2. Academic Validation
  3. Heterozygous STUB1 mutation causes familial ataxia with cognitive affective syndrome (SCA48)

Heterozygous STUB1 mutation causes familial ataxia with cognitive affective syndrome (SCA48)

  • Neurology. 2018 Nov 20;91(21):e1988-e1998. doi: 10.1212/WNL.0000000000006550.
David Genis 1,  Sara Ortega-Cubero 1,  Hector San Nicolás 1,  Jordi Corral 1,  Josep Gardenyes 1,  Laura de Jorge 1,  Eva López 1,  Berta Campos 1,  Elena Lorenzo 1,  Raúl Tonda 1,  Sergi Beltran 1,  Montserrat Negre 1,  María Obón 1,  Brigitte Beltran 1,  Laura Fàbregas 1,  Berta Alemany 1,  Fabián Márquez 1,  Lluís Ramió-Torrentà 1,  Jordi Gich 1,  Víctor Volpini 1,  Pau Pastor 2
Affiliations

Affiliations

  • 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. [email protected].
PMID: 30381368 DOI: 10.1212/WNL.0000000000006550
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).

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