Clinical and genetic keys to cerebellar ataxia due to FGF14 GAA expansions
eBioMedicine. 2024-01-01; 99: 104931
DOI: 10.1016/j.ebiom.2023.104931
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Méreaux JL(1), Davoine CS(1), Pellerin D(2), Coarelli G(3), Coutelier M(1), Ewenczyk C(3), Monin ML(4), Anheim M(5), Le Ber I(1), Thobois S(6), Gobert F(7), Guillot-Noël L(1), Forlani S(1), Jornea L(1), Heinzmann A(1), Sangare A(8), Gaymard B(9), Guyant-Maréchal L(10), Charles P(3), Marelli C(11), Honnorat J(12), Degos B(13), Tison F(14), Sangla S(15), Simonetta-Moreau M(16), Salachas F(17), Tchikviladzé M(1), Castelnovo G(18), Mochel F(1), Klebe S(19), Castrioto A(20), Fenu S(21), Méneret A(22), Bourdain F(23), Wandzel M(24), Roth V(24), Bonnet C(24), Riant F(25), Stevanin G(26), Noël S(27), Fauret-Amsellem AL(27), Bahlo M(28), Lockhart PJ(29), Brais B(30), Renaud M(31), Brice A(1), Durr A(32).
Author information:
(1)Sorbonne Université, Paris Brain Institute – ICM, Inserm, CNRS, AP-HP, Paris,
France.
(2)Department of Neurology and Neurosurgery, Montreal Neurological Hospital and
Institute, McGill University, Montreal, QC, Canada; Department of Neuromuscular
Diseases, UCL Queen Square Institute of Neurology and the National Hospital for
Neurology and Neurosurgery, University College London, London, United Kingdom.
(3)Sorbonne Université, Paris Brain Institute – ICM, Inserm, CNRS, AP-HP, Paris,
France; Unité de Génétique Clinique, AP-HP, Hôpital Pitié-Salpêtrière, Paris,
France.
(4)Centre de Reference Maladies Rares « Neurogénétique », Service de Génétique
Médicale, Bordeaux University Hospital (CHU Bordeaux), 33000, Bordeaux, France.
(5)Department 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.
(6)Department of Neurology C, Expert Parkinson Centre NS-Park/F-CRIN, Hospices
Civils de Lyon, Pierre Wertheimer Neurological Hospital, 69677, Bron, France;
Marc Jeannerod Cognitive Neuroscience Institute, CNRS, UMR 5229, Bron, France;
Faculté de Médecine Et de Maïeutique Lyon Sud Charles Mérieux, Université Claude
Bernard Lyon 1, Université de Lyon, Lyon, France.
(7)Neuro-Intensive Care Unit, Hospices Civils de Lyon, Neurological Hospital
Pierre-Wertheimer, Lyon, France; University Lyon I, Villeurbanne, France.
(8)Sorbonne Université, Paris Brain Institute – ICM, Inserm, CNRS, AP-HP, Paris,
France; Department of Neurophysiology, University Hospital Group APHP-Sorbonne
University, Pitié-Salpêtrière Site, Paris, France.
(9)Department of Neurophysiology, University Hospital Group APHP-Sorbonne
University, Pitié-Salpêtrière Site, Paris, France.
(10)Neurophysiology Department, Rouen University Hospital, Rouen, France;
Medical Genetics Department, Rouen University Hospital, Rouen, France.
(11)MMDN, University Montpellier, EPHE, INSERM and Expert Center for
Neurogenetic Diseases, CHU, 34095, Montpellier, France.
(12)Reference Center for Paraneoplastic Neurological Syndromes and Autoimmune
Encephalitis, Hospices Civils de Lyon, MeLiS Institute UMR CNRS 5284 – INSERM
U1314, Université Claude Bernard Lyon 1, Lyon, France.
(13)Neurology Department, Avicenne Hospital, APHP, Hôpitaux Universitaires de
Paris-Seine Saint Denis (HUPSSD), Sorbonne Paris Nord, Réseau NS-PARK/FCRIN,
Bobigny, France.
(14)Institut des Maladies Neurodégénératives-Clinique (IMNc), University
Hospital Bordeaux, Bordeaux, France; Institut des Maladies Neurodégénératives,
CNRS, UMR 5293, Bordeaux University, Bordeaux, France.
(15)Neurology Department, Hôpital Fondation Adolphe de Rothschild, Paris,
France.
(16)Department of Neurology, University Hospital of Toulouse, 31300, Toulouse,
France; Toulouse NeuroImaging Center (ToNIC), Inserm, UPS, Université de
Toulouse, 31024, Toulouse, France; Clinical Investigation Center (CIC 1436),
Toulouse University Hospital, INSERM, 31059, Toulouse, France.
(17)Sorbonne Université, Paris Brain Institute – ICM, Inserm, CNRS, AP-HP,
Paris, France; Département de Neurologie, Assistance Publique Hôpitaux de Paris
(APHP), Centre de Référence SLA Ile de France, Hôpital de la Pitié-Salpêtrière,
Paris, France.
(18)Department of Neurology, Nîmes University Hospital, Hopital Caremeau, Nîmes,
France.
(19)Department of Neurology, University Hospital Essen, Essen, Germany.
(20)Univ. Grenoble Alpes, Inserm, U1216, CHU Grenoble Alpes, Grenoble Institut
Neurosciences, Neurology Department, 38000, Grenoble, France.
(21)Unit of Rare Neurological Diseases, Department of Clinical Neurosciences,
Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.
(22)Sorbonne Université, Paris Brain Institute – ICM, Inserm, CNRS, AP-HP,
Paris, France; Département de Neurologie, Hôpital de la Pitié-Salpêtrière,
Assistance Publique Hôpitaux de Paris (APHP), Paris, France.
(23)Service de Neurologie, Centre Hospitalier de la Côte Basque, Bayonne,
France.
(24)Laboratoire de Génétique Médicale, CHRU Nancy, Université de Lorraine,
INSERM UMR_S1256, NGERE, Nancy, France.
(25)Service de Génétique Moléculaire Neurovasculaire, AP-HP, Saint Louis
Hospital, Paris, France.
(26)Sorbonne Université, Paris Brain Institute – ICM, Inserm, CNRS, AP-HP,
Paris, France; Bordeaux University (Université de Bordeaux), Equipe «
Neurogénétique Translationnelle – NRGEN », INCIA CNRS UMR5287, EPHE, 33000,
Bordeaux, France.
(27)Unité de Neurogénétique Moléculaire et Cellulaire, AP-HP, Hôpital
Pitié-Salpêtrière, Paris, France.
(28)Population Health and Immunity Division, Walter and Eliza Hall Institute of
Medical Research, Department of Medical Biology, University of Melbourne,
Parkville, VIC, 3052, Australia.
(29)Bruce Lefroy Centre, Murdoch Children’s Research Institute and Department of
Paediatrics, University of Melbourne, Parkville, VIC, 3052, Australia.
(30)Department of Neurology and Neurosurgery, Montreal Neurological Hospital and
Institute, McGill University, Montreal, QC, Canada.
(31)Service de Génétique Clinique et de Neurologie, Hôpital Brabois, Nancy,
France; INSERM Unité 1256 N-GERE (Nutrition-Genetics and Environmental Risk
Exposure), Université de Lorraine, Nancy, France.
(32)Sorbonne Université, Paris Brain Institute – ICM, Inserm, CNRS, AP-HP,
Paris, France; Unité de Génétique Clinique, AP-HP, Hôpital Pitié-Salpêtrière,
Paris, France. Electronic address: .
BACKGROUND: SCA27B caused by FGF14 intronic heterozygous GAA expansions with at
least 250 repeats accounts for 10-60% of cases with unresolved cerebellar
ataxia. We aimed to assess the size and frequency of FGF14 expanded alleles in
individuals with cerebellar ataxia as compared with controls and to characterize
genetic and clinical variability.
METHODS: We sized this repeat in 1876 individuals from France sampled for
research purposes in this cross-sectional study: 845 index cases with cerebellar
ataxia and 324 affected relatives, 475 controls, as well as 119 cases with
spastic paraplegia, and 113 with familial essential tremor.
FINDINGS: A higher frequency of expanded allele carriers in index cases with
ataxia was significant only above 300 GAA repeats (10.1%, n = 85) compared with
controls (1.1%, n = 5) (p