ArticleAmerican journal of human genetics2023
Extreme phenotypic heterogeneity in non-expansion spinocerebellar ataxias.
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Article in American journal of human genetics, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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22 citing papers in PubMed, 29 citations in OpenAlex.
- Genotype and Age at Onset Drive Vermis Atrophy in CACNA1A- and GAA-FGF14-related Ataxias.Cerebellum (London, England) · 2026Article
- Resting-State EEG Analysis Characterizes the Signature of CACNA1A-and GAA-FGF14-Related Channelopathies.Cerebellum (London, England) · 2025Article
- GAA-FGF14 Expansions and CACNA1A Variants: Phenotypic Overlap and Diagnostic Implications.Movement disorders : official journal of the Movement Disorder Society · 2025Article
- Phenotypic Heterogeneity in Genetic and Acquired Pediatric Cerebellar Disorders.Movement disorders : official journal of the Movement Disorder Society · 2025Article
- CACNA1A loss-of-function affects neurogenesis in human iPSC-derived neural models.Cellular and molecular life sciences : CMLS · 2025Article
- Movement Disorders in Hereditary Cerebellar Ataxia.Movement disorders clinical practice · 2025Article
- Hereditary Ataxias in Argentina.Cerebellum (London, England) · 2025Review
- Insights on the Shared Genetic Landscape of Neurodevelopmental and Movement Disorders.Current neurology and neuroscience reports · 2025Review
- Phosphoinositide Metabolism: Biochemistry, Physiology and Genetic Disorders.Journal of inherited metabolic disease · 2025Review
- Diagnostic yield and limitations of whole-genome sequencing for hereditary cerebellar ataxia.Brain communications · 2025Article
- Clinical and functional characterization of a novel STUB1 mutation in a Chinese spinocerebellar ataxia 48 pedigree.Orphanet journal of rare diseases · 2024Article
- Phenotypic Spectrum and Natural History of Gillespie Syndrome. An Updated Literature Review with 2 New Cases.Cerebellum (London, England) · 2024Review
- Spinocerebellar Ataxias: Phenotypic Spectrum of PolyQ versus Non-Repeat Expansion Forms.Cerebellum (London, England) · 2024Article
- Kv3.3 Expression Enhanced by a Novel Variant in the Kozak Sequence ofInternational journal of molecular sciences · 2024Article
- An Update on the Adult-Onset Hereditary Cerebellar Ataxias: Novel Genetic Causes and New Diagnostic Approaches.Cerebellum (London, England) · 2024Review
- Natural history of non-polyglutamine CACNA1A disease in Austria.Journal of neurology · 2024Article
- Phenotypical, genotypical and pathological characterization of the moonwalker mouse, a model of ataxia.Neurobiology of disease · 2024Article
- Detailed Analysis of ITPR1 Missense Variants Guides Diagnostics and Therapeutic Design.Movement disorders : official journal of the Movement Disorder Society · 2024Article
- CRPD frontiers in movement disorders Therapeutics: From evidence to treatment and applications: Addressing Patients' Needs in the Management of the Ataxias.Clinical parkinsonism & related disorders · 2024Article
- Clinical and genetic keys to cerebellar ataxia due to FGF14 GAA expansions.EBioMedicine · 2024Article
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Authors and funding
72 authors at 20 institutions in 10 countries.
Paulina CunhaSorbonne Université, Paris Brain Institute (ICM), Pitié-Salpêtrière Hospital, AP-HP, INSERM, CNRS, University Hospital Pitié-Salpêtrière, CS21414, 75646 PARIS Cedex 13, France.
Emilien PetitSorbonne Université, Paris Brain Institute (ICM), Pitié-Salpêtrière Hospital, AP-HP, INSERM, CNRS, University Hospital Pitié-Salpêtrière, CS21414, 75646 PARIS Cedex 13, France.
Marie CoutelierSorbonne Université, Paris Brain Institute (ICM), Pitié-Salpêtrière Hospital, AP-HP, INSERM, CNRS, University Hospital Pitié-Salpêtrière, CS21414, 75646 PARIS Cedex 13, France.
Giulia CoarelliSorbonne Université, Paris Brain Institute (ICM), Pitié-Salpêtrière Hospital, AP-HP, INSERM, CNRS, University Hospital Pitié-Salpêtrière, CS21414, 75646 PARIS Cedex 13, France.
Caterina MariottiFondazione IRCCS Istituto Neurologico Carlo Besta, 20133 Milan, Italy.
Jennifer FaberGerman Center for Neurodegenerative Disease (DZNE), 53127 Bonn, Germany; Department of Neurology, University Hospital of Bonn, 53111 Bonn, Germany.
Judith Van GaalenDepartment of Neurology, Donders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Center, 6525 Nijmegen, the Netherlands.
Joana DamasioNeurology Department, Hospital de Santo António, Centro Hospitalar Universitário de Santo António, 4099-001 Porto, Portugal; CGPP, IBMC-Institute for Molecular and Cell Biology & UnIGENe, i3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal.
Zofia FleszarGerman Center for Neurodegenerative Disease (DZNE), 72076 Tübingen, Germany; Department of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research & Center of Neurology, University of Tübingen, 72076 Tübingen, Germany.
Michele TosiUnit of Neuromuscular and Neurodegenerative Disorders, Bambino Gesu' Children's Research Hospital, IRCCS, 00165 Rome, Italy.
Clarissa RoccaDepartment of Neuromuscular Diseases, UCL Queen's Square Institute of Neurology, Queen's Square House, Queen's Square, WC1N 3BG London, UK.
Giovanna De MicheleDepartment of Neuroscience and Reproductive and Odontostomatological Sciences, University of Naples Federico II, 80131 Naples, Italy.
Martina MinneropInstitute of Neuroscience and Medicine (INM-1), Research Centre Jülich, 52428 Jülich, Germany; Institute of Clinical Neuroscience and Medical Psychology and Department of Neurology, Center for Movement Disorders and Neuromodulation, Medical Faculty & University Hospital Düsseldorf, Heinrich-Heine-University Düsseldorf, 40225 Düsseldorf, Germany.
Claire EwenczykSorbonne Université, Paris Brain Institute (ICM), Pitié-Salpêtrière Hospital, AP-HP, INSERM, CNRS, University Hospital Pitié-Salpêtrière, CS21414, 75646 PARIS Cedex 13, France.
Filippo M SantorelliMolecular Medicine & Neurogenetics, IRCCS Fondazione Stella Maris, 56128 Calambrone, Italy.
Anna HeinzmannSorbonne Université, Paris Brain Institute (ICM), Pitié-Salpêtrière Hospital, AP-HP, INSERM, CNRS, University Hospital Pitié-Salpêtrière, CS21414, 75646 PARIS Cedex 13, France.
Thomas BirdUniversity of Washington, Seattle, WA 98195, USA.
Matthias AmprosiCenter for Rare Movement Disorders, Medical University of Innsbruck, 6020 Innsbruck, Austria.
Elisabetta IndelicatoCenter for Rare Movement Disorders, Medical University of Innsbruck, 6020 Innsbruck, Austria.
Alberto BenussiCentre for Neurodegenerative Disorders, Department of Clinical and Experimental Sciences, University of Brescia, 25121 Brescia, Italy.
Perrine CharlesSorbonne Université, Paris Brain Institute (ICM), Pitié-Salpêtrière Hospital, AP-HP, INSERM, CNRS, University Hospital Pitié-Salpêtrière, CS21414, 75646 PARIS Cedex 13, France.
Claudia StendelGerman Center for Neurodegenerative Disease (DZNE), München, Germany; Department of Neurology, Friedrich-Baur Institute, University Hospital of Ludwig-Maximilians-University, Munich Cluster for Systems Neurology (SyNergy), 80336 Munich, Germany.
Silvia RomanoNeurosciences, Mental Health, and Sensory Organs (NESMOS) Department, S. Andrea Hospital, Sapienza University of Rome, 00189 Rome, Italy.
Marina ScarlatoSan Raffaele Hospital and Vita-Salute San Raffaele University, Milan, Italy.
Isabelle Le BerSorbonne Université, Paris Brain Institute (ICM), Pitié-Salpêtrière Hospital, AP-HP, INSERM, CNRS, University Hospital Pitié-Salpêtrière, CS21414, 75646 PARIS Cedex 13, France.
Maria Teresa BassiScientific Institute I.R.C.C.S. Eugenio Medea, 23842 Bosisio Parini, Italy.
Mercedes SerranoPediatric Neurology Department, Sant Joan de Déu Hospital, 08950 Barcelona, Spain.
Tanja Schmitz-HübschDepartment of Neurology and Experimental Neurology, Charité - Universitätsmedizin Berlin, 10117 Berlin, Germany.
Sarah DossDepartment of Neurology and Experimental Neurology, Charité - Universitätsmedizin Berlin, 10117 Berlin, Germany.
Gijs A J Van VelzenDepartment of Neurology, Leiden University Medical Center, 2333 Leiden, the Netherlands.
Quentin ThomasDepartment of Clinical Genetics, Dijon University Hospital, 21000 Dijon, France.
Antonio TrabaccaScientific Institute I.R.C.C.S. Eugenio Medea, 23842 Bosisio Parini, Italy.
Juan Dario Ortigoza-EscobarPediatric Neurology Department, Sant Joan de Déu Hospital, 08950 Barcelona, Spain.
Stefano D'ArrigoFondazione IRCCS Istituto Neurologico Carlo Besta, 20133 Milan, Italy.
Dagmar TimmannDepartment of Neurology and Center for Translational Neuro- and Behavioral Sciences (C-TNBS), Essen University Hospital, University of Duisburg-Essen, 45147 Essen, Germany.
Chiara PantaleoniFondazione IRCCS Istituto Neurologico Carlo Besta, 20133 Milan, Italy.
Andrea MartinuzziScientific Institute I.R.C.C.S. Eugenio Medea, 23842 Bosisio Parini, Italy.
Elsa Besse-PinotDepartment of Neurology, Clermont-Ferrand University Hospital, 63000 Clermont-Ferrand, France.
Luca MarsiliGardner Family Center for Parkinson's Disease and Movement Disorders, Department of Neurology, University of Cincinnati, Cincinnati, OH 45219, USA.
Ettore CioffiSapienza University of Rome, Department of Medico-Surgical Sciences and Biotechnologies, Polo Pontino, 04100 Latina, Italy.
Francesco NicitaUnit of Neuromuscular and Neurodegenerative Disorders, Bambino Gesu' Children's Research Hospital, IRCCS, 00165 Rome, Italy.
Alejandro GiorgettiComputational Biomedicine, Institute for Advanced Simulations IAS-5 and Institute of Neuroscience and Medicine INM-9, Forschungszentrum Jülich GmbH, 52428 Jülich, Germany; Department of Biotechnology, Università degli Studi di Verona, 37134 Verona, Italy.
Isabella MoroniFondazione IRCCS Istituto Neurologico Carlo Besta, 20133 Milan, Italy.
Romina RomanielloScientific Institute I.R.C.C.S. Eugenio Medea, 23842 Bosisio Parini, Italy.
Carlo CasaliSapienza University of Rome, Department of Medico-Surgical Sciences and Biotechnologies, Polo Pontino, 04100 Latina, Italy.
Penina PongerNeurology Department, Tel-Aviv Sourasky Medical Center, 6329302 Tel-Aviv, Israel; Sackler School of Medicine, Tel-Aviv University, 6997801 Tel-Aviv, Israel.
Giorgio CasariSan Raffaele Hospital and Vita-Salute San Raffaele University, Milan, Italy.
Susanne T De BotDepartment of Neurology, Leiden University Medical Center, 2333 Leiden, the Netherlands.
Giovanni RistoriNeurosciences, Mental Health, and Sensory Organs (NESMOS) Department, S. Andrea Hospital, Sapienza University of Rome, 00189 Rome, Italy.
Lubov BlumkinSackler School of Medicine, Tel-Aviv University, 6997801 Tel-Aviv, Israel; Pediatric Movement Disorders Clinic, Pediatric Neurology Unit, Wolfson Medical Center, 5822012 Holon, Israel.
Barbara BorroniCentre for Neurodegenerative Disorders, Department of Clinical and Experimental Sciences, University of Brescia, 25121 Brescia, Italy.
Cyril GoizetUniversity Bordeaux, Equipe « Neurogénétique Translationnelle - NRGEN », INCIA CNRS UMR5287 Université Bordeaux and Centre de Reference Maladies Rares « Neurogénétique », Service de Génétique Médicale, Bordeaux University Hospital (CHU Bordeaux), 33000 Bordeaux, France.
Cecilia MarelliMMDN, University Montpellier, EPHE, INSERM and Expert Center for Neurogenetic Diseases, CHU, 34095 Montpellier, France.
Sylvia BoeschCenter for Rare Movement Disorders, Medical University of Innsbruck, 6020 Innsbruck, Austria.
Mathieu AnheimDepartment of Neurology, Strasbourg University Hospital, 67098 Strasbourg, France; Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM-U964; CNRS-UMR7104; University of Strasbourg, 67400 Illkirch-Graffenstaden, France.
Alessandro FillaDepartment of Neuroscience and Reproductive and Odontostomatological Sciences, University of Naples Federico II, 80131 Naples, Italy.
Henry HouldenDepartment of Neuromuscular Diseases, UCL Queen's Square Institute of Neurology, Queen's Square House, Queen's Square, WC1N 3BG London, UK.
Enrico BertiniUnit of Neuromuscular and Neurodegenerative Disorders, Bambino Gesu' Children's Research Hospital, IRCCS, 00165 Rome, Italy.
Thomas KlopstockGerman Center for Neurodegenerative Disease (DZNE), München, Germany; Department of Neurology, Friedrich-Baur Institute, University Hospital of Ludwig-Maximilians-University, Munich Cluster for Systems Neurology (SyNergy), 80336 Munich, Germany.
Matthis SynofzikGerman Center for Neurodegenerative Disease (DZNE), 72076 Tübingen, Germany; Department of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research & Center of Neurology, University of Tübingen, 72076 Tübingen, Germany.
Florence RiantDepartment of Neurovascular Molecular Genetics, Assistance Publique-Hôpitaux de Paris, Hôpital Saint-Louis, 75010 Paris, France.
Ginevra ZanniUnit of Neuromuscular and Neurodegenerative Disorders, Bambino Gesu' Children's Research Hospital, IRCCS, 00165 Rome, Italy.
Stefania MagriFondazione IRCCS Istituto Neurologico Carlo Besta, 20133 Milan, Italy.
Daniela Di BellaFondazione IRCCS Istituto Neurologico Carlo Besta, 20133 Milan, Italy.
Lorenzo NanettiFondazione IRCCS Istituto Neurologico Carlo Besta, 20133 Milan, Italy.
Jorge SequeirosCGPP, IBMC-Institute for Molecular and Cell Biology & UnIGENe, i3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal.
Jorge OliveiraCGPP, IBMC-Institute for Molecular and Cell Biology & UnIGENe, i3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal.
Bart Van de WarrenburgDepartment of Neurology, Donders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Center, 6525 Nijmegen, the Netherlands.
Ludger SchölsGerman Center for Neurodegenerative Disease (DZNE), 72076 Tübingen, Germany; Department of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research & Center of Neurology, University of Tübingen, 72076 Tübingen, Germany.
Franco TaroniFondazione IRCCS Istituto Neurologico Carlo Besta, 20133 Milan, Italy.
Alexis BriceSorbonne Université, Paris Brain Institute (ICM), Pitié-Salpêtrière Hospital, AP-HP, INSERM, CNRS, University Hospital Pitié-Salpêtrière, CS21414, 75646 PARIS Cedex 13, France.
Alexandra DurrSorbonne Université, Paris Brain Institute (ICM), Pitié-Salpêtrière Hospital, AP-HP, INSERM, CNRS, University Hospital Pitié-Salpêtrière, CS21414, 75646 PARIS Cedex 13, France. Electronic address: alexandra.durr@icm-institute.org.
Centre National de la Recherche Scientifique · FRFondazione IRCCS Istituto Neurologico Carlo Besta · ITGerman Center for Neurodegenerative Diseases · DEBambino Gesù Children's Hospital · ITIRCCS Eugenio Medea · ITInnsbruck Medical University · ATAzienda Ospedaliera Sant'Andrea · ITCharité - Universitätsmedizin Berlin · DEHospital Sant Joan de Déu Barcelona · ESi3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto · PTKing's College London · GBLeiden University Medical Center · NLRadboud University Nijmegen · NLSapienza University of Rome · ITTel Aviv University · ILUniversity of Brescia · ITUniversity of Naples Federico II · ITVita-Salute San Raffaele University · ITAssistance Publique – Hôpitaux de Paris · FREssen University Hospital · DE
Funding
Medical Research Council MR/S01165X/1
Abstract
Although the best-known spinocerebellar ataxias (SCAs) are triplet repeat diseases, many SCAs are not caused by repeat expansions. The rarity of individual non-expansion SCAs, however, has made it difficult to discern genotype-phenotype correlations. We therefore screened individuals who had been found to bear variants in a non-expansion SCA-associated gene through genetic testing, and after we eliminated genetic groups that had fewer than 30 subjects, there were 756 subjects bearing single-nucleotide variants or deletions in one of seven genes: CACNA1A (239 subjects), PRKCG (175), AFG3L2 (101), ITPR1 (91), STUB1 (77), SPTBN2 (39), or KCNC3 (34). We compared age at onset, disease features, and progression by gene and variant. There were no features that reliably distinguished one of these SCAs from another, and several genes-CACNA1A, ITPR1, SPTBN2, and KCNC3-were associated with both adult-onset and infantile-onset forms of disease, which also differed in presentation. Nevertheless, progression was overall very slow, and STUB1-associated disease was the fastest. Several variants in CACNA1A showed particularly wide ranges in age at onset: one variant produced anything from infantile developmental delay to ataxia onset at 64 years of age within the same family. For CACNA1A, ITPR1, and SPTBN2, the type of variant and charge change on the protein greatly affected the phenotype, defying pathogenicity prediction algorithms. Even with next-generation sequencing, accurate diagnosis requires dialogue between the clinician and the geneticist.
Indexed as
Cerebellar AtaxiaSpinocerebellar AtaxiasAtaxiaATPases Associated with Diverse Cellular ActivitiesATP-Dependent ProteasesGenetic TestingHumansPhenotypeUbiquitin-Protein LigasesAFG3L2 protein, humanATPases Associated with Diverse Cellular ActivitiesATP-Dependent ProteasesSTUB1 protein, humanUbiquitin-Protein LigasesSpinocerebellar Ataxia, SCA, CACNA1A, PRKCG, AFG3L2, ITPR1, STUB1, SPTBN2, KCNC3, onset
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