1. Mutations in SPG11 are frequent in autosomal recessive spastic paraplegia with thin corpus callosum, cognitive decline and lower motor neuron degeneration
- Author
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Abdelmadjid Hamri, Paulo Alegria, Mathieu Anheim, Alexander Lossos, Masatoyo Nishizawa, Kiyoshi Iwabuchi, Cyril Goizet, José Leal Loureiro, Christel Depienne, Paula Coutinho, Florence Pasquier, Anne Kjersti Erichsen, Amir Boukhris, Vítor Tedim Cruz, Sylvie Forlani, Chokri Mhiri, Jeremy Truchetto, Filippo M. Santorelli, Alexandra Durr, Paola S. Denora, Christine Tranchant, Isabelle Le Ber, José Vale, Imed Feki, Hamid Azzedine, Giovanni Stevanin, Soreya Belarbi, Israela Lerer, G. Uyanik, Vardiela Meiner, Guillaume Garrigues, Alberto Luis Rosa, Alexis Brice, Chantal M. E. Tallaksen, Meriem Tazir, Masayoshi Tada, Victoria Gonzalez-Martinez, Didier Hannequin, Neurologie et thérapeutique expérimentale, Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR70-Université Pierre et Marie Curie - Paris 6 (UPMC), Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Department of neurology, Hopital Habib Bourguiba - Habib Bourguiba Hospital [Sfax], Service de Neurologie, Hopital Mustapha, Department of Neurology, Hadassah Hebrew University Medical Center [Jerusalem], Laboratorio de Biologia Cellular y Molecular, Fundacion Allende and Sanatorio Allende, Department of Human Genetics, Hadassah-Hebrew University Medical Centre, Hôpital Benbadis, Serviçio Neurologia, Hospital De Egas Moniz, Departamento de Neurologia, Hospital S. Sebastiao, Niigata University, Génétique médicale et fonctionnelle du cancer et des maladies neuropsychiatriques, Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de neurologie [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU), Department of Genetics, University Hospital, Neurology Department, CHU Strasbourg, Service de génétique médicale, Université de Bordeaux (UB)-CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Département de neurologie [Montpellier], Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui de Chauliac [Montpellier]-Université de Montpellier (UM), Neurological Clinic of Yokohama, Yokohama, Department of Histopathology, Ullevål University Hospital, Département de neurologie[Lille], Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Ulleval University Hospital, Département de Neurologie, CHU Strasbourg-Hopital Civil, Service de Neurologie [Strasbourg], Unit of Molecular Medicine, IRCCS, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), ANR-05-MRAR-0001,Cav3pathies,Approches physiopathologique et moléculaire de la signalisation calcique dans les caveolinopathies musculaires(2005), Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR70-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui de Chauliac [CHU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Université de Montpellier (UM), Département de neurologie [Lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), and Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)
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Male ,Genetic Linkage ,DNA Mutational Analysis ,Neurological disorder ,MESH: Base Sequence ,Corpus callosum ,Gastroenterology ,Corpus Callosum ,MESH: Magnetic Resonance Imaging ,MESH: Genotype ,0302 clinical medicine ,MESH: Mental Retardation ,MESH: Child ,MESH: Motor Neuron Disease ,MESH: Proteins ,Cognitive decline ,Age of Onset ,MESH: DNA Mutational Analysis ,Child ,0303 health sciences ,MESH: Spastic Paraplegia, Hereditary ,Cognitive disorder ,Brain ,Magnetic Resonance Imaging ,3. Good health ,Pedigree ,medicine.anatomical_structure ,Phenotype ,Child, Preschool ,Female ,[SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] ,Paraplegia ,Psychology ,Adult ,medicine.medical_specialty ,MESH: Mutation ,Adolescent ,Genotype ,MESH: Pedigree ,MESH: Age of Onset ,Molecular Sequence Data ,Genes, Recessive ,MESH: Phenotype ,MESH: Corpus Callosum ,Lower motor neuron ,03 medical and health sciences ,MESH: Brain ,Internal medicine ,Intellectual Disability ,medicine ,Humans ,Motor Neuron Disease ,MESH: Genes, Recessive ,030304 developmental biology ,MESH: Adolescent ,MESH: Humans ,MESH: Molecular Sequence Data ,Base Sequence ,Spastic Paraplegia, Hereditary ,MESH: Child, Preschool ,Proteins ,MESH: Adult ,medicine.disease ,MESH: Male ,MESH: Cognition Disorders ,Mutation ,Physical therapy ,Neurology (clinical) ,Age of onset ,Cognition Disorders ,MESH: Female ,MESH: Linkage (Genetics) ,030217 neurology & neurosurgery ,Executive dysfunction - Abstract
Hereditary spastic paraplegias (HSP) are neurodegenerative diseases mainly characterized by lower limb spasticity associated, in complicated forms, with additional neurological signs. We have analysed a large series of index patients (n = 76) with this condition, either from families with an autosomal recessive inheritance (n = 43) or isolated patients (n = 33), for mutations in the recently identified SPG11 gene. We found 22 truncating mutations, including the first four splice-site mutations, segregating in seven isolated cases and 13 families. Nineteen mutations were novel. Two recurrent mutations were found in Portuguese and North-African patients indicating founder effects in these populations. The mutation frequency varied according to the phenotype, from 41%, in HSP patients presenting with a thin corpus callosum (TCC) visualized by MRI, to 4.5%, in patients with mental impairment without a TCC. Disease onset occurred during the first to the third decade mainly by problems with gait and/or mental retardation. After a mean disease duration of 14.9 +/- 6.6 years, the phenotype of 38 SPG11 patients was severe with 53% of patients wheelchair bound or bedridden. In addition to mental retardation, 80% of the patients showed cognitive decline with executive dysfunction. Interestingly, the phenotype also frequently included lower motor neuron degeneration (81%) with wasting (53%). Slight ocular cerebellar signs were also noted in patients with long disease durations. In addition to a TCC (95%), brain MRI revealed white matter alterations (69%) and cortical atrophy (81%), which worsened with disease duration. In conclusion, our study reveals the high frequency of SPG11 mutations in patients with HSP, a TCC and cognitive impairment, including in isolated patients, and extends the associated phenotype.
- Published
- 2008