergio Aguilera-Albesa, Alejandra Darling, Belén Pérez-Dueñas, Vincenzo Lupo, Pablo Mir, Silvia Jesús-Maestre, Roser Maria Pons, Amparo Andrés-Bordería, Candela Fuster, Ana Sánchez-Monteagudo, Maria Josep Martí, Esteban Muñoz, Ángeles Ruiz-Gómez, Mar O'Callaghan Gordo, Dolores Martínez-Rubio, Esther Moreno, Patrícia Janeiro, Anna Duat-Rodríguez, Irene Martínez-Torres, Isabel Sastre-Bataller, Raquel Baviera-Muñoz, Ainhoa García-Ribes, María Jesús Martínez-González, Itxaso Martí-Carrera, Clara Marco-Marín, Cristina Tello, Raquel Bernadó-Fonz, Nerea Gorría-Redondo, Paula Sancho, Isabel Hinarejos

Journal: International journal of molecular sciences 2022;23(19):11847

PMID: 36233161

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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 , , and , suggesting an NBIA-like phenotype. Eleven patients showed very early-onset ataxia and CA with cortical hyperintensities caused by mutations in , , , , PMPCA, and . 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.

Address: Rare Neurodegenerative Diseases Laboratory, Centro de Investigación Príncipe Felipe (CIPF), 46012 Valencia, Spain .; Joint Unit CIPF-IIS La Fe Rare Diseases, 46012 Valencia, Spain.; Paediatric Neurology Unit, Department of Paediatrics, Hospital Universitario de Navarra, Navarrabiomed, 31008 Pamplona, Spain.; 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.; Biodonostia Health Research Institute, Paediatric Group, Donostia University Hospital, Department of Paediatrics, University of the Basque Country UPV/EHU, 20014 San Sebastian, Spain.; Paediatric Neurology Unit, Hospital Universitario Cruces, 48903 Barakaldo, País Vasco, 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.; Paediatric Neurology Unit, Hospital Infantil Universitario Niño Jesús, 28009 Madrid, Spain.; Centro de Referencia de Doenças Hereditarias do Metabolismo, CHULN, Hospital Santa Maria, 1649-035 Lisbon, Portugal.; Department of Paediatrics, Hospital Regional Universitario, 29010 Malaga, Spain.; Paediatric Neurology Unit, Hospital Sant Joan de Déu, 08950 Barcelona, Spain.; Department of Paediatrics, Hospital Universitari Son Espases, 07120 Palma de Mallorca, Spain.; Unit of Parkinson and Movement Disorders, Department of Neurology, Hospital Universitari Clínic, 08036 Barcelona, Spain.; Paediatric Neurology, Hospital Agia Sofía, 11527 Athens, Greece.; 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.; Department of Paediatric Neurology, Hospital Universitari Vall d'Hebron, Vall d'Hebron Institut de Recerca, 08035 Barcelona, Spain.; Department of Biotechnology, Faculty of Veterinary and Experimental Sciences, Universidad Católica de Valencia "San Vicente Mártir", 46001 Valencia, Spain.

DOI: 10.3390/ijms231911847

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Medical:

https://medlineplus.gov/movementdisorders.html

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https://assays.cancer.gov/CPTAC-103

Research Materials:

https://antibodies.cancer.gov/detail/CPTC-YWHAE-1

MeSH Terms: Ataxia, Brain, Humans, Iron, Kinesins, Movement Disorders, Mutation, Neurodegenerative Diseases, Phenotype, Phosphotransferases (Alcohol Group Acceptor)