David Genis1, Sara Ortega-Cubero1, Hector San Nicolás1, Jordi Corral1, Josep Gardenyes1, Laura de Jorge1, Eva López1, Berta Campos1, Elena Lorenzo1, Raúl Tonda1, Sergi Beltran1, Montserrat Negre1, María Obón1, Brigitte Beltran1, Laura Fàbregas1, Berta Alemany1, Fabián Márquez1, Lluís Ramió-Torrentà1, Jordi Gich1, Víctor Volpini1, Pau Pastor2. 1. From the Unit of Ataxias, Spastic Paraparesis, and Rare Neurological Diseases (D.G., B.A.) and Neuropsychology Unit (J.G.), Neurology Service (F.M., L.R.-T.), Nuclear Medicine Unit (M.N.), Genetic Unit, Laboratori Clinic Territorial de Girona (M.O.), and MRI Center, Institute of Diagnostic Imaging (IDI), and Radiology Department (B.B.), University Hospital "Dr. Josep Trueta," Hospital de Santa Caterina, Parc Hospitalari Martí i Julià; Group of Investigation in Neurodegeneration and Neuroinflammation (D.G., B.A., F.M., L.R.-T., J.G.), Institut d'Investigació Biomèdica de Girona Dr. Josep Trueta (IDIBGI), Girona; Medical Sciences Department (B.A., L.R.-T.), University of Girona; Neurogenetics Laboratory, Division of Neurosciences (S.O.-C., E. Lorenzo, P.P.), Center for Applied Medical Research, University of Navarra, Pamplona; Department of Neurology and Neurosurgery (S.O.-C., H.S.N.), Hospital Universitario de Burgos (HUBU); CIBERNED, Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (S.O.-C., E. Lorenzo, P.P.), Instituto de Salud Carlos III, Madrid; Molecular Diagnostic Centre for Hereditary Diseases (CDGM) (J.C., J.G., L.d.J., E. López, B.C., V.V.), Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), L'Hospitalet de Llobregat, Barcelona; Centro Nacional de Análisis Genómico (CNAG-CRG) (R.T., S.B.), Center for Genomic Regulation, Barcelona Institute of Science and Technology (BIST); Universitat Pompeu Fabra (UPF) (R.T., S.B.), Barcelona; National Bioinformatics Institute (R.T.), Madrid; Clinical Psychology (L.F.), Hospital de Dia de Malalties Neurodegeneratives, Hospital de Santa Caterina, Parc Hospitalari Martí i Julià, Girona; and Movement Disorders Unit, Department of Neurology (P.P.), University Hospital Mutua de Terrassa, Barcelona, Spain. 2. From the Unit of Ataxias, Spastic Paraparesis, and Rare Neurological Diseases (D.G., B.A.) and Neuropsychology Unit (J.G.), Neurology Service (F.M., L.R.-T.), Nuclear Medicine Unit (M.N.), Genetic Unit, Laboratori Clinic Territorial de Girona (M.O.), and MRI Center, Institute of Diagnostic Imaging (IDI), and Radiology Department (B.B.), University Hospital "Dr. Josep Trueta," Hospital de Santa Caterina, Parc Hospitalari Martí i Julià; Group of Investigation in Neurodegeneration and Neuroinflammation (D.G., B.A., F.M., L.R.-T., J.G.), Institut d'Investigació Biomèdica de Girona Dr. Josep Trueta (IDIBGI), Girona; Medical Sciences Department (B.A., L.R.-T.), University of Girona; Neurogenetics Laboratory, Division of Neurosciences (S.O.-C., E. Lorenzo, P.P.), Center for Applied Medical Research, University of Navarra, Pamplona; Department of Neurology and Neurosurgery (S.O.-C., H.S.N.), Hospital Universitario de Burgos (HUBU); CIBERNED, Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (S.O.-C., E. Lorenzo, P.P.), Instituto de Salud Carlos III, Madrid; Molecular Diagnostic Centre for Hereditary Diseases (CDGM) (J.C., J.G., L.d.J., E. López, B.C., V.V.), Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), L'Hospitalet de Llobregat, Barcelona; Centro Nacional de Análisis Genómico (CNAG-CRG) (R.T., S.B.), Center for Genomic Regulation, Barcelona Institute of Science and Technology (BIST); Universitat Pompeu Fabra (UPF) (R.T., S.B.), Barcelona; National Bioinformatics Institute (R.T.), Madrid; Clinical Psychology (L.F.), Hospital de Dia de Malalties Neurodegeneratives, Hospital de Santa Caterina, Parc Hospitalari Martí i Julià, Girona; and Movement Disorders Unit, Department of Neurology (P.P.), University Hospital Mutua de Terrassa, Barcelona, Spain. pastorpau@gmail.com.
Abstract
OBJECTIVE: To describe a new spinocerebellar ataxia (SCA48) characterized by early cerebellar cognitive-affective syndrome (CCAS) and late-onset SCA. METHODS: This is a descriptive study of a family that has been followed for more than a decade with periodic neurologic and neuropsychological examinations, MRI, brain SPECT perfusion, and genetic analysis. Whole exome sequencing was performed in 3 affected and 1 unaffected family member and subsequently validated by linkage analysis of chromosome 16p13.3. RESULTS: Six patients fully developed cognitive-affective and complete motor cerebellar syndrome associated with vermian and hemispheric cerebellar atrophy, suggesting a continuum from a dysexecutive syndrome slowly evolving to a complete and severe CCAS with late truncal ataxia. Three presymptomatic patients showed focal cerebellar atrophy in the vermian, paravermian, and the medial part of cerebellar lobes VI and VII, suggesting that cerebellar atrophy preceded the ataxia, and that the neurodegeneration begins in cerebellar areas related to cognition and emotion, spreading later to the whole cerebellum. Among the candidate variants, only the frameshift heterozygous c.823_824delCT STUB1 (p.L275Dfs*16) pathogenic variant cosegregated with the disease. The p.L275Dfs*16 heterozygous STUB1 pathogenic variant leads to neurodegeneration and atrophy in cognition- and emotion-related cerebellar areas and reinforces the importance of STUB1 in maintaining cognitive cerebellar function. CONCLUSIONS: We report a heterozygous STUB1 pathogenic genetic variant causing dominant cerebellar ataxia. Since recessive mutations in STUB1 gene have been previously associated with SCAR16, these findings suggest a previously undescribed SCA locus (SCA48; MIM# 618093).
OBJECTIVE: To describe a new spinocerebellar ataxia (SCA48) characterized by early cerebellar cognitive-affective syndrome (CCAS) and late-onset SCA. METHODS: This is a descriptive study of a family that has been followed for more than a decade with periodic neurologic and neuropsychological examinations, MRI, brain SPECT perfusion, and genetic analysis. Whole exome sequencing was performed in 3 affected and 1 unaffected family member and subsequently validated by linkage analysis of chromosome 16p13.3. RESULTS: Six patients fully developed cognitive-affective and complete motor cerebellar syndrome associated with vermian and hemispheric cerebellar atrophy, suggesting a continuum from a dysexecutive syndrome slowly evolving to a complete and severe CCAS with late truncal ataxia. Three presymptomatic patients showed focal cerebellar atrophy in the vermian, paravermian, and the medial part of cerebellar lobes VI and VII, suggesting that cerebellar atrophy preceded the ataxia, and that the neurodegeneration begins in cerebellar areas related to cognition and emotion, spreading later to the whole cerebellum. Among the candidate variants, only the frameshift heterozygous c.823_824delCTSTUB1 (p.L275Dfs*16) pathogenic variant cosegregated with the disease. The p.L275Dfs*16 heterozygous STUB1 pathogenic variant leads to neurodegeneration and atrophy in cognition- and emotion-related cerebellar areas and reinforces the importance of STUB1 in maintaining cognitive cerebellar function. CONCLUSIONS: We report a heterozygous STUB1 pathogenic genetic variant causing dominant cerebellar ataxia. Since recessive mutations in STUB1 gene have been previously associated with SCAR16, these findings suggest a previously undescribed SCA locus (SCA48; MIM# 618093).
Authors: R Palvadeau; Z E Kaya-Güleç; G Şimşir; A Vural; Ö Öztop-Çakmak; G Genç; M S Aygün; O Falay; A Nazlı Başak; S Ertan Journal: Neurogenetics Date: 2019-11-19 Impact factor: 2.660
Authors: Jan Senderek; Petra Lassuthova; Dagmara Kabzińska; Lisa Abreu; Jonathan Baets; Christian Beetz; Geir J Braathen; David Brenner; Joline Dalton; Lois Dankwa; Tine Deconinck; Peter De Jonghe; Bianca Dräger; Katja Eggermann; Melina Ellis; Carina Fischer; Tanya Stojkovic; David N Herrmann; Rita Horvath; Helle Høyer; Stephan Iglseder; Marina Kennerson; Katharina Kinslechner; Jennefer N Kohler; Ingo Kurth; Nigel G Laing; Phillipa J Lamont; Löscher Wolfgang N; Albert Ludolph; Wilson Marques; Garth Nicholson; Royston Ong; Susanne Petri; Gianina Ravenscroft; Adriana Rebelo; Giulia Ricci; Sabine Rudnik-Schöneborn; Anja Schirmacher; Beate Schlotter-Weigel; Ludger Schoels; Rebecca Schüle; Matthis Synofzik; Bruno Francou; Tim M Strom; Johannes Wagner; David Walk; Julia Wanschitz; Daniela Weinmann; Jochen Weishaupt; Manuela Wiessner; Reinhard Windhager; Peter Young; Stephan Züchner; Stefan Toegel; Pavel Seeman; Andrzej Kochański; Michaela Auer-Grumbach Journal: Neurology Date: 2020-11-03 Impact factor: 9.910
Authors: Yasaman Pakdaman; Siren Berland; Helene J Bustad; Sigrid Erdal; Bryony A Thompson; Paul A James; Kjersti N Power; Ståle Ellingsen; Martin Krooni; Line I Berge; Adrienne Sexton; Laurence A Bindoff; Per M Knappskog; Stefan Johansson; Ingvild Aukrust Journal: Int J Mol Sci Date: 2021-05-30 Impact factor: 5.923