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1. Massive sequencing of 70 genes reveals a myriad of missing genes or mechanisms to be uncovered in hereditary spastic paraplegias

Author

Paula Coutinho, Eva Brandão, Alexis Brice, Mathilde Mairey, Jorge Sequeiros, José Leal Loureiro, Laure Raymond, P. R. G. Ribeiro, Isabel Alonso, Giovanni Stevanin, S. Sara Morais, Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS), Departamento de Neurologia, Hospital S. Sebastiao, and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)

Subjects
0301 basic medicine, Male, Spastin, Kinesins, Disease, Biology, medicine.disease_cause, DNA sequencing, Article, 03 medical and health sciences, 0302 clinical medicine, Genetics, medicine, Inheritance Mode, Humans, Gene, Genetics (clinical), Mutation, Genetic heterogeneity, Spastic Paraplegia, Hereditary, [SCCO.NEUR]Cognitive science/Neuroscience, Inheritance (genetic algorithm), Proteins, Phenotype, 3. Good health, Pedigree, 030104 developmental biology, Genetic Loci, Female, 030217 neurology & neurosurgery
Abstract

International audience; Hereditary spastic paraplegias (HSP) are neurodegenerative disorders characterized by lower limb spasticity and weakness that can be complicated by other neurological or non-neurological signs. Despite a high genetic heterogeneity (460 causative genes), 40–70% of the families remain without a molecular diagnosis. Analysis of one of the pioneer cohorts of 193 HSP families generated in the early 1990s in Portugal highlighted that SPAST and SPG11 are the most frequent diagnoses. We have now explored 98 unsolved families from this series using custom next generation sequencing panels analyzing up to 70 candidate HSP genes. We identified the likely disease-causing variant in 20 of the 98 families with KIF5A being the most frequently mutated gene. We also found 52 variants of unknown significance (VUS) in 38% of the cases. These new diagnoses resulted in 42% of solved cases in the full Portuguese cohort (81/193). Segregation of the variants was not always compatible with the presumed inheritance, indicating that the analysis of all HSP genes regardless of the inheritance mode can help to explain some cases. Our results show that there is still a large set of unknown genes responsible for HSP and most likely novel mechanisms or inheritance modes leading to the disease to be uncovered, but this will require international collaborative efforts, particularly for the analysis of VUS.

Published
2017
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2. Ataxia with oculomotor apraxia type 2: clinical, biological and genotype/phenotype correlation study of a cohort of 90 patients

Author

R. Murphy, Michel Koenig, Christine Tranchant, C. Barbot, Larissa Arning, A. M’zahem, Paula Coutinho, B. Monga, Matthis Synofzik, Mitsunori Watanabe, Jean Pouget, Meriem Tazir, Mathieu Anheim, Mustafa A. Salih, J. P. Delaunoy, P. Charles, Jeanette Koht, J. De Bleecker, Ludger Schöls, Alexandra Durr, Jorge Sequeiros, Marie-Céline Fleury, I. Le Ber, Traki Benhassine, Cyril Goizet, Alexis Brice, Abdelmadjid Hamri, Cecilia Marelli, Maowia M. Mukhtar, Brigitte Chabrol, José Gazulla, Nathalie Drouot, M. Chbicheb, Lamia Alipacha, M. Fritsch, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de Neurologie [Strasbourg], CHU Strasbourg-Hopital Civil, 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), Faculté de Médecine, Université de Lubumbashi, Department of Neurology, Hospital S.Sebastião, UnIGENe, IBMC, Division of Pediatric Neurology, King Saud University [Riyadh] (KSU), Laboratoire de Diagnostic Génétique, Department of Human Genetics, Ruhr University Bochum (RUB), Research Division for Clinical Neurogenetics, Centre of Neurology and Hertie-Institute for Clinical Brain Research, BMC –Institute for Molecular and Cell Biology (ICBAS), Universidade do Porto, Service de génétique médicale, Université de Bordeaux (UB)-CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CRICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Faculty of Medicine [Oslo], University of Oslo (UiO), Service of Neurology, Hospital Universitario Miguel Servet, Ghent University Hospital, Institute of Endemic Diseases, University of Khartoum, Laboratoire de Recherche en Neurosciences, CHU Mustapha, Laboratoire de Biologie Cellulaire et Moléculaire, Université de Bab Ezzouar, Service de Neurologie, Hôpital de Narbonne, Hôpital Benbadis-CHU Constantine, Service de pédiatrie et neurologie pédiatrique, Université de la Méditerranée - Aix-Marseille 2-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Service de neurologie et maladie neuromusculaire, Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), The Adelaide and Meath Hospital, University of Dublin, Hirosaki University-Institute of Brain Science, Departamento de Neurologia, Hospital S. Sebastiao, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université de Lubumbashi (UNILU), Universidade do Porto = University of Porto, and Peney, Maité

Subjects
Male, Pathology, Gene mutation, Apraxia, AMYOTROPHIC-LATERAL-SCLEROSIS, Cohort Studies, 0302 clinical medicine, Medicine and Health Sciences, Oculomotor apraxia, Age of Onset, 0303 health sciences, Ophthalmoplegia, Autosomal recessive cerebellar ataxia, Magnetic Resonance Imaging, 3. Good health, Phenotype, Spinocerebellar ataxia, Disease Progression, Cerebellar atrophy, Female, alpha-Fetoproteins, medicine.symptom, Alpha-fetoprotein, RNA Helicases, GENE-MUTATIONS, Adult, medicine.medical_specialty, Ataxia, Genotype, ALPHA-FETOPROTEIN, Mutation, Missense, 03 medical and health sciences, medicine, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, CHROMOSOME 9Q34, FRIEDREICHS-ATAXIA, 030304 developmental biology, Retrospective Studies, SPINOCEREBELLAR ATAXIA, business.industry, OCULAR MOTOR APRAXIA, DNA Helicases, Apraxia, Ideomotor, medicine.disease, Multifunctional Enzymes, TELANGIECTASIA-LIKE DISORDER, Neurology (clinical), business, RECESSIVE CEREBELLAR ATAXIAS, 030217 neurology & neurosurgery, PERIPHERAL NEUROPATHY
Abstract

International audience; Ataxia with oculomotor apraxia type 2 (AOA2) is an autosomal recessive disease due to mutations in the senataxin gene, causing progressive cerebellar ataxia with peripheral neuropathy, cerebellar atrophy, occasional oculomotor apraxia and elevated alpha-feto-protein (AFP) serum level. We compiled a series of 67 previously reported and 58 novel ataxic patients who underwent senataxin gene sequencing because of suspected AOA2. An AOA2 diagnosis was established for 90 patients, originating from 15 countries worldwide, and 25 new senataxin gene mutations were found. In patients with AOA2, median AFP serum level was 31.0 microg/l at diagnosis, which was higher than the median AFP level of AOA2 negative patients: 13.8 microg/l, P = 0.0004; itself higher than the normal level (3.4 microg/l, range from 0.5 to 17.2 microg/l) because elevated AFP was one of the possible selection criteria. Polyneuropathy was found in 97.5% of AOA2 patients, cerebellar atrophy in 96%, occasional oculomotor apraxia in 51%, pyramidal signs in 20.5%, head tremor in 14%, dystonia in 13.5%, strabismus in 12.3% and chorea in 9.5%. No patient was lacking both peripheral neuropathy and cerebellar atrophy. The age at onset and presence of occasional oculomotor apraxia were negatively correlated to the progression rate of the disease (P = 0.03 and P = 0.009, respectively), whereas strabismus was positively correlated to the progression rate (P = 0.03). An increased AFP level as well as cerebellar atrophy seem to be stable in the course of the disease and to occur mostly at or before the onset of the disease. One of the two patients with a normal AFP level at diagnosis had high AFP levels 4 years later, while the other had borderline levels. The probability of missing AOA2 diagnosis, in case of sequencing senataxin gene only in non-Friedreich ataxia non-ataxia-telangiectasia ataxic patients with AFP level > or =7 microg/l, is 0.23% and the probability for a non-Friedreich ataxia non-ataxia-telangiectasia ataxic patient to be affected with AOA2 with AFP levels > or =7 microg/l is 46%. Therefore, selection of patients with an AFP level above 7 microg/l for senataxin gene sequencing is a good strategy for AOA2 diagnosis. Pyramidal signs and dystonia were more frequent and disease was less severe with missense mutations in the helicase domain of senataxin gene than with missense mutations out of helicase domain and deletion and nonsense mutations (P = 0.001, P = 0.008 and P = 0.01, respectively). The lack of pyramidal signs in most patients may be explained by masking due to severe motor neuropathy.

Published
2009
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3. Mutations in SPG11 are frequent in autosomal recessive spastic paraplegia with thin corpus callosum, cognitive decline and lower motor neuron degeneration

Author

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)

Subjects
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
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4. Mutations in SPG11, encoding spatacsin, are a major cause of spastic paraplegia with thin corpus callosum

Author

Hamid Azzedine, Alessandro Filla, Merle Ruberg, Paula Coutinho, Filippo M. Santorelli, Enrico Bertini, Vítor Tedim Cruz, Elodie Martin, N. Elleuch, D. Grid, Jacques Chomilier, Alessandra Tessa, Naima Bouslam, Perrine Charles, Alexandra Durr, Bertrand Fontaine, Eric LeGuern, Paola S. Denora, Christian Confavreux, Giovanni Stevanin, Anne Marie Ouvrard-Hernandez, Alexis Brice, Meriem Tazir, José Leal Loureiro, Alexander Lossos, 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), Unit of Molecular Medicine, IRCCS, UnIGENe, Universidade do Porto, Institut de minéralogie et de physique des milieux condensés (IMPMC), Université Pierre et Marie Curie - Paris 6 (UPMC)-IPG PARIS-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Département de neurologie, Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble, Department of Neurology, Hadassah Hebrew University Medical Center [Jerusalem], Departamento de Neurologia, Hospital S. Sebastiao, Department of neurology, Hopital Habib Bourguiba - Habib Bourguiba Hospital [Sfax], Hopital Neurologique, Ministère de la santé, Service de Neurologie A-Hopital Neurologique Pierre Wertheimer, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Généthon, Service de Neurologie, Hopital Mustapha, Affections de la Myeline et des Canaux Ioniques Musculaires, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Neurological Sciences, Università degli studi di Napoli Federico II, ANR-05-MRAR-0001,Cav3pathies,Approches physiopathologique et moléculaire de la signalisation calcique dans les caveolinopathies musculaires(2005), Université Mohammed V, Service de neurologie 1 [CHU Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Hôpital neurologique, Hospices Civils de Lyon (HCL), Neurologie Expérimentale et Thérapeutique, IFR70-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Mustapha, Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CRICM), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Department of Computer Science and Engineering, New York University [New York] (NYU), NYU System (NYU)-NYU System (NYU), Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR70-Institut National de la Santé et de la Recherche Médicale (INSERM), Universidade do Porto = University of Porto, Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Diderot - Paris 7 (UPD7)-Institut de Physique du Globe de Paris (IPG Paris)-Centre National de la Recherche Scientifique (CNRS), University of Naples Federico II = Università degli studi di Napoli Federico II, Service de Neurologie [CHU Pitié-Salpêtrière], IFR70-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Stevanin, G, Santorelli, Fm, Azzedine, H, Coutinho, P, Chomilier, J, Denora, P, Martin, E, OUVRARD HERNANDEZ, Am, Tessa, A, Bouslam, N, Lossos, A, Charles, P, Loureiro, Jl, Elleuch, N, Confavreux, C, Cruz, Vt, Ruberg, M, Leguern, E, Grid, D, Tazir, M, Fontaine, B, Filla, Alessandro, Bertini, E, Durr, A, Brice, A., Université Mohammed V de Rabat [Agdal] (UM5), and Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Genetic Linkage, [SDV]Life Sciences [q-bio], DNA Mutational Analysis, MESH: Rats, Sprague-Dawley, MESH: Base Sequence, Corpus callosum, Corpus Callosum, Rats, Sprague-Dawley, MESH: Genotype, 0302 clinical medicine, MESH: Child, Chlorocebus aethiops, Spastic, MESH: Proteins, MESH: Animals, Age of Onset, MESH: DNA Mutational Analysis, Child, ComputingMilieux_MISCELLANEOUS, Genetics, Cerebral Cortex, 0303 health sciences, MESH: Spastic Paraplegia, Hereditary, Pedigree, MESH: COS Cells, COS Cells, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Paraplegia, Adult, MESH: Mutation, Adolescent, Genotype, MESH: Rats, MESH: Pedigree, MESH: Age of Onset, Molecular Sequence Data, Locus (genetics), Biology, MESH: Corpus Callosum, Frameshift mutation, 03 medical and health sciences, Chromosome 15, Genetic linkage, medicine, Animals, Humans, 030304 developmental biology, MESH: Adolescent, Chromosomes, Human, Pair 15, MESH: Humans, MESH: Molecular Sequence Data, Base Sequence, Spastic Paraplegia, Hereditary, Proteins, MESH: Adult, medicine.disease, MESH: Cercopithecus aethiops, MESH: Cerebral Cortex, Rats, nervous system diseases, MESH: Lod Score, Corticospinal tract, Mutation, Lod Score, MESH: Linkage (Genetics), 030217 neurology & neurosurgery, MESH: Chromosomes, Human, Pair 15
Abstract

Autosomal recessive hereditary spastic paraplegia (ARHSP) with thin corpus callosum (TCC) is a common and clinically distinct form of familial spastic paraplegia that is linked to the SPG11 locus on chromosome 15 in most affected families. We analyzed 12 ARHSP-TCC families, refined the SPG11 candidate interval and identified ten mutations in a previously unidentified gene expressed ubiquitously in the nervous system but most prominently in the cerebellum, cerebral cortex, hippocampus and pineal gland. The mutations were either nonsense or insertions and deletions leading to a frameshift, suggesting a loss-of-function mechanism. The identification of the function of the gene will provide insight into the mechanisms leading to the degeneration of the corticospinal tract and other brain structures in this frequent form of ARHSP.

Published
2007
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5. Spastic paraplegia with thin corpus callosum: description of 20 new families, refinement of the SPG11 locus, candidate gene analysis and evidence of genetic heterogeneity

Author

Giovanni, Stevanin, Giorgia, Montagna, Hamid, Azzedine, Enza Maria Valente, Alexandra, Durr, Valentina, Scarano, Naima, Bouslam, Denise, Cassandrini, Denora, Paola S., Chiara, Criscuolo, Soraya, Belarbi, Antonio, Orlacchio, Philippe, Jonveaux, Gabriella, Silvestri, Anne Marie Ouvrad Hernandez, De Michele, G., Meriem, Tazir, Caterina, Mariotti, Knut, Brockmann, Alessandro, Malandrini, Van Der Knapp, M. S., Marcella, Neri, Hassan, Tonekaboni, Melone, Mariarosa A. B., Alessandra, Tessa, Teresa Dotti, M., Michela, Tosetti, Pauri, Flavia, Antonio, Federico, Casali, Carlo, Cruz, Vitor T., Loureiro, Jose L., Federico, Zara, Sylvie, Forlani, Enrico, Bertini, Paula, Coutinho, Alessandro, Filla, Alexis, Brice, Santorelli, Filippo M., Casali, C., Neurologie et thérapeutique expérimentale, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR70-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Unit of Molecular Medicine, IRCCS, Mendel Institute, Department of Neurological Sciences, University of Naples Federico II = Università degli studi di Napoli Federico II, Pediatric Neurology and Neuromuscular Diseases Unit, Università degli studi di Genova = University of Genoa (UniGe), Service de Neurologie, Hopital Mustapha, Department of Neurosciences, Università degli Studi di Roma Tor Vergata [Roma], Service de Génétique [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Department of Neuroscience, Catholic University, Département de neurologie, Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble, Besta Neurological Institute, Department of Pediatrics and Neuropediatrics, Georg-August-University = Georg-August-Universität Göttingen, Institute of Neurological Sciences, Department of Child Neurology, VU University Medical Center [Amsterdam], Medical Genetics, Università degli Studi di Ferrara = University of Ferrara (UniFE), Stella Maris, Department of Neurology and ORL, Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome] (UNIROMA), Departamento de Neurologia, Hospital S. Sebastiao, ANR-05-MRAR-0001,Cav3pathies,Approches physiopathologique et moléculaire de la signalisation calcique dans les caveolinopathies musculaires(2005), Stevanin, G, Montagna, G, Azzedine, H, Valente, Em, Durr, A, Scarano, V, Bouslam, N, Cassandrini, D, Denora, P, Criscuolo, C, Belarbi, S, Orlacchio, A, Jonveaux, P, Silvestri, G, Hernandez, Am, DE MICHELE, G, Tazir, M, Mariotti, C, Brockmann, K, Malandrini, A, VAN DER KNAPP, M, Neri, M, Tonekaboni, H, Melone, Mariarosa Anna Beatrice, Tessa, A, Dotti, Mt, Tosetti, M, Pauri, F, Federico, A, Casali, C, Cruz, Vt, Loureiro, Jl, Zara, F, Forlani, S, Bertini, E, Coutinho, P, Filla, A, Brice, A, Santorelli, Fm, Pediatric surgery, 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], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Università degli studi di Napoli Federico II, Universita degli studi di Genova, Georg-August-University [Göttingen], Università degli Studi di Ferrara (UniFE), University of Naples Federico II, and Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome]

Subjects
Male, Candidate gene, Genetic Linkage, Corpus Callosum, Consanguinity, Autosomal recessive hereditary spastic, Genetic heterogeneity, 0302 clinical medicine, MESH: Child, Spastic Paraplegia, Autosomal recessive hereditary spastic paraplegia, Linkage, SPG11, Thin corpus callosum, Adolescent, Child, Child, Preschool, Chromosomes, Human, Pair 15, Female, Humans, Infant, Lod Score, Pedigree, Phenotype, Spastic Paraplegia, Hereditary, Genes, Recessive, Genetic Heterogeneity, Genetics, Genetics (clinical), Cellular and Molecular Neuroscience, 0303 health sciences, MESH: Spastic Paraplegia, Hereditary, MESH: Genetic Heterogeneity, MESH: Infant, autosomal recessive hereditary spastic paraplegia, genetic heterogeneity, linkage, spg11, thin corpus callosum, Hereditary, Settore MED/26 - Neurologia, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Human, Hereditary spastic paraplegia, MESH: Pedigree, Locus (genetics), Biology, MESH: Phenotype, MESH: Corpus Callosum, Chromosomes, 03 medical and health sciences, Gene mapping, Genetic linkage, medicine, Recessive, Preschool, MESH: Genes, Recessive, 030304 developmental biology, MESH: Adolescent, MESH: Consanguinity, Autosome, MESH: Humans, Thin corpus callosum, SPG11, Linkage, Haplotype, MESH: Child, Preschool, Pair 15, medicine.disease, MESH: Male, Genes, MESH: Lod Score, MESH: Linkage (Genetics), MESH: Female, 030217 neurology & neurosurgery, MESH: Chromosomes, Human, Pair 15
Abstract

We studied 20 Mediterranean families (40 patients) with autosomal recessive hereditary spastic paraplegia and thin corpus callosum (ARHSP-TCC, MIM 604360) to characterize their clinical and genetic features. In six families (17 patients) of Algerian Italian, Moroccan, and Portuguese ancestry, we found data consistent with linkage to the SPG11 locus on chromosome 15q13-15, whereas, in four families (nine patients of Italian, French, and Portuguese ancestry) linkage to the SPG11 locus could firmly be excluded, reinforcing the notion that ARHSP-TCC is genetically heterogeneous. Patients from linked and unlinked families could not be distinguished on the basis of clinical features alone. In SPG11-linked kindred, haplotype reconstruction allowed significant refinement to 6 cM, of the minimal chromosomal interval, but analysis of two genes (MAP1A and SEMA6D) in this region did not identify causative mutations. Our findings suggest that ARHSP-TCC is the most frequent form of ARHSP in Mediterranean countries and that it is particularly frequent in Italy.

Published
2006
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