Author: "G, Stevanin" - Searchworks@Jio Institute Digital Library Search Results

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305 results on '"G, Stevanin"'

1. Current Knowledge of Endolysosomal and Autophagy Defects in Hereditary Spastic Paraplegia

Author: Liriopé Toupenet Marchesi, G. Stevanin, Marion Leblanc, Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), 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)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), École pratique des hautes études (EPHE), and Université Paris sciences et lettres (PSL)
Subjects: 0301 basic medicine, Nervous system, autophagy, spastic paraplegia, Endosome, Hereditary spastic paraplegia, QH301-705.5, Kinesins, Nerve Tissue Proteins, Review, Degeneration (medical), Biology, Genetic Heterogeneity, 03 medical and health sciences, 0302 clinical medicine, lysosomes, GTP-Binding Proteins, Valosin Containing Protein, medicine, Humans, Biology (General), Pathological, Motor Neurons, Spastic Paraplegia, Hereditary, Genetic heterogeneity, Autophagy, Membrane Proteins, Proteins, General Medicine, medicine.disease, 030104 developmental biology, medicine.anatomical_structure, Gene Expression Regulation, endosomes, [SDE]Environmental Sciences, Neuroscience, 030217 neurology & neurosurgery, Signal Transduction, trans-Golgi Network
Abstract: International audience; Hereditary spastic paraplegia (HSP) refers to a group of neurological disorders involving the degeneration of motor neurons. Due to their clinical and genetic heterogeneity, finding common effective therapeutics is difficult. Therefore, a better understanding of the common pathological mechanisms is necessary. The role of several HSP genes/proteins is linked to the endolysosomal and autophagic pathways, suggesting a functional convergence. Furthermore, impairment of these pathways is particularly interesting since it has been linked to other neurodegenerative diseases, which would suggest that the nervous system is particularly sensitive to the disruption of the endolysosomal and autophagic systems. In this review, we will summarize the involvement of HSP proteins in the endolysosomal and autophagic pathways in order to clarify their functioning and decipher some of the pathological mechanisms leading to HSP..
Published: 2021
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2. NPTX1 mutations trigger endoplasmic reticulum stress and cause autosomal dominant cerebellar ataxia

Author: François Ancien, Nicolas Sgarioto, Roxanne Larivière, Bernard Brais, Martje G Pauly, David-Alexandre Trégouët, Eric A. Shoubridge, Ganapathi Varma Saripella, Natalie Deininger, Marie Coutelier, Dimitri Gilis, Maxime Jacoupy, Léna Guillot-Noel, Khalid H El Hachimi, Alexandra Durr, Alexis Brice, Flore Renaud, Sabrina Sayah, G. Stevanin, Alexandre Janer, Perrine Charles, Marianne Rooman, Nicolas Auger, C. Helmchen, Isabelle Le Ber, Tobias B. Haack, Fabrizio Pucci, Rémi Valter, and Astrid Nümann
Subjects: Genetics, Arthrogryposis, Cerebellar ataxia, Cerebellar Ataxia, Genetic heterogeneity, ATF6, Endoplasmic reticulum, Nerve Tissue Proteins, Biology, medicine.disease, Endoplasmic Reticulum Stress, Phenotype, Pedigree, C-Reactive Protein, Autosomal dominant cerebellar ataxia, Mutation, Exome Sequencing, medicine, Missense mutation, Humans, Neurology (clinical), medicine.symptom, Exome sequencing
Abstract: With more than 40 causative genes identified so far, autosomal dominant cerebellar ataxias exhibit a remarkable genetic heterogeneity. Yet, half the patients are lacking a molecular diagnosis. In a large family with nine sampled affected members, we performed exome sequencing combined with whole-genome linkage analysis. We identified a missense variant in NPTX1, NM_002522.3:c.1165G>A: p.G389R, segregating with the phenotype. Further investigations with whole-exome sequencing and an amplicon-based panel identified four additional unrelated families segregating the same variant, for whom a common founder effect could be excluded. A second missense variant, NM_002522.3:c.980A>G: p.E327G, was identified in a fifth familial case. The NPTX1-associated phenotype consists of a late-onset, slowly progressive, cerebellar ataxia, with downbeat nystagmus, cognitive impairment reminiscent of cerebellar cognitive affective syndrome, myoclonic tremor and mild cerebellar vermian atrophy on brain imaging. NPTX1 encodes the neuronal pentraxin 1, a secreted protein with various cellular and synaptic functions. Both variants affect conserved amino acid residues and are extremely rare or absent from public databases. In COS7 cells, overexpression of both neuronal pentraxin 1 variants altered endoplasmic reticulum morphology and induced ATF6-mediated endoplasmic reticulum stress, associated with cytotoxicity. In addition, the p.E327G variant abolished neuronal pentraxin 1 secretion, as well as its capacity to form a high molecular weight complex with the wild-type protein. Co-immunoprecipitation experiments coupled with mass spectrometry analysis demonstrated abnormal interactions of this variant with the cytoskeleton. In agreement with these observations, in silico modelling of the neuronal pentraxin 1 complex evidenced a destabilizing effect for the p.E327G substitution, located at the interface between monomers. On the contrary, the p.G389 residue, located at the protein surface, had no predictable effect on the complex stability. Our results establish NPTX1 as a new causative gene in autosomal dominant cerebellar ataxias. We suggest that variants in NPTX1 can lead to cerebellar ataxia due to endoplasmic reticulum stress, mediated by ATF6, and associated to a destabilization of NP1 polymers in a dominant-negative manner for one of the variants.
Published: 2021

3. The gene for Machado–Joseph disease maps to the same 3-cM interval as the spinal cerebellar ataxia 3 gene on chromosome 14q

Author: G. Stevanin, P.S. Sousa, G. Cancel, A. Dürr, O. Dubourg, G.A. Nicholson, J. Weissenbach, E. Jardim, Y. Agid, E. Cassa, and A. Brice
Subjects: autosomal dominant cerebellar ataxia type I, chromosome 14, linkage analysis, Machado–Joseph disease, microsatellite, spinal cerebellar ataxia 3, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract: Machado–Joseph disease (MJD) is an autosomal dominant neurodegenerative disorder in families of Portuguese–Azorean ancestry. The gene responsible for MJD has been assigned to a 29-cM interval on chromosome 14q. A large Brazilian family with MJD was genotyped with six new microsatellite markers spanning 19 cM on chromosome 14q. Linkage analysis and haplotype reconstruction reduced theMJDcandidate region to a 3-cM interval between markers D14S280 and D14S81, permitting positional cloning. This interval also contains thespinal cerebellar ataxia 3(SCA3) gene, responsible for a genetic subtype of the type I autosomal dominant cerebellar ataxias, clinically related to MJD. This result supports the hypothesis that abnormalities in the same gene may be responsible for both disorders. The minor clinical differences between the two diseases may result from allelic heterogeneity.
Published: 1994
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4. SCA5 (Spinocerebellar Ataxia 5)☆

Author: A. Durr and G. Stevanin
Subjects: Pathology, medicine.medical_specialty, Dendritic spine, Cerebellar ataxia, business.industry, Neurodegeneration, Autosomal recessive cerebellar ataxia, Nystagmus, medicine.disease, Atrophy, nervous system, medicine, Spinocerebellar ataxia, Spectrin, medicine.symptom, business, Neuroscience
Abstract: Spinocerebellar ataxia 5 (SCA5) is a rare autosomal dominant form of cerebellar ataxia in which patients present with a slowly progressive cerebellar ataxia with frequent gaze-evoked nystagmus and, less frequently, a decreased vibration sense, tremor and facial myokymia with severe cerebellar global atrophy. To date, there are four Caucasian families described with four different mutations, as well as a Japanese family with an in-frame deletion, all identified in the beta-III spectrin gene ( SPTBN2 ). Allelic disorders include congenital cerebral palsy and infantile autosomal recessive cerebellar ataxia with mental impairment at the heterozygous and homozygous states, respectively. Analysis of the SCA5 mouse model and functional studies indicate that reduced localization of glutamate receptors at dendritic spines of Purkinje cells are a key element of the pathophysiology of this disease. This is the first spectrin, component of the cytoskeleton, connected to cerebellar ataxia.
Published: 2017
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5. SPG3A is the most frequent cause of hereditary spastic paraplegia with onset before age 10 years

Author: Alexis Brice, Isabelle Nelson, Sylvie Forlani, C. Depienne, Cyril Goizet, Pascale Ribai, Alexandra Durr, Merle Ruberg, Michito Namekawa, F. Fellmann, and G. Stevanin
Subjects: Adult, Male, Pediatrics, medicine.medical_specialty, Adolescent, Hereditary spastic paraplegia, Disease duration, DNA Mutational Analysis, GTP Phosphohydrolases, Central nervous system disease, Degenerative disease, GTP-Binding Proteins, medicine, Humans, Genetic Predisposition to Disease, In patient, Genetic Testing, Peripheral Nerves, Age of Onset, Aged, Family Health, Spastic Paraplegia, Hereditary, business.industry, Brain, Membrane Proteins, Middle Aged, medicine.disease, Surgery, Phenotype, Mutation, Autosomal Dominant Hereditary Spastic Paraplegia, Neurology (clinical), Wallerian Degeneration, business
Abstract: Seven families with six different SPG3A mutations were identified among 106 with autosomal dominant hereditary spastic paraplegia (HSP). Two mutations were novel (T162P, C375R). SPG3A was twice as frequent as SPG4 in patients with onset before age 10 years (31.8%). Later onset was not observed. The phenotype was pure HSP, but disease duration was longer than in non-SPG3A/SPG4 patients, leading ultimately to greater handicap.
Published: 2006
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6. Fourth meeting of the European Neurological Society 25–29 June 1994 Barcelona, Spain

Author: H. Hattig, C. Delli Pizzi, M. C. Addonizio, Michelle Davis, A. R. Giovagnoli, L. Florensa, M. Roth, J. de Kruijk, Francisco Lacruz, Ph. Dewailly, A. Toygar, C. Avendano, P.P. De Deyn, J. F. Hurtevent, F. Lomeila, T. W. Wong, Gordon T. Plant, M. Bud, H. J. Willison, DH Miller, D. W. Langdon, R. Cioni, J. Servan, A. Kaygisiz, E. Racadot, D. B. Schens, E. Picciola, L. Falip, C. Bouchard, J. Jotova, A. Jorge-Santamaria, P. Misra, A. Dufour, C. P. Panagopoulos, A. Venneri, B. Sredni, B. Angelard, M. Janelidze, M. Carreno, J. Obenberger, J. Pouget, H. W. Moser, R. Kaufmann, J. A. Molina, D. Linden, A. Martin Urda, E. Uvestad, A. Krone, J. P. Cochin, J. Mallecourt, A. Cambon-Thomsen, K. Violleau, P. Osschmann, A. M. Durocher, E. Bussaglia, D. M. Danielle, H. Efendi, C. Van Broeckhoven, K. G. Jordan, W. Rautenberg, C. Iniguez, J. M. Delgado, Graham Watson, M. Lawden, Gareth J. Barker, K. Stiasny, James T. Becker, G. Campanella, E. Peghi, A. Poli, A. Haddad, T. Yamawaki, Giacomo P. Comi, S. Sotgiu, B. Ersmark, A. Pomes, M. Ziegler, P. Ferrante, P. Ruppi, H. KuÇukoglu, R. Bouton, U. K. Rinne, P. Vieregge, M. Dary, P. Giunti, Peter J. Goadsby, S. Jung, E. Secor, A. Steinberg, N. Vila, M. A. Hernandez, M. Cursi, A. Enqelhardt, A. Engelhardt, J. Veitch, F. Di Silverio, F. Arnaud, B. Neundörfer, R. Brucher, Dominique Caparros-Lefebvre, B. Meyer, Marianne Dieterich, M. H. Snidaro, R. Gomez, R. Cerbo, M. Ragno, J. M. Vance, S. Nemni, A. Caliskan, F. Barros, I. Velcheva, D. Ceballos-Baumann, V. Barak, A. Avila, N. Antonova, F. Resche, S. Pappata, L. Varela, S. R. Silveira Santos, A. Cammarota, L. Naccache, Y. Nara, E. Tournier-Lasserves, R. Mobner, T. Chase, A. Ensenyat, J. Ulrich, G. Giegerich, M. Rother, M. Revilla, N. Nitschke, K. Honczarenko, E. Basart Tarrats, J. Blin, B. Jacob, J. Santamaria, S. Knezevic, J. L. Castillo, M. Antem, J. Colomer, O. Busse, Didier Hannequin, S. Carrier, J. B. Ruidavets, C. Rozman, J. Bogoussslavsky, J. Pascual Calvet, E. Monros, J. M. Polo, M. Zucconl, Javier Muruzabal, R. R. Allen, R. Rivolta, K. Haugaard, A. Nespolo, K. Hoang-Xuang, G. Bussone, T. Avramidis, E. Corsini, Christiana Franke, T. Vinogradova, H. Boot, K. Vestergaard, G. H. Jansen, N. Argentino, M. Raltzig, W. Linssen, Mark B. Pepys, P. Roblot, L. Lauritzen, E. Fainardi, D. Morin, T. X. Arbizu Urdiain, J. Wollenhaupt, S. Bostantjopoulou, G. Pavesi, A. D. Forman, Giovanni Fabbrini, D. Jean, J. J. Archelos, M. I. Blanchs, M. Del Gobbo, Anna Carla Turconi, Ch. Derouesné, Elio Scarpini, A. Visbeck, P. Castejon, J. P. Renou, F. Mounier-Vehier, G. Potagas, Ch. Duyckaerts, A. Filla, R. Schneider, G. Ronen, K. Nagata, J. P. Vedel, A. Henneberg, G. van Melle, C. Baratti, H. Knott, M. C. Prevett, A. Bes, B. Metin, Jos V. Reempts, L. Martorell, Mefkure Eraksoy, H. O. Handwerker, D. S. Younger, O. Oktem, D. Frongillo, C. Soriano-Soriano, L. Niehaus, F. Zipp, A. Tartaro, S Newman, R. H. Browne, P. Davous, R. Sanchez, M. Muros, M. E. Kornhuber, A. Lavarone, M. Mohr, M. R. Garcia, S. Russell, H. Kellar-Wood, M. R. Tola, B. Ostermeyer, Ch. Tzekov, K. Sartor, E. B. Ringelstein, P. P. Gazzaniga, Paul Krack, H. Fidaner, H. Rico, T. Dbaiss, F. Alameda, E. Torchiana, L. Rumbach, I. Charques, J. M. Bogaard, C. D. Frith, L. J. Rappelle, R. Brenner, A. Joutel, K. Fuxe, G. HÄcker, M. J. Blaser, J. Valls-SolÇ, G. Ulm, M. Alberdi, A. Bock, F. W. Bertelsmann, U. Wieshmann, J. Visa, J. R. Lupski, D. D'Amico, L. M. P. Ramos, A. A. Vanderbark, R. Horn, M. Warmuth, Dietmar Kühne, Mark S. Palmer, C. Ehrenheim, E. Canga, S. Viola, O. Scarpino, P. Naldi, R. Almeida, A. A. Raymond, J. Gamez, Stephan Arnold, A. DiGiovanni, J. Dalmau, C. C. Chari, H. F. Beer, J. C. Koetsier, J. Iriarte, E. Yunis, J. Casadevall, E. Le Guern, E. Stenager, S. R. Benbadis, J. M. Warter, F. Burklin, I. Theodorou, L. Johannesen, G. A. Graveland, X. Leclerc, I. Vecchio, L. Ozelius, G. Nicoletti, R. K. Gherardi, E. Esperet, M. L. Delodovici, F. Cattin, F. Paiau, Giorgio Sacilotto, C. A. J. Broere, D. Chavdarov, J. P. Willmer, C. H. Hawkes, Th. Naegele, E. Ellie, E. Dartigues, M. J. Guardiola, S. Hesse, Z. Levic, Marco Rovaris, P. Saugeir-Veber, B. A. Yaqub, H. F. Durwen, R. Larumbe, J. Ballabrina, M. Sendtner, J. Röther, M. Horstink, C. Kluglein, M.P. Montesi, H. Apaydin, J. Montoya, E. Waubant, Ch. Verellen-Dunoulin, A. Nicolai, J. Lopez-Delval, R. Lemon, G. Cantinho, E. Granieri, A. Zeviani, Wolfgang H. Oertel, U. Ficola, V. Di Piero, V. Fragola, K. Sabev, M. V. Guitera, I. Turki, F. Bolgert, P. Ingrand, J. M. Gobernado, L. M. E. Grimaldi, S. Baybas, B. Eymard, Y. Rolland, Y. Robitaille, Ta. Pampols, P. J. Koehler, A. Carroacedo, J. Vilchez, S. Di Vittorio, I. R. Rise, T. Nagy, M. Kuffner, E. Palazzini, A. Ott, J. Pruim, T. X. Arbizu, E. Manetti, C. Cervera, S. Felber, G. Gursoy, J. Scholz, G. A. Buscaino, M. S. Chen, A. Pascual, J. Hazan, J. U. Gajda, J. G. Cea, G. Bottini, G. Damalik, F. Le Doze, G. Bonaldi, J. M. Hew, C. Messina, A. M. Kennedy, J. M. Carney, N. M. F. Murray, M. Parent, M. Koepp, V. Dimova, D. De Leo, K. Jellinger, G. Salemi, S. Mientus, M. L. Hansen, F. Mazzucchelli, J. Vieth, M. Mauri, E. Bartels, L. Johannsen, C. Humphreys, J. Emile, D. N. Landon, E. Kansu, R. Sanchez-Pernaute, Rsj Frackowiak, M. Gonzalez Torres, L. Oller, C. Machedo, J. Kother, M. Billiard, H. Durak, T. Schindler, A. Frank, A. Uncini, A. Sbriccoli, C. Farinas, D. W. Paty, N. Fast, A. T. Zangaladze, A. Kerkhofs, J. M. Pino Garcia, I. De la Fuente, B. Marini, L. Gomez, I. Rubio, Alessandra Bardoni, C. Brodie, P. Acin, U. Sliwka, S. A. Hawkins, S. Tardieu, F. Vitullo, J. M. Pereira Monteino, R. Gagliardi, T. Jezewski, A. Cano, T. Lempert, F. Abad Alegria, G. Rotondo, D. Ince, C. Martinez Parra, Y. Huang, H. Luders, Y. Steinvil, F. G. A. Van Der Meche, R. Bianchi, A. Sanchez, T. Sevilla, J. M. Ketelslegers, A. Domzal-Stryga, M. Pandolfo, M. O. Josse, K. W. Neff, I. Blanco, G. W. Bruyn, O. W. Witte, J. L. Thibault, G. Andersen, J. Pariset, A. Marcone, R. J. M. Lane, A. Hofman, M. Verin, T. Matilla, P. Bedoucha, J. Roche, M. Lai, M. Collard, A. Ugarte, F. Gallecho, D. Silbersweig, C. Kennard, J. P. Azulay, T. W. Ho, P. L. I. Dellemijn, R. Girardello, F. Baas, B. Voss, F. Rozenberg, E. M. Brocker, V. Stanev, A. A. J. Soeterboek, A. Marra, A. Rey, E. Ertem, M. Sawradewicz-Rybak, J. De Keyser, P. Cavallari, F. Proust, Y. Chevalier, H. C. Hansen, D. Leys, C. A. Davie, K. Hoang-Xuan, C. Bairati, H. van Crevel, Thomas T. Warner, B. Bompais, A. Dobbeleir, T Campbell, C. Macko, C. J. M. Klijn, M. Dussallant, T. P. Berlit, W. Rozenbaum, M. J. van den Bent, W. A. Rocca, M. Muller, H. Hundemer, U. Zifko, M. Campera, F. Drislane, D. Ranoux, T. M. Kloss, Anil Kumar, I. Ruolt, C. Bargnani, B. Marescau, N. A. Losseff, S. Notermans, B. Kint, E. T. Burke, C. Aykut, J. Matias Guiu, P. Maquet, T. Drogendijk, M. Leone, K. von Ammon, M. Pepeliarska, C. Prados, L. DiGiamberardino, T. Logtenberg, G. Lenoir, I. Castaldo, Damhaut, M. Radionova, G. Sirabian, R. Navon, Giovanni Antonini, K. Al Moutaery, E. Chamas, R. Schönhuber, M. Giannini, B. Debilly, I. Labatut, H. Henon, J. A. Egido, M. Baudrimont, J. N. Lorenzo, J. E. C. Bromberg, R. Antonacci, J. J. Vilchez, T. Moulin, B. Rautenstrauss, Giovanni Meola, J. Noth, S Mammi, P. Laforet, F. Lopez, C. Gehring, S. Bort, G. Rancurel, D. Decamps, S. Kostadinova, Y. Shapira, B. Neundoerfer, D. Chavrot, M. Solimena, J. P. Salier, W. Deberdt, R. Hoff-Jörgensen, A. Messina, S. Meairs, G. Rosoklija, E. Nelis, I. Bertran, C. Ertekin, J. Lohmeyer, Mitermayer Galvao dos Reis, L. Calo, E. Maccagnano, A. P. Hays, J. Verlooy, M. G. Forno, T. Blanco, L. Bail, Gabriella Silvestri, J. Montero, F. Bertrand, R. T. Ghnassia, C. Besses, T. Sereghy, F. Shalit, G. Bogliun, S. Braghi, St. Baykouchev, C. Franke, A. Lasa, L. C. Archard, J. Kriebel, S. Shaunak, M. Nocito, Alexander Tsiskaridze, E. Manfredini, T. Seigal, David G. Gadian, M. Barlas, J. D. Degos, C. Seeber, J. Caemert, J. L. Mas, R. B. Pepinsky, M. G. D'Angelo, N. Baumann, S. Yorifuji, H. P. Endtz, M. A. Cassatella, R. A. C. Hughes, V. Golzi, A. Bittencourt, A. Ferreira, M. Sanson, C. Alper, M. Vermeulen, M. A. A. van Walderveen, E. Alexiou, C. H. Lucas, M. Fiorelli, Y. N. Debbink, R. Gil, S. Congia, T. Banerjee, J. M. Bouchard, A. N. Pinto, A. Ceballos-Baumann, G. Grollier, P. I. M. Schmitz, M. D. Catata, N. Lahat, N. S. Rao, P. Papathanasopoulos, J. Valls-Solé, D. Claus, G. Schroter, A. Castro, C. Videbaek, R. Martinez Dreke, A. D. Platts, M. Hermesl, A. C. PeÇanha-Martins, M. Cardoso Silva, P. Masnou, M. J. A. Tanner, Ch. Confavreux, B. Mishu, H. Rasmussen, L. Valenciano, Carlo Pozzilli, S. W. Li, V. Salzman, Y. Vashtang, Massimo Franceschi, M. Severo, G. Deuschl, S. Setien, G. Mariani, A. Protti, J. Castillo, M. J. B. Taphoorn, M. Frontali, I. Milonas, D. Decoq, J. A. Navarro, S. Castellvi-Pel, C. Ertikin, M. Urtasun, Y. Lajat, B. E. Kendall, E. Verdu, B. Gueguen, E. Boisen, R. Couderc, A Danek, JM Stevens, F. Nicoli, L. Feltri, M. L. Vazquez-Andre, J. A. Morgan-Hughes, L. D'Angelo, F. Y. Liew, L. F. Pascual, J. Patrignani Ochoa, Vittorio Martinelli, J. Cophignon, L. Zhang, S. Martin, J. F. Meder, H. C. Buschmann, L. Bertin, J. van Gijn, A. Barreiro, A. Cools, C. Leon, A. Berod, E. A. Anllo, E. Zanette, L. Petrov, R. Barona, B. Gallicchio, P. J. Cozzone, N. Diederich, G. Cancel, L. Schelosky, P. Orizaola, K. Yulug, S. Ozer, Valeria A. Sansone, B. Guiraud-Chaumeil, K. Voigt, P. Labauge, M. Eoli, J. Zhu, J. Aguirre, M. Ferrarini, B. Zyluk, E. Planas, A. Cadilha, C. Tortorella, H. Bismuth, C. E. Counsell, A. Laun, A. Ferlini, Rio J. Montalban, N. Biary, L. Becker, M. Fardeau, M. Poloni, V. M. S. de Bruin, C. Fornada, J. Barros, E. Ganzmann, E. Touze, D. Wallach, J. Peila, H. Fujimura, M. T. Iba-Zizen, G. Macchi, C. Villoslada, R. Gouider, Ph. Rondepierre, P. Grummich, P. Chiodi, C. Conte, M. Michels, P. Annunziata, G. Semana, C. Sommer, J. Vajsar, D. Zekin, J. Kulisevsky, David G. Munoz, B. Jacotot, M. Magoni, A. Luxen, T. Garcia-Silva, S. Di Cesare, Christophe Tzourio, M. Gomori, I. Picomell, L. Santoro, F. Villa, Giovanni Pennisi, T. Ribalta, J. M. Molto, L. Marzorati, P. Loiseau, F. Gemignani, A. Gironell, J. Wissel, A. Prusinski, F. Cailloux, P. Villanueva-Hemandez, P. Cozzone, T. Del Ser, J. Sans-Sabrafen, M. Zappia, P. W. A. Willems, G. Tchernia, D. Gardeur, R. Bauer, F. Palomo, H. Metz, S. Lamoureux, C. Chastang, I. Reinhard, A. Goldfarb, S. Harder, Jordi Río, C. Ozkara, E. Tekinsoy, P. Vontobell, J. De Recondo, M. Rabasa, L. Lacomblez, F. Boon, Dgt Thomas, V. Palma, Renato Mantegazza, A. Dervis, M. Nueckel, B. YalÇinerner, I. Duran, G. Dalla Volta, A. Zubimendi, J. Pinheiro, A. Marbini, Xavier Montalban, H. Wekerle, X. Pereira Monteino, F. Crespo, F. Koskas, N. Battistini, C. Ruiz, H. Offner, J. de Pommery, P. Kanovsky, J. Y. Barnett, J. Pardo, G. Tomei, R. Rene, H. M. Lokhorst, P. Thajeb, H. Bilgin, D. McGehee, R. Fahsold, L. Morgante, Katie Sidle, C. Delwaide, M. N. Diaye, P. H. Rice, A. Creange, C. Sabev, K. Stephan, K. WeilBenborn, G. Magnani, L. Grymonprez, F. Cardellach, M. Kaps, N. G. Meco, F. Vega, V. Bonifati, A. Desomer, M. Baldy-Moulinier, G. Kvale, F. J. Authier, B. Yegen, T. Ho, J. M. Rozet, E. A. Cabanis, L. Bruce, L. Ambrosoli, M. A. Petrella, M. Hernandez, P. Timmings, H. B. van der Worp, F. Mahieux, A. Urbano-Marquez, D. A. Krendel, A. A. Garcia, R. Divari, R. Michalowicz, M. R. Piedmonte, M. Bondavalli, M. Zanca, P. F. Ippel, Onofre Combarros, B. Tavitian, E. Hirsch, I. Anastasopoulos, A. Roses, A. Köhler, P. Vienna, V. Timmerman, P. Sergi, F. Cornelio, A. Di Pasquale, R. Verleger, S. Castellvirel, J. Proano, B. van Moll, F. Rubio, W. Hacke, I. Lavenu, L. Zetta, M. W. Tas, N. Bittmann, M. Bonamini, O. R. Hommes, V. Dousset, N. Afsar, S. Belal, R. R. Myers, J. Goes, Giuseppe Vita, E. Clementi, V. G. Karepov, M. Jueptner, A Vincent, P. Emmrich, Th. Heb, A. Caballo, J. Gallego, T. Mokrusch, C. Perla, L. Gebuhrer, O. 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Butterfield, P. P. Costa, F. deRino, F. Bamonti, J. M. Cesar, C. H. Lahoz, I. Mosely, M. Starck, M. H. Lemaitre, K. M. Stephan, S. Tex, R. Bokonjic, I. Mollee, L. Pastena, M. Gutierrez, F. Boiler, M. C. Martinez-Para, M. Velicogna, O. Obuz, A. Grinspan, M. Guarino, L. M. Cartier, E. Ruiz, D. Gambi, S. Messina, M. Villa, Michael G. Hanna, J. Valk, Leone Pascual, M. Clanet, Z. Argov, B. Ryniewicz, E. Magni, B. Berlanga, K. S. Wong, C. Gellera, C. Prevost, F. Gonzalez-Huix, R. Petraroli, J. E. G. Benedikz, I. Kojder, C. Bommelaer, L. Perusse, M. R. Bangioanni, Guy M. McKhann, A. Molina, C. Fresquet, E. Sindern, Florence Pasquier, M. J. Rosas, M. Altieri, O. Simoncini, M. Koutroumanidis, C. A. F. Tulleken, M. Dary-Auriol, S. Oueslati, H. Kruyer, I. Nishisho, C. R. Horning, A. Vital, G. V. Czettritz, J. Ph. Neau, B. Mihout, A. Ameri, M. Francis, S. Quasthoff, D. Taussig, S. Blunt, P. Valentin, C. Y. Gao, O. Heinzlef, H. d'Allens, C. Coudero, M. Erfas, G. Borghero, P. J. Modrego Pardo, M. C. Patrosso, N. L. Gershfeld, P. A. J. M. Boon, O. Sabouraud, M. Lara, J. Svennevig, G. L. Lenzi, A. Barrio, H. Villaroya, JosÇ M. Manubens, O. Boespflug-Tanguy, M. Carreras, D. A. Costiga, J. P. Breux, S. Lynn, C. Oliveras Ley, A. G. Herbaut, J. Nos, C. Tornali, Y. A. Hekster, J. L. Chopard, J. M. Manubens, P. Chemouilli, A. Jovicic, F. Dworzak, S. Smirne, S. E. Soudain, B. Gallano, D. Lubach, G. Masullo, G. Izquierdo, A. Pascual Leone Pascual, A. Sessa, V. Freitas, O. Crambes, L. Ouss, G. W. Van Dijk, P. Marchettini, P. Confalonieri, M. Donaghy, A. Munnich, M. Corbo, and M. E. L. van der Burg
Subjects: Neurology, business.industry, Media studies, Library science, Medicine, Neurology (clinical), business
Published: 1994
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7. SCA14 in Norway, two families with autosomal dominant cerebellar ataxia and a novel mutation in the PRKCG gene

Author: J, Koht, G, Stevanin, A, Durr, E, Mundwiller, A, Brice, and C M E, Tallaksen
Subjects: Adult, Aged, 80 and over, Male, Adolescent, Cerebellar Ataxia, Norway, DNA Mutational Analysis, Mutation, Missense, Middle Aged, Young Adult, Humans, Spinocerebellar Ataxias, Female, Protein Kinase C, Aged, Spinocerebellar Degenerations
Abstract: Despite a similar prevalence of autosomal dominant cerebellar ataxia (ADCA) in Norway compared to other European countries, less than 10% of the families are explained by the CAG trinucleotide expansions. We wanted to find the occurence of SCA14 in the dominant ataxia population and describe the phenotype.We screened a large dominant cerebellar ataxia cohort for mutations in the PRKCG gene. Patients were evaluated according to a standard clinical protocol for ataxia patients.A novel mutation was found in two families, a C to A transversion altering Histidine to a Glutamine at codon 139, located in a highly concerved region in the gene. It completely co-segregated with the affected family members and was not seen in 576 control chromosomes. Genetic analysis revealed common alleles at three microsatellite markers between these two families suggesting a shared ancestral chromosome. Affected subjects displayed a mild, slowly progressive cerebellar syndrome that included gait and limb ataxia and saccadic pursuit and head tremor in one. Age at onset ranged from 10 to 45 years.These are the first families with SCA14 reported from Scandinavia and a new mutation in the PRKCG gene. The occurrence in the Norwegian dominant ataxia cohort is 3.5%.
Published: 2011

8. Familial cortical myoclonic tremor with epilepsy: the third locus (FCMTE3) maps to 5p

Author: Pierre Labauge, Christel Depienne, Lucien Rumbach, Edouard Hirsch, Delphine Bouteiller, Cécile Saint-Martin, Marie Vidailhet, G. Stevanin, Eloi Magnin, Eric LeGuern, Emmanuelle Apartis, 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), Les chimiokines et leurs récepteurs : fonctions cérébrales et neuroendocriniennes, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Biologie du Développement de Marseille (IBDM), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), 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), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)
Subjects: Adult, Male, Benign adult familial myoclonic epilepsy, Genetic Linkage, Epilepsies, Myoclonic, Locus (genetics), Neurological disorder, Central nervous system disease, 03 medical and health sciences, Epilepsy, 0302 clinical medicine, Tremor, medicine, Humans, Polymorphic Microsatellite Marker, Genetic Testing, Genotyping, Aged, 030304 developmental biology, Cerebral Cortex, Genetics, 0303 health sciences, Gene map, business.industry, Chromosome Mapping, Middle Aged, medicine.disease, Genetic Loci, Chromosomes, Human, Pair 5, Female, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Neurology (clinical), business, 030217 neurology & neurosurgery
Abstract: International audience; BACKGROUND: Familial cortical myoclonic tremor with epilepsy (FCMTE) is defined by autosomal dominant adult-onset cortical myoclonus (CM) and seizures in 40% of patients. Two loci, 8q23.3-q24.11 (FAME1/FCMTE1) and 2p11.1-q12.2 (FAME2/FCMTE2), were previously reported without an identified gene. Unlinked families argue for a third mutated gene. METHODS: A genome-wide scan was performed in a large FCMTE family using Linkage-12 microarrays (Illumina). Refinement of the locus on 5p was performed by genotyping 13 polymorphic microsatellite markers in the 45 available family members. RESULTS: This large French FCMTE family included 16 affected relatives. The first symptoms were CM in 5 patients (31.2%), seizures in 5 patients (31.2%), and both at the same time in 6 patients (37.5%). A total of 12.5% (2/16) had only CM without seizures. The genome-wide scan identified a single region on 5p15.31-p15, with a multipoint lod score of 3.66. Further genotyping of all family members confirmed that the region spans 9.31 Mb between D5S580 and D5S2096, 2-point lod scores reaching 6.3 at theta = 0 for D5S486. Sequencing of the SEMA5A and CTNND2 genes failed to detect mutations. CONCLUSIONS: We report the clinical and genetic characteristics of a large familial cortical myoclonic tremor with epilepsy family. The third gene maps to 5p15.31-p15. Identification of the mutated gene is ongoing.
Published: 2010
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9. SCA5

Author: G. Stevanin and A. Durr
Published: 2010
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10. High throughput genotyping: microarray-based resequencing for autosomal-dominant hereditary spastic paraplegia

Author: S Poths, Sven Klimpe, H. Stolze, Jan Kassubek, Peter Bauer, S. Otto, Alexis Brice, Nina Schlipf, Michaela Auer-Grumbach, Ludger Schöls, Thomas Klopstock, C. Dufke, G Stevanin, Stephan Klebe, A. Seibel, Christian Beetz, Rebecca Schüle, and Michael Bonin
Subjects: Genetics, Microarray, Autosomal Dominant Hereditary Spastic Paraplegia, High throughput genotyping, Neurology (clinical), Biology
Published: 2009
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11. Chapter 4 Clinical and Genetic Aspects of Spinocerebellar Ataxias with Emphasis on Polyglutamine Expansions

Author: Alexandra Dürr, Alexis Brice, and G. Stevanin
Subjects: Neurological signs, Genetics, congenital, hereditary, and neonatal diseases and abnormalities, Heterogeneous group, Cerebellar ataxia, Genetic counseling, Disease duration, Locus (genetics), Biology, medicine.disease, medicine, Spinocerebellar ataxia, medicine.symptom, Genetic diagnosis, Neuroscience
Abstract: Publisher Summary This chapter discusses the clinical and genetical aspects of spinocerebellar ataxias with emphasis on polyglutamine expansions. Autosomal dominant cerebellar ataxias (ADCAs), alternatively called spinocerebellar ataxias (SCAs), are a highly heterogeneous group of neurodegenerative disorders characterized by cerebellar ataxia variably associated with other neurological signs. Seven of these disorders are often referred to as polyglutamine diseases caused by translated CAG repeat expansions. Clinically, these disorders are characterized by a wide range of phenotypes depending on the responsible locus, the size of the expansion, and disease duration. These disorders manifest above a threshold of CAG repeats that varies according to the gene. When large and not interrupted, the CAG repeats are unstable upon transmission, mostly resulting in expansions particularly during paternal transmissions. This observation and the strong negative correlation between the size of the expansion and the age at onset account for the phenomenon of anticipation often observed in families. The relative frequency of the responsible genes varies according to geographical origin, and polyglutamine diseases account for 40–80% of ADCAs. Genetic diagnosis, now possible in several of these disorders, does not yet permit specific treatment but allows accurate genetic counseling and offers the possibility of presymptomatic and prenatal testing.
Published: 2007
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12. Predominant dystonia with marked cerebellar atrophy: a rare phenotype in familial dystonia

Author: I. Le Ber, F. Clot, L. Vercueil, A. Camuzat, M. Viemont, N. Benamar, P. De Liege, A. M. Ouvrard-Hernandez, P. Pollak, G. Stevanin, A. Brice, and A. Durr
Subjects: Adult, Male, congenital, hereditary, and neonatal diseases and abnormalities, Pediatrics, medicine.medical_specialty, Ataxia, Cerebellar Ataxia, Genotype, DNA Mutational Analysis, Inheritance Patterns, Chromosome Disorders, Genes, Recessive, Spasmodic dysphonia, Atrophy, Cerebellar Diseases, Cerebellum, otorhinolaryngologic diseases, medicine, Humans, Genetic Predisposition to Disease, Genetic Testing, Dystonia, Cerebellar ataxia, business.industry, Genetic Diseases, X-Linked, Focal dystonia, Middle Aged, medicine.disease, Magnetic Resonance Imaging, Surgery, Phenotype, Dystonic Disorders, Mutation, Disease Progression, Cerebellar atrophy, Neurology (clinical), medicine.symptom, business, Dystonic disorder
Abstract: Dystonia syndromes constitute a heterogeneous group of phenotypes that may be caused by different heredodegenerative, metabolic, or genetic diseases.To describe the characteristics of an unusual dystonia-plus phenotype associated with cerebellar atrophy.We selected patients with predominant dystonia and cerebellar atrophy among the 861 families referred to us for genetic testing from 1992 to 2003. The main secondary heredodegenerative causes and the major genes responsible for hereditary dystonias and autosomal dominant or recessive ataxias were excluded.We identified 12 patients in 8 families with an unusual dystonia-plus phenotype characterized by dystonia and cerebellar atrophy on brain MRI. The mean age at onset was 27.3 +/- 11.5 years (range: 9 to 42 years) and the mean disease duration 14.7 +/- 7.7 years (range: 4 to 30). At onset, dystonia was focal or multifocal, mainly affecting vocal cords (n = 8) and upper limbs (n = 2). During the disease course spasmodic dysphonia became severe in five patients, leading to complete aphonia in two. Dystonia became generalized in five. Cerebellar ataxia was limited to unsteadiness in most patients and progressed very slowly. The paucity of clinical cerebellar signs contrasted with the marked cerebellar atrophy on brain MRI in most patients. Four families with two affected sibs support the hypothesis of an autosomal recessive disorder. However, X-linked inheritance is possible since only men were affected.We have characterized an unusual familial phenotype associating dystonia and cerebellar atrophy in 12 male patients.
Published: 2006

13. Autosomal dominant cerebellar ataxia with progressive pigmentary macular dystrophy

Author: G. Stevanin, Alexandra Dürr, Géraldine Cancel, Alexis Brice, C. Zander, and Anne-Sophie Lebre
Subjects: Pathology, medicine.medical_specialty, Cerebellum, Ataxin 7, biology, Neuropathology, Macular dystrophy, Macular degeneration, medicine.disease, medicine.anatomical_structure, Autosomal dominant cerebellar ataxia, Anticipation (genetics), medicine, biology.protein, Genotype-Phenotype Correlations
Published: 2001
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14. Clinical and genetic study of familial essential tremor in an isolate of Northern Tajikistan

Author: S N, Illarioshkin, I A, Ivanova-Smolenskaya, R A, Rahmonov, E D, Markova, G, Stevanin, and A, Brice
Subjects: Adult, Genetic Markers, Tajikistan, Genotype, Anticipation, Genetic, Genetic Linkage, Essential Tremor, Middle Aged, Severity of Illness Index, Pedigree, Phenotype, Haplotypes, Mutation, Humans, Chromosomes, Human, Pair 3, Age of Onset, Lod Score, Aged
Published: 2000

15. KIF1A missense mutations in SPG30: Distinct phenotypes according to the nature of the mutations

Author: S. Klebe, A. Lossos, H. Azzedine, E. Mundwiller, V. Meiner, M. Gaussen, C. Marelli, M. Nawara, W. Carpentier, V. Meyer, A. Raststetter, E. Martin, L. Orlando, G. Gyapay, K. El-Hachimi, B. Zimmermann, I. Lerer, A. Brice, A. Durr, and G. Stevanin
Subjects: Genetics, Neurology, Missense mutation, Neurology (clinical), Biology, Phenotype, KIF1A
Published: 2013
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16. Analysis of the SCA1 CAG repeat in a large number of families with dominant ataxia: clinical and molecular correlations

Author: O, Dubourg, A, Dürr, G, Cancel, G, Stevanin, H, Chneiweiss, C, Penet, Y, Agid, and A, Brice
Subjects: Adult, Male, Cerebellar Ataxia, Mutation, Humans, Chromosomes, Human, Pair 6, Female, DNA, Age of Onset, Middle Aged, Child, Genes, Dominant, Repetitive Sequences, Nucleic Acid
Abstract: Autosomal dominantly inherited ataxias are a clinically and genetically heterogeneous group of neurodegenerative disorders. The gene involved in one subtype, spinocerebellar ataxia 1 (SCA1), was first localized to chromosome 6p. An unstable CAG repeat has been identified as the responsible mutation. In this study, 88 families with various types of inherited ataxias and 16 individuals with sporadic cerebellar ataxia were investigated to determine the frequency of this mutation, the behavior of the SCA1 CAG repeat during transmission, and the clinical features specific to this form of disease. Only 12 of the families carried the SCA1 mutation; 10 of the 12 were of French origin. When transmitted paternally, the repeat was more unstable and larger in size. Age at onset was inversely correlated with the number of CAG repeats. Anticipation in age at onset of about 11 years was observed in offspring. Analysis of the clinical features did not distinguish SCA1 from other forms of dominantly inherited ataxias. In the absence of distinguishing clinical characteristics, the diagnosis of SCA1 in single affected patients or family members can only be made by direct detection of the mutation, opening the way for presymptomatic testing.
Published: 1995

17. Novel SPG10 Mutation Associated with Hereditary Spastic Paraplegia and Dysautonomia (P05.194)

Author: Alexis Brice, C. Depienne, Brigitte Samama, G. Stevanin, Pierre Labauge, J. de Seze, Nicolas Collongues, Andoni Echaniz-Laguna, Nelly Boehm, Eric LeGuern, and Alexandra Durr
Subjects: Proband, medicine.medical_specialty, Pathology, Neurology, medicine.diagnostic_test, Hereditary spastic paraplegia, business.industry, Dysautonomia, medicine.disease, Skin biopsy, medicine, Spastic, Missense mutation, Neurology (clinical), medicine.symptom, business, Paraplegia
Abstract: Objective: We report the characteristics of a French family with a novel missense mutation c.580 G>C in exon 7 of the KIF5A/SPG10 gene. Background Hereditary spastic paraplegias (HSP) are a group of clinically and genetically heterogeneous neurodegenerative disorders. Design/Methods: Patients were identified in the Department of Neurology at the Strasbourg University Hospital. Clinical (including the spastic paraplegia rating scale), biological (including blood inflammatory indexes, CSF analysis, long chain fatty acids, folic acid, vitamin B12 and E levels), neurophysiological (evoked potentials, electromyography, nerve conduction velocities) and morphological (brain and spinal cord MRI) exams were performed in the patients and their siblings. The coding regions including the flanking intronic sequences of SPAST (SPG4 RefSeq NM_014946.3), REEP1 (RefSeq NM_022912.2 SPG31) and KIF5A (SPG10, RefSeq NM_004984.2) genes were amplified using standard procedures. We performed a skin biopsy to analyse the axonal network using PGP 9.5, synaptophysin and electron microscopy. Results: We have identified a novel mutation in KIF5A/SPG10 gene associated with 1) late-onset HSP; 2) autonomic dysfunction; 3) rapid progression followed by a mild recovery in the sister and a progressive/continuous accumulation of disability in the brother; 4) central demyelination and spinal cord atrophy on MRI scans in the proband; and 5) loss of vesicles at the presynaptic membrane in the proband on skin biopsy. Conclusions: This study extends the range of neurological impairment associated with SPG10 HSP. For patients who accumulate progressive neurological disability without typical demyelinating lesions on brain MRI and with normal CSF, screening of the KIF5A gene could be envisaged if there is a family history of HSP. Furthermore, skin biopsy could be used to evidence abnormality in vesicles axonal transport in patients with HSP. Disclosure: Dr. Collongues has received personal compensation for activities with Biogen Idec, Bayer Schering Pharma, Teva Neuroscience, Merck-Serono, Sanofi-Aventis Pharmaceuticals, Inc., and Novartis. Dr. Depienne has nothing to disclose. Dr. Boehm has nothing to disclose. Dr. Echaniz-Laguna has nothing to disclose. Dr. Samama has nothing to disclose. Dr. Durr has nothing to disclose. Dr. Stevanin has nothing to disclose. Dr. Leguern has nothing to disclose. Dr. Brice has nothing to disclose. Dr. Labauge has nothing to disclose. Dr. De Seze has received personal compensation for activities with Bayer Schering, Biogen Idec, LFB, Merck Serono, Novartis, Sanofi-Aventis, and Teva Neuroscience.Dr. De Seze has received personal compensation in an editorial capacity for Elsevier.
Published: 2012
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18. Mitochondrial Morpho-Functional Dysfunction in SPG31 Patients (P01.206)

Author: C. Goizet, G. Benard, C. Depienne, A. Boukhris, G. Sole, I. Coupry, J. Pilliod, M.-L. Martin-Negrier, S. Forlani, A. Durr, A. Brice, D. Lacombe, R. Rossignol, and G. Stevanin
Subjects: Neurology (clinical)
Published: 2012
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19. Combination of Positional Cloning and New Generation Sequencing Identifies 3 Novel Genes in Spastic Paraplegia Involved in Common Metabolic Pathways (P01.205)

Author: E. Martin, Salah A. Elmalik, Christelle Tesson, F. Mochel, Emeline Mundwiller, Abdulrahman Alswaid, Magdalena Nawara, Chokri Mhiri, Ahmed Bouhouche, Mustafa A. Salih, Alexandra Durr, M. Al Balwi, Alexis Brice, S. Al Rasheed, Amir Boukhris, Filippo M. Santorelli, Maha S. Zaki, Joseph G. Gleeson, Ali Benomar, Frédéric Darios, and G. Stevanin
Subjects: Novel gene, Genetics, Metabolic pathway, Positional cloning, Spastic, medicine, Neurology (clinical), Biology, Paraplegia, medicine.disease
Published: 2012
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20. Endothelin 1 is not a candidate gene for spinal cerebellar ataxia 1

Author: Alexis Brice, Géraldine Cancel, G. Stevanin, J.-C. Pages, Howard M. Cann, Yves Agid, and C. Khati
Subjects: Male, medicine.medical_specialty, Candidate gene, Genetic Linkage, Neurological disorder, Peptide hormone, Biology, Bioinformatics, Gene mapping, Internal medicine, Genetics, medicine, Humans, Molecular Biology, Gene, Genetics (clinical), Spinocerebellar Degenerations, Cerebellar ataxia, Endothelins, Chromosome Mapping, General Medicine, medicine.disease, Endothelin 1, Pedigree, Endocrinology, Haplotypes, Chromosomes, Human, Pair 6, Female, medicine.symptom
Published: 1993

21. Chromosomal assignment of the second locus for autosomal dominant cerebellar ataxia (SCA2) to chromosome 12q23-24.1

Author: S. Gispert, R. Twells, G. Orozco, A. Brice, J. Weber, L. Heredero, K. Scheufler, B. Riley, R. Allotey, C. Nothers, R. Hillermann, A. Lunkes, C. Khati, G. Stevanin, A. Hernandez, C. Magariño, T. Klockgether, A. Durr, H. Chneiweiss, J. Enczmann, M. Farrall, J. Beckmann, M. Mullan, P. Wernet, Y. Agid, H.-J. Freund, R. Williamson, G. Auburger, and S. Chamberlain
Subjects: Genetic Markers, Male, congenital, hereditary, and neonatal diseases and abnormalities, Genetic Linkage, Locus (genetics), Biology, Dysdiadochokinesia, Autosomal dominant cerebellar ataxia, Dysmetria, Genetics, medicine, Humans, Genes, Dominant, Spinocerebellar Degenerations, Chromosomes, Human, Pair 12, Genetic heterogeneity, Chromosome Mapping, Cuba, medicine.disease, Pedigree, Spinocerebellar ataxia, Gait Ataxia, Female, France, medicine.symptom, Founder effect
Abstract: The autosomal dominant cerebellar ataxias (ADCA) are a group of neurodegenerative disorders characterized by onset with gait ataxia, dysarthria, dysmetria and dysdiadochokinesia. We have demonstrated previously genetic heterogeneity within these disorders by excluding the disease locus from the documented spinocerebellar ataxia locus (SCA1) on chromosome 6p in a large Cuban founder population. We now report the assignment of a second locus for ADCA (SCA2) to chromosome 12q23–24.1 following linkage analyses carried out for the Cuban pedigrees, with probable flanking markers D12S58 and phospholipase A2. Investigation of linkage to the interval containing SCA2 for seven French ADCA families, previously excluded from linkage to SCA1, provides preliminary data suggesting the existence of a third ADCA locus (SCA3).
Published: 1993

22. Clinical and genetic analysis of a Tunisian family with autosomal dominant cerebellar ataxia type 1linked to the SCA2 locus

Author: Samir Belal, C. Khati, Géraldine Cancel, G. Stevanin, Georg Auburger, C. Ben Hamida, Yves Agid, M. Ben Hamida, Alexis Brice, and Fayçal Hentati
Subjects: Adult, Genetic Markers, Male, medicine.medical_specialty, Tunisia, Genetic Linkage, Locus (genetics), Polymerase Chain Reaction, Central nervous system disease, Autosomal dominant cerebellar ataxia, Genetic linkage, medicine, Humans, Aged, Spinocerebellar Degenerations, Aged, 80 and over, Genetics, Cerebellar ataxia, Genetic heterogeneity, business.industry, Haplotype, Chromosome Mapping, Middle Aged, medicine.disease, Pedigree, Surgery, Microsatellite, Female, Neurology (clinical), Lod Score, medicine.symptom, business
Abstract: Autosomal dominant cerebellar ataxias (ADCA) type 1 are a clinically and genetically heterogeneous group of neurodegenerative disorders. We report a large Tunisian ADCA type 1 family in which 17 patients (mean age at onset ± SD = 35.6. ± 15.3 years) were examined. There was mean anticipation of 10.3 ± 15.4 years in this family; anticipation was greater in paternal (28 ± 8.2 years) than in maternal (2.7 ± 10.9 years) transmission. Linkage analysis performed with microsatellite markers linked to the spinal cerebellar ataxia 1 (SCA1) locus on chromosome 6p and the SCA2 locus on chromosome 12q excluded linkage to SCA1, but there was close linkage with marker D12S105 (Zmax = 2.51 at 6 = 0.00). This result was confirmed by multipoint analysis, which generated a maximal lod score of 3.46 at this locus. Multipoint analysis and haplotype reconstruction reduced the interval containing the SCA2 locus to 6.4 cM, a narrowing of the 35-cM interval in a previously described Cuban SCA2 family with a clinical picture similar to that of our family, including a high frequency of postural and action tremor.
Published: 1994
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23. Huntington's disease-like phenotype due to trinucleotide repeat expansions in the TBP and JPH3 genes.

Author: A. Brice, G. Stevanin, A. Durr, H. Fujigasaki, A-S. Lebre, A. Camuzat, C. Jeannequin, C. Dodé, J. Takahashi, C. Sân, and R. Bellance
Published: 2003

24. Genetic heterogeneity of autosomal dominant cerebellar ataxia type 1

Author: Alexandra Durr, G. Stevanin, Yves Agid, Howard M. Cann, Alexis Brice, C. Khati, Samir Belal, Hervé Chneiweiss, and A Seck
Subjects: Adult, Male, Genetics, Polymorphism, Genetic, Cerebellar Ataxia, Cerebellar ataxia, Genetic Linkage, Genetic heterogeneity, Locus (genetics), Middle Aged, Biology, medicine.disease, Genetic analysis, Pedigree, Autosomal dominant cerebellar ataxia, Genetic linkage, medicine, Humans, Female, France, Neurology (clinical), medicine.symptom, Allele, Predictive testing, Alleles
Abstract: We performed linkage analysis between the gene responsible for spinal cerebellar ataxia 1 (SCA1) and the highly polymorphic chromosome 6 locus, D6S89, in 10 French families with autosomal dominant cerebellar ataxia (ADCA) type 1. These families were clinically indistinguishable except for one family with loss of hearing and vision. Very close linkage was observed in four families, with no evidence of recombination between SCA1 and D6S89. Linkage with D6S89 was excluded in the six others, thus demonstrating genetic heterogeneity for ADCA type 1. The D6S89 marker, which is very closely linked to the disease locus, can be used to identify SCA1 families and will lead to predictive testing.
Published: 1993
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25. Implication of folate deficiency in CYP2U1 loss of function

Author: Livia Parodi, Khalid Hamid El Hachimi, Stéphane Zuily, Marine Legendre, Diana Rodriguez, Dario Saracino, Aleksandra Trifunovic, Silvina Perin, Nicolas Villain, Marijana Croon, Thierry Kuntzer, Mahmoud Y. Issa, Fanny Mochel, Filippo M. Santorelli, Foudil Lamari, Priscilla Thomas, Cyril Goizet, Chantal Tse, Claire Ewenczyk, Florence Fellmann, Maha S. Zaki, Arnaud Mourier, Patrick Giavalisco, Laurent Le Corre, Aurélien Trimouille, Emilie Blond, Milica Popovic, Frédéric Darios, Anastasia D. Gazi, Cyril Mignot, Isabelle Kemlin, Sophie M. Steculorum, Cécilia Marelli-Tosi, Joseph G. Gleeson, Mathilde Renaud, Claire Pujol, Jean-Luc Boucher, S. Mathieu, Shahira Elshafie, Anne Legrand, Serge Picaud, Alexandra Durr, Giulia Coarelli, Giovanni Stevanin, Manon Valet, Daniele Galatolo, Rana Alkouri, Alexandre Seyer, Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Biologie mitochondriale – Mitochondrial biology, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Paris-Centre de Recherche Cardiovasculaire (PARCC (UMR_S 970/ U970)), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Universität zu Köln, Institut de la Vision, Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de Neurologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-IFR70-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université, Sorbonne Université (SU), Fayoum University, National Research Centre - NRC (EGYPT), Défaillance Cardiovasculaire Aiguë et Chronique (DCAC), Université de Lorraine (UL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Mécanismes moléculaires dans les démences neurodégénératives (MMDN), Université de Montpellier (UM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Institut National de la Santé et de la Recherche Médicale (INSERM)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL), CHU Bordeaux [Bordeaux], Université de Bordeaux (UB), Service de Neuropédiatrie [CHU Trousseau], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université-Sorbonne Université, University of California [San Diego] (UC San Diego), University of California, Service de Biochimie Métabolique [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Université de Lausanne (UNIL), Hospices Civils de Lyon (HCL), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL), Profilomic [Boulogne-Billancourt], Max planck Institute for Biology of Ageing [Cologne], Laboratoire de Chimie et de Biochimie Pharmacologiques et Toxicologiques (LCBPT - UMR 8601), Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS), Institut de biochimie et génétique cellulaires (IBGC), Université Bordeaux Segalen - Bordeaux 2-Centre National de la Recherche Scientifique (CNRS), Max Planck Institute for Metabolism Research [Cologne, Allemagne], Max-Planck-Gesellschaft, Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), The Core is supported by 'Investissements d’avenir' (ANR-10-IAIHU-06 and ANR-11-INBS-0011-NeurATRIS) and the 'Fondation pour la Recherche Medicale. This study was supported financially by the Association Strümpell-Lorrain–Hereditary Spastic Paraplegia patient association (to C. Pujol and G. Stevanin), the Tom Wahlig–Stiftung Foundation (to K.H. El Hachimi and G. Stevanin), the EMBO short-term fellowship (C. Pujol), French state funds through the Agence Nationale de la Recherche under the framework programme Investissements d’Avenir (ANR-10-INBS-07 PHENOMIN), and the European Union through an internal call under the Seventh Framework Programme (NEUROMICS, to G. Stevanin)., ANR-10-IAHU-0006,IHU-A-ICM,Institut de Neurosciences Translationnelles de Paris(2010), ANR-11-INBS-0011,NeurATRIS,Infrastructure de Recherche Translationnelle pour les Biothérapies en Neurosciences(2011), ANR-10-INBS-0007,PHENOMIN,INFRASTRUCTURE NATIONALE EN PHENOGENOMIQUE SOURIS(2010), European Project: 305121,EC:FP7:HEALTH,FP7-HEALTH-2012-INNOVATION-1,NEUROMICS(2012), Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-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)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Universität zu Köln = University of Cologne, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), CHU Trousseau [APHP], University of California (UC), Université de Lausanne = University of Lausanne (UNIL), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris]-Université de Paris (UP)-Centre National de la Recherche Scientifique (CNRS), Service de Neurologie [CHU Pitié-Salpêtrière], IFR70-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), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Lemesle, Marie, Institut de Neurosciences Translationnelles de Paris - - IHU-A-ICM2010 - ANR-10-IAHU-0006 - IAHU - VALID, Infrastructures - Infrastructure de Recherche Translationnelle pour les Biothérapies en Neurosciences - - NeurATRIS2011 - ANR-11-INBS-0011 - INBS - VALID, Infrastructures - INFRASTRUCTURE NATIONALE EN PHENOGENOMIQUE SOURIS - - PHENOMIN2010 - ANR-10-INBS-0007 - INBS - VALID, Integrated European –omics research project for diagnosis and therapy in rare neuromuscular and neurodegenerative diseases - NEUROMICS - - EC:FP7:HEALTH2012-10-01 - 2017-09-30 - 305121 - VALID, Sorbonne Université (SU)-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), and Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)
Subjects: Proteomics, Immunology, Mitochondrion, Biology, Folic Acid Deficiency, 03 medical and health sciences, chemistry.chemical_compound, Mice, 0302 clinical medicine, Folic Acid, Immunology and Allergy, Animals, Humans, Cytochrome P450 Family 2, Gene, Loss function, 030304 developmental biology, Mice, Knockout, 0303 health sciences, Neopterin, Brain, Phenotype, 3. Good health, Mitochondria, Mice, Inbred C57BL, Disease Models, Animal, chemistry, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, Coenzyme Q – cytochrome c reductase, Mutation, Cancer research, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, CYP2U1, 030217 neurology & neurosurgery, Function (biology), Biomarkers
Abstract: International audience; Hereditary spastic paraplegias are heterogeneous neurodegenerative disorders. Understanding of their pathogenicmechanisms remains sparse, and therapeutic options are lacking. We characterized a mouse model lacking the Cyp2u1 gene, lossof which is known to be involved in a complex form of these diseases in humans. We showed that this model partially recapitulated the clinical and biochemical phenotypes of patients. Using electron microscopy, lipidomic, and proteomicstudies, we identified vitamin B2 as a substrate of the CYP2U1 enzyme, as well as coenzyme Q, neopterin, and IFN-α levels asputative biomarkers in mice and fluids obtained from the largest series of CYP2U1-mutated patients reported so far. We alsoconfirmed brain calcifications as a potential biomarker in patients. Our results suggest that CYP2U1 deficiency disruptsmitochondrial function and impacts proper neurodevelopment, which could be prevented by folate supplementation in ourmouse model, followed by a neurodegenerative process altering multiple neuronal and extraneuronal tissues.
Published: 2021
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26. Hereditary spastic paraplegia type 43 (SPG43) is caused by mutation in C19orf12

Author: Tyler Mark Pierson, Stephan Züchner, Oumarou Diallo, Katherine V. Bricceno, Nichole D. Hein, Camilo Toro, Craig Blackstone, Bryan J. Traynor, Kenneth H. Fischbeck, Katherine G. Meilleur, Shoji Tsuji, Dennis M.D. Landis, William A. Gahl, Hiroyuki Ishiura, Charles Marques Lourenço, Janel O. Johnson, Guida Landouré, Giovanni Stevanin, Peng Peng Zhu, Garth A. Nicholson, Carlo Rinaldi, Wilson Marques, Modibo Sangare, Fiorella Speziani, Leslie G. Biesecker, Barrington G. Burnett, John K. Fink, John Accardi, Michael A. Gonzalez, Alexandra Durr, Marion Stoll, G., Landouré, P., Zhu, C. M., Lourenço, J. O., Johnson, C., Toro, K. V., Bricceno, Rinaldi, Carlo, K. G., Meilleur, M., Sangaré, O., Diallo, T. M., Pierson, H., Ishiura, S., Tsuji, N., Hein, J. K., Fink, M., Stoll, G., Nicholson, M. A., Gonzalez, F., Speziani, A., Dürr, G., Stevanin, L. G., Biesecker, N. I., H., J., Accardi, D. M., D, W. A., Gahl, B. J., Traynor, W., Marque, S., Züchner, C., Blackstone, K. H., Fischbeck, and B. G., Burnett
Subjects: Male, Neurodegeneration with brain iron accumulation, C19orf12, Intracellular Space, Neurodegenerative, medicine.disease_cause, Missense mutation, Spastic Paraplegia, 2.1 Biological and endogenous factors, Aetiology, Peptide sequence, NIH Intramural Sequencing Center, Genetics (clinical), Exome sequencing, Sequence Deletion, Genetics, Genetics & Heredity, Mutation, diagnosis/genetics/metabolism, cent, NBIA, Homozygote, Brain, Magnetic Resonance Imaging, Protein Transport, metabolism, Magnetic Resonance Imaging, Male, Mitochondrial Protein, Hereditary, metabolism/pathology, Homozygote, Humans, Intracellular Space, Adolescent, Hereditary spastic paraplegia, SPG43, Clinical Sciences, Molecular Sequence Data, Biology, chemistry/genetics/metabolism, Molecular Sequence Data, Mutation, Protein Transport, Sequence Alignment, Sequence Deletion, Spastic Paraplegia, Article, Mitochondrial Proteins, Rare Diseases, Amino Acid Sequence, Brain, Clinical Research, medicine, Humans, Amino Acid Sequence, hereditary spastic paraplegia, Gene, Spastic Paraplegia, Hereditary, Haplotype, Human Genome, Neurosciences, medicine.disease, Molecular biology, Sequence Alignment
Abstract: We report here the genetic basis for a form of progressive hereditary spastic paraplegia (SPG43) previously described in two Malian sisters. Exome sequencing revealed a homozygous missense variant (c.187G>C; p.Ala63Pro) in C19orf12, a gene recently implicated in neurodegeneration with brain iron accumulation (NBIA). The same mutation was subsequently also found in a Brazilian family with features of NBIA, and we identified another NBIA patient with a three-nucleotide deletion (c.197_199del; p.Gly66del). Haplotype analysis revealed that the p.Ala63Pro mutations have a common origin, but MRI scans showed no brain iron deposition in the Malian SPG43 subjects. Heterologous expression of these SPG43 and NBIA variants resulted in similar alterations in the subcellular distribution of C19orf12. The SPG43 and NBIA variants reported here as well as the most common C19orf12 missense mutation reported in NBIA patients are found within a highly conserved, extended hydrophobic domain in C19orf12, underscoring the functional importance of this domain.
Published: 2013

27. From spastic paraplegia to infantile neurodegenerative disorder: Expanding the phenotypic spectrum associated with biallelic SPAST variants.

Author: Degoutin M, Angelini C, Bar C, El Khedoud WA, Barnerias C, Boulariah-Hadjou R, Estiar MA, Ewenczyk C, Gan-Or Z, Lacombe D, Lefeuvre C, Majethia P, Messaoud-Khelifi M, Narayanan DL, Rouleau GA, Suchowersky O, Shukla A, Guillaud-Bataille M, Stevanin G, and Goizet C
Subjects: Humans, Male, Female, Child, Child, Preschool, Neurodegenerative Diseases genetics, Neurodegenerative Diseases complications, Infant, Adolescent, Pedigree, Adult, Intellectual Disability genetics, Mutation, Paraplegia, Spastic Paraplegia, Hereditary genetics, Spastin genetics, Phenotype
Abstract: Purpose: Heterozygous pathogenic variants in SPAST are known to cause Hereditary Spastic Paraplegia 4 (SPG4), the most common form of HSP, characterized by progressive bilateral lower limbs spasticity with frequent sphincter disorders. However, there are very few descriptions in the literature of patients carrying biallelic variants in SPAST., Methods: Targeted Sanger sequencing, panel sequencing and exome sequencing were used to identify the genetic causes in 9 patients from 6 unrelated families with symptoms of HSP or infantile neurodegenerative disorder., Results: We describe 5 patients with pure HSP with a variable age of onset, mostly in infancy, and 4 patients with profound intellectual disability and progressively worsening tetrapyramidal syndrome. The patients' parents, heterozygous carriers of pathogenic SPAST variants, included both asymptomatic carriers and patients with classic forms of SPG4., Conclusion: Biallelic variants of SPAST may explain cases of hereditary spastic paraplegia with autosomal recessive inheritance. Furthermore, some biallelic variants may also cause psychomotor regression with an infantile neurodegenerative disorder, associated with a tetrapyramidal syndrome, a new phenotype associated with the SPAST gene., (© 2024 The Author(s). European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)
Published: 2025
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28. Hereditary Spastic Paraplegia Linked to Abnormal Splicing From an AIMP1 Missense Variant.

Author: Morais S, Leal Loureiro J, Brandão E, Sequeiros J, Stevanin G, and Santos M
Abstract: Hereditary spastic paraplegias (HSP) are a diverse group of neurodegenerative diseases characterized by lower limb spasticity and weakness. To date, over 80 genes have been associated with HSP, but many families remain without a molecular diagnosis. In this study, linkage analysis and whole-exome sequencing (WES) were performed to identify the causal gene in a HSP family with autosomal recessive inheritance. Multipoint linkage analysis revealed a maximum significant multipoint LOD score of 4.6 on chromosome 4. WES analysis focused on this region led to the identification of a homozygous missense variant in AIMP1 (c.223G>A). Minigene assays showed that the presumed missense variant in AIMP1 caused loss of the exon 3 donor splice site. Ultimately, this led to the use of an alternative splice site within the intron and the insertion of a premature stop codon. The identification of a novel AIMP1 causal variant contributes to the growing list of HSP genes. Furthermore, it shows that, considering also previous reported cases, disruption of AIMP1 causes a spectrum of disorders ranging from intellectual disability to more complex neurodegenerative diseases., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)
Published: 2024
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29. Biallelic variants in ERLIN1: a series of 13 individuals with spastic paraparesis.

Author: Cogan G, Zaki MS, Issa M, Keren B, Guillaud-Bataille M, Renaldo F, Isapof A, Lallemant P, Stevanin G, Guillot-Noel L, Courtin T, Buratti J, Freihuber C, Gleeson JG, Howarth R, Durr A, de Sainte Agathe JM, and Mignot C
Subjects: Humans, Female, Male, Child, Adolescent, Adult, Membrane Proteins genetics, Alleles, Phenotype, Mutation, Child, Preschool, Young Adult, Intellectual Disability genetics, Paraparesis, Spastic genetics, Pedigree
Abstract: Biallelic variants in the ERLIN1 gene were recently reported as the cause of two motor neuron degeneration diseases, SPG62 and a recessive form of amyotrophic lateral sclerosis. However, only 12 individuals from five pedigrees have been identified so far. Thus, the description of the disease remains limited. Following the discovery of a homozygous pathogenic variant in a girl with SPG62, presenting with intellectual disability, and epilepsy, we gathered the largest series of SPG62 cases reported so far (13 individuals) to better understand the phenotype associated with ERLIN1. We collected molecular and clinical data for 13 individuals from six families with ERLIN1 biallelic variants. We performed RNA-seq analyses to characterize intronic variants and used Alphafold and a transcripts database to characterize the molecular consequences of the variants. We identified three new variants suspected to alter the bell-shaped ring formed by the ERLIN1/ERLIN2 complex. Affected individuals had childhood-onset paraparesis with slow progression. Six individuals presented with gait ataxia and three had superficial sensory loss. Aside from our proband, none had intellectual disability or epilepsy. Biallelic pathogenic ERLIN1 variants induce a rare, predominantly pure, spastic paraparesis, with possible cerebellar and peripheral nerve involvement., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)
Published: 2024
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30. Clinical phenotyping and genetic diagnosis of a large cohort of Sudanese families with hereditary spinocerebellar degenerations.

Author: Yahia A, Hamed AAA, Mohamed IN, Elseed MA, Salih MA, El-Sadig SM, Siddig HE, Nasreldien AEM, Abdullah MA, Elzubair M, Omer FY, Bakhiet AM, Abubaker R, Abozar F, Adil R, Emad S, Musallam MA, Eltazi IZM, Omer Z, Malik H, Mohamed MOE, Elhassan AA, Mohamed EOE, Ahmed AKMA, Ahmed EAA, Eltaraifee E, Hussein BK, Abd Allah ASI, Salah L, Nimir M, Tag Elseed OM, Elhassan TEA, Elbashier A, Alfadul ESA, Fadul M, Ali KF, Taha SOMA, Bushara EE, Amin M, Koko M, Ibrahim ME, Ahmed AE, Elsayed LEO, and Stevanin G
Subjects: Humans, Female, Male, Sudan, Adult, Child, Adolescent, Child, Preschool, Genetic Testing methods, Infant, Consanguinity, Phenotype, Spinocerebellar Degenerations genetics, Spinocerebellar Degenerations diagnosis, Pedigree
Abstract: Hereditary spinocerebellar degenerations (SCDs) is an umbrella term that covers a group of monogenic conditions that share common pathogenic mechanisms and include hereditary spastic paraplegia (HSP), cerebellar ataxia, and spinocerebellar ataxia. They are often complicated with axonal neuropathy and/or intellectual impairment and overlap with many neurological conditions, including neurodevelopmental disorders. More than 200 genes and loci inherited through all modes of Mendelian inheritance are known. Autosomal recessive inheritance predominates in consanguineous communities; however, autosomal dominant and X-linked inheritance can also occur. Sudan is inhabited by genetically diverse populations, yet it has high consanguinity rates. We used next-generation sequencing, genotyping, bioinformatics analysis, and candidate gene approaches to study 90 affected patients from 38 unrelated Sudanese families segregating multiple forms of SCDs. The age-at-onset in our cohort ranged from birth to 35 years; however, most patients manifested childhood-onset diseases (the mean and median ages at onset were 7.5 and 3 years, respectively). We reached the genetic diagnosis in 63% and possibly up to 73% of the studied families when considering variants of unknown significance. Combining the present data with our previous analysis of 25 Sudanese HSP families, the success rate reached 52-59% (31-35/59 families). In this article we report candidate variants in genes previously known to be associated with SCDs or other phenotypically related monogenic disorders. We also highlight the genetic and clinical heterogeneity of SCDs in Sudan, as we did not identify a major causative gene in our cohort, and the potential for discovering novel SCD genes in this population., (© 2023. The Author(s).)
Published: 2024
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31. Decreasing ganglioside synthesis delays motor and cognitive symptom onset in Spg11 knockout mice.

Author: Fortier M, Cauhapé M, Buono S, Becker J, Menuet A, Branchu J, Ricca I, Mero S, Dorgham K, El Hachimi KH, Dobrenis K, Colsch B, Samaroo D, Devaux M, Durr A, Stevanin G, Santorelli FM, Colombo S, Cowling B, and Darios F
Subjects: Animals, Humans, Mice, Cognitive Dysfunction metabolism, Cognitive Dysfunction genetics, Glucosyltransferases genetics, Glucosyltransferases metabolism, Mice, Inbred C57BL, Neurofilament Proteins, Neurons metabolism, Proteins genetics, Proteins metabolism, Sialyltransferases genetics, Sialyltransferases deficiency, Gangliosides metabolism, Mice, Knockout, Spastic Paraplegia, Hereditary genetics, Spastic Paraplegia, Hereditary metabolism
Abstract: Biallelic variants in the SPG11 gene account for the most common form of autosomal recessive hereditary spastic paraplegia characterized by motor and cognitive impairment, with currently no therapeutic option. We previously observed in a Spg11 knockout mouse that neurodegeneration is associated with accumulation of gangliosides in lysosomes. To test whether a substrate reduction therapy could be a therapeutic option, we downregulated the key enzyme involved in ganglioside biosynthesis using an AAV-PHP.eB viral vector expressing a miRNA targeting St3gal5. Downregulation of St3gal5 in Spg11 knockout mice prevented the accumulation of gangliosides, delayed the onset of motor and cognitive symptoms, and prevented the upregulation of serum levels of neurofilament light chain, a biomarker widely used in neurodegenerative diseases. Importantly, similar results were observed when Spg11 knockout mice were administrated venglustat, a pharmacological inhibitor of glucosylceramide synthase expected to decrease ganglioside synthesis. Downregulation of St3gal5 or venglustat administration in Spg11 knockout mice strongly decreased the formation of axonal spheroids, previously associated with impaired trafficking. Venglustat had similar effect on cultured human SPG11 neurons. In conclusion, this work identifies the first disease-modifying therapeutic strategy in SPG11, and provides data supporting its relevance for therapeutic testing in SPG11 patients., Competing Interests: Declaration of competing interest G.S. received a grant from the PSL-Biogen program 2019–2023, unrelated to this work. S.B., J.Be., A.M., S.C. and B.Cow. were employees of Dynacure SA. J.Br., G.S. and F.D. are authors of a patent related to this work., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
Published: 2024
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32. GRID1/GluD1 homozygous variants linked to intellectual disability and spastic paraplegia impair mGlu1/5 receptor signaling and excitatory synapses.

Author: Ung DC, Pietrancosta N, Badillo EB, Raux B, Tapken D, Zlatanovic A, Doridant A, Pode-Shakked B, Raas-Rothschild A, Elpeleg O, Abu-Libdeh B, Hamed N, Papon MA, Marouillat S, Thépault RA, Stevanin G, Elegheert J, Letellier M, Hollmann M, Lambolez B, Tricoire L, Toutain A, Hepp R, and Laumonnier F
Subjects: Humans, Male, Female, Homozygote, Receptors, Glutamate genetics, Receptors, Glutamate metabolism, Receptor, Metabotropic Glutamate 5 metabolism, Receptor, Metabotropic Glutamate 5 genetics, Pedigree, Adult, Paraplegia genetics, Paraplegia metabolism, Animals, Child, Neurons metabolism, Adolescent, HEK293 Cells, Mutation genetics, Intellectual Disability genetics, Synapses metabolism, Synapses genetics, Receptors, Metabotropic Glutamate genetics, Receptors, Metabotropic Glutamate metabolism, Signal Transduction genetics
Abstract: The ionotropic glutamate delta receptor GluD1, encoded by the GRID1 gene, is involved in synapse formation, function, and plasticity. GluD1 does not bind glutamate, but instead cerebellin and D-serine, which allow the formation of trans-synaptic bridges, and trigger transmembrane signaling. Despite wide expression in the nervous system, pathogenic GRID1 variants have not been characterized in humans so far. We report homozygous missense GRID1 variants in five individuals from two unrelated consanguineous families presenting with intellectual disability and spastic paraplegia, without (p.Thr752Met) or with (p.Arg161His) diagnosis of glaucoma, a threefold phenotypic association whose genetic bases had not been elucidated previously. Molecular modeling and electrophysiological recordings indicated that Arg161His and Thr752Met mutations alter the hinge between GluD1 cerebellin and D-serine binding domains and the function of this latter domain, respectively. Expression, trafficking, physical interaction with metabotropic glutamate receptor mGlu1, and cerebellin binding of GluD1 mutants were not conspicuously altered. Conversely, upon expression in neurons of dissociated or organotypic slice cultures, we found that both GluD1 mutants hampered metabotropic glutamate receptor mGlu1/5 signaling via Ca 2+ and the ERK pathway and impaired dendrite morphology and excitatory synapse density. These results show that the clinical phenotypes are distinct entities segregating in the families as an autosomal recessive trait, and caused by pathophysiological effects of GluD1 mutants involving metabotropic glutamate receptor signaling and neuronal connectivity. Our findings unravel the importance of GluD1 receptor signaling in sensory, cognitive and motor functions of the human nervous system., (© 2024. The Author(s).)
Published: 2024
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33. Clinically approved immunomodulators ameliorate behavioral changes in a mouse model of hereditary spastic paraplegia type 11.

Author: Hörner M, Popp S, Branchu J, Stevanin G, Darios F, Klebe S, Groh J, and Martini R
Abstract: We have previously demonstrated that neuroinflammation by the adaptive immune system acts as a robust and targetable disease amplifier in a mouse model of Spastic Paraplegia, type 11 (SPG11), a complicated form of Hereditary Spastic Paraplegia (HSP). While we identified an impact of neuroinflammation on distinct neuropathological changes and gait performance, neuropsychological features, typical and clinically highly relevant symptoms of complicated HSPs, were not addressed. Here we show that the corresponding SPG11 mouse model shows distinct behavioral abnormalities, particularly related to social behavior thus partially reflecting the neuropsychological changes in patients. We provide evidence that some behavioral abnormalities can be mitigated by genetic inactivation of the adaptive immune system. Translating this into a clinically applicable approach, we show that treatment with the established immunomodulators fingolimod or teriflunomide significantly attenuates distinct behavioral abnormalities, with the most striking effect on social behavior. This study links neuroinflammation to behavioral abnormalities in a mouse model of SPG11 and may thus pave the way for using immunomodulators as a treatment approach for SPG11 and possibly other complicated forms of HSP with neuropsychological involvement., Competing Interests: JB was employed by EVerZOM. SP was employed by TSE systems. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Hörner, Popp, Branchu, Stevanin, Darios, Klebe, Groh and Martini.)
Published: 2024
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34. Clinical and genetic keys to cerebellar ataxia due to FGF14 GAA expansions.

Author: Méreaux JL, Davoine CS, Pellerin D, Coarelli G, Coutelier M, Ewenczyk C, Monin ML, Anheim M, Le Ber I, Thobois S, Gobert F, Guillot-Noël L, Forlani S, Jornea L, Heinzmann A, Sangare A, Gaymard B, Guyant-Maréchal L, Charles P, Marelli C, Honnorat J, Degos B, Tison F, Sangla S, Simonetta-Moreau M, Salachas F, Tchikviladzé M, Castelnovo G, Mochel F, Klebe S, Castrioto A, Fenu S, Méneret A, Bourdain F, Wandzel M, Roth V, Bonnet C, Riant F, Stevanin G, Noël S, Fauret-Amsellem AL, Bahlo M, Lockhart PJ, Brais B, Renaud M, Brice A, and Durr A
Subjects: Child, Humans, Ataxia diagnosis, Ataxia genetics, Australia, Canada, Cross-Sectional Studies, Cerebellar Ataxia diagnosis, Cerebellar Ataxia genetics, Friedreich Ataxia genetics
Abstract: 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 < 0.0001) whereas GAA 250-299 alleles were detected in 1.7% of both groups. Eight of 14 index cases with GAA 250-299 repeats had other causal pathogenic variants (4/14) and/or discordance of co-segregation (5/14), arguing against GAA causality. We compared the clinical signs in 127 GAA ≥300 carriers to cases with non-expanded GAA ataxia resulting in defining a key phenotype triad: onset after 45 years, downbeat nystagmus, episodic ataxic features including diplopia; and a frequent absence of dysarthria. All maternally transmitted alleles above 100 GAA were unstable with a median expansion of +18 repeats per generation (r 2 = 0.44; p < 0.0001). In comparison, paternally transmitted alleles above 100 GAA mostly decreased in size (-15 GAA (r 2 = 0.63; p < 0.0001)), resulting in the transmission bias observed in SCA27B pedigrees., Interpretation: SCA27B diagnosis must consider both the phenotype and GAA expansion size. In carriers of GAA 250-299 repeats, the absence of documented familial transmission and a presentation deviating from the key SCA27B phenotype, should prompt the search for an alternative cause. Affected fathers have a reduced risk of having affected children, which has potential implications for genetic counseling., Funding: This work was supported by the Fondation pour la Recherche Médicale, grant number 13338 to JLM, the Association Connaître les Syndrome Cérébelleux - France (to GS) and by the European Union's Horizon 2020 research and innovation program under grant agreement No 779257 ("SOLVE-RD" to GS). DP holds a Fellowship award from the Canadian Institutes of Health Research (CIHR). SK received a grant (01GM1905C) from the Federal Ministry of Education and Research, Germany, through the TreatHSP network. This work was supported by the Australian Government National Health and Medical Research Council grants (GNT2001513 and MRFF2007677) to MB and PJL., Competing Interests: Declaration of interests MA received consulting fees from Reata pharmaceuticals, Merz, AbbVie, Orkyn, Ever Pharma, Ipsen; honoraria from Reata pharmaceuticals, Merz, AbbVie, Orkyn, Ever Pharma, Ipsen and participated on an advisory board for Reata Pharmaceuticals. ILB received grants from Pfizer, Fondation Plan Alzheimer, JPND/ANR, Alector; consulting fees from Prevail Therapeutics, Alector, JEITO and participated on an advisory board of Prevail Therapeutics. CM reveived financial support for attending meetings and travel from Nutricia and participated on an advisory board of Medesis Pharma society. BD had public funding contracts for Clinical Research: Contrat de Recherche Clinique (CRC) 2021 (APHP), CRC 2023 (APHP) and Agence Régionale de Santé (ARS); received honoraria from MERZ, IPSEN Pharma, LVL Medical; received support for attending meetings from MERZ Pharma, ADELIA; participated on an advisory board of MERZ, ORION Pharma and received equipment from MERZ. SF received support for participation in national and international meetings from Alnylam. MB received honoraria for thesis examinations; is member of Australian Academy of Health and Medical Sciences Australian Learned Academies Data Internetworking Network (ALADIN) Project Steering Committee; Australian Academy of Health and Medical Sciences Reports Committee; Clinical Genomics Advisory Committee, Kinghorn Sequencing Center; Gen V Scientific Advisory Committee, Murdoch Children's Research Institute; Viertel Foundation Medical Advisory Board; Australian Academy of Health and Medical Sciences Reports Committee; Present American Epilepsy Society Basic Sciences Committee; Gen V Bioresource Genetics Working Group. AD received grants from Biogen, WAVELIFE, ROCHE, TRIPLET Therapeutics, NIH RO1 (National Institute of Health), National Hospital Clinical Research Program; consulting fees from Wavelife science, ROCHE, TRIPLET Therapeutics, Pfizer, ASKBIO, Genome Quebec, VICO therapeutics; participated on an advisory board for REATA; is the president of the Société Francophone de Neurogénétique., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)
Published: 2024
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35. Machado-Joseph disease in a Sudanese family links East Africa to Portuguese families and allows reestimation of ancestral age of the Machado lineage.

Author: Martins S, Yahia A, Costa IPD, Siddig HE, Abubaker R, Koko M, Corral-Juan M, Matilla-Dueñas A, Brice A, Durr A, Leguern E, Ranum LPW, Amorim A, Elsayed LEO, Stevanin G, and Sequeiros J
Subjects: Male, Humans, Young Adult, Adult, Portugal, Muscle Cramp, Dysarthria, Phylogeny, Africa, Eastern, Machado-Joseph Disease genetics, Machado-Joseph Disease diagnosis
Abstract: Machado-Joseph disease (MJD/SCA3) is the most frequent dominant ataxia worldwide. It is caused by a (CAG) n expansion. MJD has two major ancestral backgrounds: the Machado lineage, found mainly in Portuguese families; and the Joseph lineage, present in all five continents, probably originating in Asia. MJD has been described in a few African and African-American families, but here we report the first diagnosed in Sudan to our knowledge. The proband presented with gait ataxia at age 24; followed by muscle cramps and spasticity, and dysarthria, by age 26; he was wheel-chair bound at 29 years of age. His brother had gait problems from age 20 years and, by age 21, lost the ability to run, showed dysarthria and muscle cramps. To assess the mutational origin of this family, we genotyped 30 SNPs and 7 STRs flanking the ATXN3_CAG repeat in three siblings and the non-transmitting father. We compared the MJD haplotype segregating in the family with our cohort of MJD families from diverse populations. Unlike all other known families of African origin, the Machado lineage was observed in Sudan, being shared with 86 Portuguese, 2 Spanish and 2 North-American families. The STR-based haplotype of Sudanese patients, however, was distinct, being four steps (2 STR mutations and 2 recombinations) away from the founder haplotype shared by 47 families, all of Portuguese extraction. Based on the phylogenetic network constructed with all MJD families of the Machado lineage, we estimated a common ancestry at 3211 ± 693 years ago., (© 2023. The Author(s).)
Published: 2023
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36. White matter abnormalities in 15 subjects with SPG76.

Author: Alkhalifa A, Chen S, Hasiloglu ZI, Filosto M, Cali E, Houlden H, Sgobbi de Souza P, Alavi A, Goizet C, Stevanin G, Taithe F, Nicita F, Vasco G, Tozza S, Cocozza S, Carboni N, Figus A, Wu J, Basak AN, Brais B, Rouleau G, and La Piana R
Subjects: Humans, Retrospective Studies, Magnetic Resonance Imaging, White Matter diagnostic imaging, White Matter pathology, Spastic Paraplegia, Hereditary diagnostic imaging, Spastic Paraplegia, Hereditary genetics, Paraparesis, Spastic
Abstract: Background and Objectives: Hereditary spastic paraplegias (HSPs) are heterogenous genetic disorders characterized by progressive pyramidal tract involvement. SPG76 is a recently identified form of HSP, caused by biallelic calpain-1 (CAPN1) variants. The most frequently described MRI abnormality in SPG76 is mild cerebellar atrophy and non-specific white matter abnormalities were reported in only one case. Following the identification of prominent white matter abnormalities in a subject with CAPN1 variants, which delayed the diagnosis, we aimed to verify the presence of MRI patterns of white matter involvement specific to this HSP., Methods: We performed a retrospective radiological qualitative analysis of 15 subjects with SPG76 (4 previously unreported) initially screened for white matter involvement. Moreover, we performed quantitative analyses in our proband with available longitudinal studies., Results: We observed bilateral, periventricular white matter involvement in 12 subjects (80%), associated with multifocal subcortical abnormalities in 5 of them (33.3%). Three subjects (20%) presented only multifocal subcortical involvement. Longitudinal quantitative analyses of our proband revealed increase in multifocal white matter lesion count and increased area of periventricular white matter involvement over time., Discussion: SPG76 should be added to the list of HSPs with associated white matter abnormalities. We identified periventricular white matter involvement in subjects with SPG76, variably associated with multifocal subcortical white matter abnormalities. These findings, in the presence of progressive spastic paraparesis, can mislead the diagnostic process towards an acquired white matter disorder., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)
Published: 2023
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37. Autosomal Dominant MPAN: Mosaicism Expands the Clinical Spectrum to Atypical Late-Onset Phenotypes.

Author: Angelini C, Durand CM, Fergelot P, Deforges J, Vital A, Menegon P, Sarrazin E, Bellance R, Mathis S, Gonzalez V, Renaud M, Frismand S, Schmitt E, Rouanet M, Burglen L, Chabrol B, Desnous B, Arveiler B, Stevanin G, Coupry I, and Goizet C
Subjects: Humans, Mitochondrial Proteins genetics, Iron metabolism, Mutation genetics, Membrane Proteins genetics, Phenotype, Mosaicism, Movement Disorders
Abstract: Background: Mitochondrial membrane protein-associated neurodegeneration (MPAN) is caused by mutations in the C19orf12 gene. MPAN typically appears in the first two decades of life and presents with progressive dystonia-parkinsonism, lower motor neuron signs, optic atrophy, and abnormal iron deposits predominantly in the basal ganglia. MPAN, initially considered as a strictly autosomal recessive disease (AR), turned out to be also dominantly inherited (AD)., Objectives: Our aim was to better characterize the clinical, molecular, and functional spectra associated with such dominant pathogenic heterozygous C19orf12 variants., Methods: We collected clinical, imaging, and molecular information of eight individuals from four AD-MPAN families and obtained brain neuropathology results for one. Functional studies, focused on energy and iron metabolism, were conducted on fibroblasts from AD-MPAN patients, AR-MPAN patients, and controls., Results: We identified four heterozygous C19orf12 variants in eight AD-MPAN patients. Two of them carrying the familial variant in mosaic displayed an atypical late-onset phenotype. Fibroblasts from AD-MPAN showed more severe alterations of iron storage metabolism and autophagy compared to AR-MPAN cells., Conclusion: Our data add strong evidence of the realness of AD-MPAN with identification of novel monoallelic C19orf12 variants, including at the mosaic state. This has implications in diagnosis procedures. We also expand the phenotypic spectrum of MPAN to late onset atypical presentations. Finally, we demonstrate for the first time more drastic abnormalities of iron metabolism and autophagy in AD-MPAN than in AR-MPAN. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)
Published: 2023
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38. IRF2BPL Causes Mild Intellectual Disability Followed by Late-Onset Ataxia.

Author: Heide S, Davoine CS, Cunha P, Scherer-Gagou C, Keren B, Stevanin G, Charles P, Heron D, Brice A, and Durr A
Abstract: Background and Objectives: Neurodevelopmental and neurodegenerative disorders have long been considered as different clinical and molecular entities, and only a few genes are known to be involved in both processes. The IRF2BPL (interferon regulatory factor 2 binding protein like) gene was implicated in a severe pediatric phenotype characterized by developmental and epileptic encephalopathy and early regression. In parallel, inherited IRF2BPL variants have been reported in cohorts of patients with late-onset progressive dystonic and ataxic syndrome with few information about the neurodevelopment of these patients. This study aimed to describe both neurodevelopmental and neurodegenerative aspects of the phenotype in adults with IRF2BPL pathogenic variant., Methods: We report here the clinical and molecular data of 18 individuals carrying truncating IRF2BPL variants (identified by either exome or genome sequencing), including a large pedigree of 16 patients presenting with a neurodevelopmental disorder (NDD) associated with late-onset cerebellar ataxia and atrophy., Results: Genome sequencing identified the p.(Gln117*) variant in a large family first assessed for familial ataxia, with multiple individuals presenting with NDD. The p.(Ser313*) variant was identified by exome sequencing in a second family with a young adult patient with NDD without ataxia which was inherited from her asymptomatic mother, suggesting incomplete penetrance of IRF2BPL -linked disorders., Discussion: This study illustrates the importance of neurologic evaluation of adult patients initially diagnosed with NDD to detect a late-onset neurodegenerative condition. Two different disorders may be clinically diagnosed in the same family, when not considering that NDD and late cerebellar changes may be part of the same molecular spectrum such as for IRF2BPL ., Competing Interests: The authors report no relevant disclosures. Go to Neurology.org/NG for full disclosures., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)
Published: 2023
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39. The mitochondrial seryl-tRNA synthetase SARS2 modifies onset in spastic paraplegia type 4.

Author: Parodi L, Barbier M, Jacoupy M, Pujol C, Lejeune FX, Lallemant-Dudek P, Esteves T, Pennings M, Kamsteeg EJ, Guillaud-Bataille M, Banneau G, Coarelli G, Oumoussa BM, Fraidakis MJ, Stevanin G, Depienne C, van de Warrenburg B, Brice A, and Durr A
Subjects: Humans, Genome-Wide Association Study, Mutation, Spastin genetics, Spastin metabolism, Serine-tRNA Ligase genetics, Serine-tRNA Ligase metabolism, Spastic Paraplegia, Hereditary genetics
Abstract: Purpose: Hereditary spastic paraplegia type 4 is extremely variable in age at onset; the same variant can cause onset at birth or in the eighth decade. We recently discovered that missense variants in SPAST, which influences microtubule dynamics, are associated with earlier onset and more severe disease than truncating variants, but even within the early and late-onset groups there remained significant differences in onset. Given the rarity of the condition, we adapted an extreme phenotype approach to identify genetic modifiers of onset., Methods: We performed a genome-wide association study on 134 patients bearing truncating pathogenic variants in SPAST, divided into early- and late-onset groups (aged ≤15 and ≥45 years, respectively). A replication cohort of 419 included patients carrying either truncating or missense variants. Finally, age at onset was analyzed in the merged cohort (N = 553)., Results: We found 1 signal associated with earlier age at onset (rs10775533, P = 8.73E-6) in 2 independent cohorts and in the merged cohort (N = 553, Mantel-Cox test, P < .0001). Western blotting in lymphocytes of 20 patients showed that this locus tends to upregulate SARS2 expression in earlier-onset patients., Conclusion: SARS2 overexpression lowers the age of onset in hereditary spastic paraplegia type 4. Lowering SARS2 or improving mitochondrial function could thus present viable approaches to therapy., Competing Interests: Conflict of Interest The authors declare no conflict of interest., (Copyright © 2022 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.)
Published: 2022
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40. CNS-associated T-lymphocytes in a mouse model of Hereditary Spastic Paraplegia type 11 (SPG11) are therapeutic targets for established immunomodulators.

Author: Hörner M, Groh J, Klein D, Ilg W, Schöls L, Dos Santos S, Bergmann A, Klebe S, Cauhape M, Branchu J, El Hachimi KH, Stevanin G, Darios F, and Martini R
Subjects: Animals, Central Nervous System pathology, Disease Models, Animal, Disease Progression, Immunologic Factors pharmacology, Immunologic Factors therapeutic use, Mice, Mutation, Proteins genetics, T-Lymphocytes pathology, Spastic Paraplegia, Hereditary drug therapy, Spastic Paraplegia, Hereditary genetics, Spastic Paraplegia, Hereditary pathology
Abstract: Pharmacological targeting of neuroinflammation in distinct models of genetically mediated disorders of the central nervous system (CNS) has been shown to attenuate disease outcome significantly. These include mouse models mimicking distinct subtypes of neuronal ceroid lipofuscinoses (NCL, CLN diseases) as well as hereditary spastic paraplegia type 2 (HSP/SPG2). We here show in a model of another, complicated HSP form (SPG11) that there is neuroinflammation in distinct compartments of the diseased CNS. Using a proof-of-principle experiment, we provide evidence that genetically targeting the adaptive immune system dampens disease progression including gait disturbance, demonstrating a pathogenic impact of neuroinflammation. Translating these studies into a clinically applicable approach, we show that the established immunomodulators fingolimod and teriflunomide significantly attenuate the neurodegenerative phenotype and improve gait performance in the SPG11 model, even when applied relatively late during disease progression. Particularly abnormalities in gait coordination, representing ataxia, could be attenuated, while features indicative of reduced strength during walking did not respond to treatment. Our study identifies neuroinflammation by the adaptive immune system as a robust and targetable disease amplifier in a mouse model of SPG11 and may thus pave the way for a translational approach in humans implicating approved immunomodulators., (Copyright © 2022 Elsevier Inc. All rights reserved.)
Published: 2022
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41. Heterozygous PNPT1 Variants Cause Spinocerebellar Ataxia Type 25.

Author: Barbier M, Bahlo M, Pennisi A, Jacoupy M, Tankard RM, Ewenczyk C, Davies KC, Lino-Coulon P, Colace C, Rafehi H, Auger N, Ansell BRE, van der Stelt I, Howell KB, Coutelier M, Amor DJ, Mundwiller E, Guillot-Noël L, Storey E, Gardner RJM, Wallis MJ, Brusco A, Corti O, Rötig A, Leventer RJ, Brice A, Delatycki MB, Stevanin G, Lockhart PJ, and Durr A
Subjects: Ataxia, Australia, Exoribonucleases, France, Humans, Cerebellar Ataxia, Interferon Type I genetics, Spinocerebellar Ataxias genetics, Spinocerebellar Ataxias pathology
Abstract: Objective: Dominant spinocerebellar ataxias (SCA) are characterized by genetic heterogeneity. Some mapped and named loci remain without a causal gene identified. Here we applied next generation sequencing (NGS) to uncover the genetic etiology of the SCA25 locus., Methods: Whole-exome and whole-genome sequencing were performed in families linked to SCA25, including the French family in which the SCA25 locus was originally mapped. Whole exome sequence data were interrogated in a cohort of 796 ataxia patients of unknown etiology., Results: The SCA25 phenotype spans a slowly evolving sensory and cerebellar ataxia, in most cases attributed to ganglionopathy. A pathogenic variant causing exon skipping was identified in the gene encoding Polyribonucleotide Nucleotidyltransferase PNPase 1 (PNPT1) located in the SCA25 linkage interval. A second splice variant in PNPT1 was detected in a large Australian family with a dominant ataxia also mapping to SCA25. An additional nonsense variant was detected in an unrelated individual with ataxia. Both nonsense and splice heterozygous variants result in premature stop codons, all located in the S1-domain of PNPase. In addition, an elevated type I interferon response was observed in blood from all affected heterozygous carriers tested. PNPase notably prevents the abnormal accumulation of double-stranded mtRNAs in the mitochondria and leakage into the cytoplasm, associated with triggering a type I interferon response., Interpretation: This study identifies PNPT1 as a new SCA gene, responsible for SCA25, and highlights biological links between alterations of mtRNA trafficking, interferonopathies and ataxia. ANN NEUROL 2022;92:122-137., (© 2022 American Neurological Association.)
Published: 2022
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42. Genetic diagnosis in Sudanese and Tunisian families with syndromic intellectual disability through exome sequencing.

Author: Yahia A, Ayed IB, Hamed AA, Mohammed IN, Elseed MA, Bakhiet AM, Guillot-Noel L, Abozar F, Adil R, Emad S, Abubaker R, Musallam MA, Eltazi IZM, Omer Z, Maaroof OM, Soussi A, Bouzid A, Kmiha S, Kamoun H, Salih MA, Ahmed AE, Elsayed L, Masmoudi S, and Stevanin G
Subjects: Exome, Humans, Microcephaly genetics, Mutation, Paraplegia genetics, Pedigree, Phenotype, Sudan, Tunisia, Exome Sequencing, Adenosine Deaminase genetics, Intellectual Disability diagnosis, RNA-Binding Proteins genetics, Tumor Suppressor Proteins genetics, Ubiquitin-Protein Ligases genetics
Abstract: Background: Intellectual disability is a form of neurodevelopmental disorders that begin in childhood and is characterized by substantial intellectual difficulties as well as difficulties in conceptual, social, and practical areas of living. Several genetic and nongenetic factors contribute to its development; however, its most severe forms are generally attributed to single-gene defects. High-throughput technologies and data sharing contributed to the diagnosis of hundreds of single-gene intellectual disability subtypes., Method: We applied exome sequencing to identify potential variants causing syndromic intellectual disability in six Sudanese patients from four unrelated families. Data sharing through the Varsome portal corroborated the diagnosis of one of these patients and a Tunisian patient investigated through exome sequencing. Sanger sequencing validated the identified variants and their segregation with the phenotypes in the five studied families., Result: We identified three pathogenic/likely pathogenic variants in CCDC82, ADAT3, and HUWE1 and variants of uncertain significance in HERC2 and ATP2B3. The patients with the CCDC82 variants had microcephaly and spasticity, two signs absent in the two previously reported families with CCDC82-related intellectual disability., Conclusion: In conclusion, we report new patients with pathogenic mutations in the genes CCDC82, ADAT3, and HUWE1. We also highlight the possibility of extending the CCDC82-linked phenotype to include spastic paraplegia and microcephaly., (© 2022 John Wiley & Sons Ltd/University College London.)
Published: 2022
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43. De Novo and Dominantly Inherited SPTAN1 Mutations Cause Spastic Paraplegia and Cerebellar Ataxia.

Author: Van de Vondel L, De Winter J, Beijer D, Coarelli G, Wayand M, Palvadeau R, Pauly MG, Klein K, Rautenberg M, Guillot-Noël L, Deconinck T, Vural A, Ertan S, Dogu O, Uysal H, Brankovic V, Herzog R, Brice A, Durr A, Klebe S, Stock F, Bischoff AT, Rattay TW, Sobrido MJ, De Michele G, De Jonghe P, Klopstock T, Lohmann K, Zanni G, Santorelli FM, Timmerman V, Haack TB, Züchner S, Schüle R, Stevanin G, Synofzik M, Basak AN, and Baets J
Subjects: Humans, Mutation genetics, Paraplegia genetics, Pedigree, Phenotype, Spectrin genetics, Carrier Proteins genetics, Cerebellar Ataxia genetics, Intellectual Disability genetics, Microfilament Proteins genetics, Spastic Paraplegia, Hereditary genetics
Abstract: Background: Pathogenic variants in SPTAN1 have been linked to a remarkably broad phenotypical spectrum. Clinical presentations include epileptic syndromes, intellectual disability, and hereditary motor neuropathy., Objectives: We investigated the role of SPTAN1 variants in rare neurological disorders such as ataxia and spastic paraplegia., Methods: We screened 10,000 NGS datasets across two international consortia and one local database, indicative of the level of international collaboration currently required to identify genes causative for rare disease. We performed in silico modeling of the identified SPTAN1 variants., Results: We describe 22 patients from 14 families with five novel SPTAN1 variants. Of six patients with cerebellar ataxia, four carry a de novo SPTAN1 variant and two show a sporadic inheritance. In this group, one variant (p.Lys2083del) is recurrent in four patients. Two patients have novel de novo missense mutations (p.Arg1098Cys, p.Arg1624Cys) associated with cerebellar ataxia, in one patient accompanied by intellectual disability and epilepsy. We furthermore report a recurrent missense mutation (p.Arg19Trp) in 15 patients with spastic paraplegia from seven families with a dominant inheritance pattern in four and a de novo origin in one case. One further patient carrying a de novo missense mutation (p.Gln2205Pro) has a complex spastic ataxic phenotype. Through protein modeling we show that mutated amino acids are located at crucial interlinking positions, interconnecting the three-helix bundle of a spectrin repeat., Conclusions: We show that SPTAN1 is a relevant candidate gene for ataxia and spastic paraplegia. We suggest that for the mutations identified in this study, disruption of the interlinking of spectrin helices could be a key feature of the pathomechanism. © 2022 International Parkinson and Movement Disorder Society., (© 2022 International Parkinson and Movement Disorder Society.)
Published: 2022
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44. NPTX1 mutations trigger endoplasmic reticulum stress and cause autosomal dominant cerebellar ataxia.

Author: Coutelier M, Jacoupy M, Janer A, Renaud F, Auger N, Saripella GV, Ancien F, Pucci F, Rooman M, Gilis D, Larivière R, Sgarioto N, Valter R, Guillot-Noel L, Le Ber I, Sayah S, Charles P, Nümann A, Pauly MG, Helmchen C, Deininger N, Haack TB, Brais B, Brice A, Trégouët DA, El Hachimi KH, Shoubridge EA, Durr A, and Stevanin G
Subjects: Humans, Exome Sequencing, Mutation, Pedigree, C-Reactive Protein genetics, Cerebellar Ataxia genetics, Endoplasmic Reticulum Stress genetics, Nerve Tissue Proteins genetics
Abstract: With more than 40 causative genes identified so far, autosomal dominant cerebellar ataxias exhibit a remarkable genetic heterogeneity. Yet, half the patients are lacking a molecular diagnosis. In a large family with nine sampled affected members, we performed exome sequencing combined with whole-genome linkage analysis. We identified a missense variant in NPTX1, NM_002522.3:c.1165G>A: p.G389R, segregating with the phenotype. Further investigations with whole-exome sequencing and an amplicon-based panel identified four additional unrelated families segregating the same variant, for whom a common founder effect could be excluded. A second missense variant, NM_002522.3:c.980A>G: p.E327G, was identified in a fifth familial case. The NPTX1-associated phenotype consists of a late-onset, slowly progressive, cerebellar ataxia, with downbeat nystagmus, cognitive impairment reminiscent of cerebellar cognitive affective syndrome, myoclonic tremor and mild cerebellar vermian atrophy on brain imaging. NPTX1 encodes the neuronal pentraxin 1, a secreted protein with various cellular and synaptic functions. Both variants affect conserved amino acid residues and are extremely rare or absent from public databases. In COS7 cells, overexpression of both neuronal pentraxin 1 variants altered endoplasmic reticulum morphology and induced ATF6-mediated endoplasmic reticulum stress, associated with cytotoxicity. In addition, the p.E327G variant abolished neuronal pentraxin 1 secretion, as well as its capacity to form a high molecular weight complex with the wild-type protein. Co-immunoprecipitation experiments coupled with mass spectrometry analysis demonstrated abnormal interactions of this variant with the cytoskeleton. In agreement with these observations, in silico modelling of the neuronal pentraxin 1 complex evidenced a destabilizing effect for the p.E327G substitution, located at the interface between monomers. On the contrary, the p.G389 residue, located at the protein surface, had no predictable effect on the complex stability. Our results establish NPTX1 as a new causative gene in autosomal dominant cerebellar ataxias. We suggest that variants in NPTX1 can lead to cerebellar ataxia due to endoplasmic reticulum stress, mediated by ATF6, and associated to a destabilization of NP1 polymers in a dominant-negative manner for one of the variants., (© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com.)
Published: 2022
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45. Clinical and genetic spectra of 1550 index patients with hereditary spastic paraplegia.

Author: Méreaux JL, Banneau G, Papin M, Coarelli G, Valter R, Raymond L, Kol B, Ariste O, Parodi L, Tissier L, Mairey M, Ait Said S, Gautier C, Guillaud-Bataille M, Forlani S, de la Grange P, Brice A, Vazza G, Durr A, Leguern E, and Stevanin G
Subjects: High-Throughput Nucleotide Sequencing, Humans, Kinesins genetics, Membrane Transport Proteins genetics, Mutation genetics, Pedigree, Proteins genetics, Spastin genetics, Exome Sequencing, Spastic Paraplegia, Hereditary diagnosis, Spastic Paraplegia, Hereditary genetics
Abstract: Hereditary spastic paraplegia refers to rare genetic neurodevelopmental and/or neurodegenerative disorders in which spasticity due to length-dependent damage to the upper motor neuron is a core sign. Their high clinical and genetic heterogeneity makes their diagnosis challenging. Multigene panels allow a high-throughput targeted analysis of the increasing number of genes involved using next-generation sequencing. We report here the clinical and genetic results of 1550 index cases tested for variants in a panel of hereditary spastic paraplegia related genes analysed in routine diagnosis. A causative variant was found in 475 patients (30.7%) in 35/65 screened genes. SPAST and SPG7 were the most frequently mutated genes, representing 142 (9.2%) and 75 (4.8%) index cases of the whole series, respectively. KIF1A, ATL1, SPG11, KIF5A and REEP1 represented more than 1% (>17 cases) each. There were 661 causative variants (382 different ones) and 30 of them were structural variants. This large cohort allowed us to obtain an overview of the clinical and genetic spectrum of hereditary spastic paraplegia in clinical practice. Because of the wide phenotypic variability, there was no very specific sign that could predict the causative gene, but there were some constellations of symptoms that were found often related to specific subtypes. Finally, we confirmed the diagnostic effectiveness of a targeted sequencing panel as a first-line genetic test in hereditary spastic paraplegia. This is a pertinent strategy because of the relative frequency of several known genes (i.e. SPAST, KIF1A) and it allows identification of variants in the rarest involved genes and detection of structural rearrangements via coverage analysis, which is less efficient in exome datasets. It is crucial because these structural variants represent a significant proportion of the pathogenic hereditary spastic paraplegia variants (∼6% of patients), notably for SPAST and REEP1. In a subset of 42 index cases negative for the targeted multigene panel, subsequent whole-exome sequencing allowed a theoretical diagnosis yield of ∼50% to be reached. We then propose a two-step strategy combining the use of a panel of genes followed by whole-exome sequencing in negative cases., (© The Author(s) (2022). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com.)
Published: 2022
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46. Insights into Clinical, Genetic, and Pathological Aspects of Hereditary Spastic Paraplegias: A Comprehensive Overview.

Author: Elsayed LEO, Eltazi IZ, Ahmed AE, and Stevanin G
Abstract: Hereditary spastic paraplegias (HSP) are a heterogeneous group of motor neurodegenerative disorders that have the core clinical presentation of pyramidal syndrome which starts typically in the lower limbs. They can present as pure or complex forms with all classical modes of monogenic inheritance reported. To date, there are more than 100 loci/88 spastic paraplegia genes (SPG) involved in the pathogenesis of HSP. New patterns of inheritance are being increasingly identified in this era of huge advances in genetic and functional studies. A wide range of clinical symptoms and signs are now reported to complicate HSP with increasing overall complexity of the clinical presentations considered as HSP. This is especially true with the emergence of multiple HSP phenotypes that are situated in the borderline zone with other neurogenetic disorders. The genetic diagnostic approaches and the utilized techniques leave a diagnostic gap of 25% in the best studies. In this review, we summarize the known types of HSP with special focus on those in which spasticity is the principal clinical phenotype ("SPGn" designation). We discuss their modes of inheritance, clinical phenotypes, underlying genetics, and molecular pathways, providing some observations about therapeutic opportunities gained from animal models and functional studies. This review may pave the way for more analytic approaches that take into consideration the overall picture of HSP. It will shed light on subtle associations that can explain the occurrence of the disease and allow a better understanding of its observed variations. This should help in the identification of future biomarkers, predictors of disease onset and progression, and treatments for both better functional outcomes and quality of life., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest, except a grant received by GS from Biogen, but unrelated to this work., (Copyright © 2021 Elsayed, Eltazi, Ahmed and Stevanin.)
Published: 2021
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47. Implication of folate deficiency in CYP2U1 loss of function.

Author: Pujol C, Legrand A, Parodi L, Thomas P, Mochel F, Saracino D, Coarelli G, Croon M, Popovic M, Valet M, Villain N, Elshafie S, Issa M, Zuily S, Renaud M, Marelli-Tosi C, Legendre M, Trimouille A, Kemlin I, Mathieu S, Gleeson JG, Lamari F, Galatolo D, Alkouri R, Tse C, Rodriguez D, Ewenczyk C, Fellmann F, Kuntzer T, Blond E, El Hachimi KH, Darios F, Seyer A, Gazi AD, Giavalisco P, Perin S, Boucher JL, Le Corre L, Santorelli FM, Goizet C, Zaki MS, Picaud S, Mourier A, Steculorum SM, Mignot C, Durr A, Trifunovic A, and Stevanin G
Subjects: Animals, Biomarkers metabolism, Brain metabolism, Disease Models, Animal, Humans, Mice, Mice, Inbred C57BL, Mice, Knockout, Mitochondria genetics, Mitochondria metabolism, Mutation genetics, Phenotype, Proteomics methods, Cytochrome P450 Family 2 genetics, Cytochrome P450 Family 2 metabolism, Folic Acid pharmacology, Folic Acid Deficiency genetics, Folic Acid Deficiency metabolism
Abstract: Hereditary spastic paraplegias are heterogeneous neurodegenerative disorders. Understanding of their pathogenic mechanisms remains sparse, and therapeutic options are lacking. We characterized a mouse model lacking the Cyp2u1 gene, loss of which is known to be involved in a complex form of these diseases in humans. We showed that this model partially recapitulated the clinical and biochemical phenotypes of patients. Using electron microscopy, lipidomic, and proteomic studies, we identified vitamin B2 as a substrate of the CYP2U1 enzyme, as well as coenzyme Q, neopterin, and IFN-α levels as putative biomarkers in mice and fluids obtained from the largest series of CYP2U1-mutated patients reported so far. We also confirmed brain calcifications as a potential biomarker in patients. Our results suggest that CYP2U1 deficiency disrupts mitochondrial function and impacts proper neurodevelopment, which could be prevented by folate supplementation in our mouse model, followed by a neurodegenerative process altering multiple neuronal and extraneuronal tissues., Competing Interests: Disclosures: F. Darios reports "other" from Dynacure SAS outside the submitted work. D. Galatolo is supported by a grant from Treat SPG56. G. Stevanin reports grants from ASL-HSP association, the Tom-Wahlig-Stiftung Foundation, and the European Union 7th Framework Programme (Neuromics); non-financial support from Agence Nationale de la Recherche (framework programme Investissements d'Avenir) during the conduct of the study; and grants from Biogen outside the submitted work. N. Vilain reports grants from Fondation Bettencourt-Schueller, Fondation Servier, Union Nationale pour les Intérêts de la Médecine, and Fondation pour la Recherche sur l'Alzheimer; non-financial support from Movement Disorders Society, Merz-Pharma, and GE Healthcare SAS; and "other" from Biogen, Eisai, Eli-Lilly, Roche, Janssen - Johnson & Johnson, and Alector outside the submitted work. No other disclosures were reported., (© 2021 Pujol et al.)
Published: 2021
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48. Correction: Clinical, neuropathological, and genetic characterization of STUB1 variants in cerebellar ataxias: a frequent cause of predominant cognitive impairment.

Author: Roux T, Barbier M, Papin M, Davoine CS, Sayah S, Coarelli G, Charles P, Marelli C, Parodi L, Tranchant C, Goizet C, Klebe S, Lohmann E, Van Maldergem L, van Broeckhoven C, Coutelier M, Tesson C, Stevanin G, Duyckaerts C, Brice A, and Durr A
Published: 2021
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49. An identical-by-descent novel splice-donor variant in PRUNE1 causes a neurodevelopmental syndrome with prominent dystonia in two consanguineous Sudanese families.

Author: Koko M, Yahia A, Elsayed LE, Hamed AA, Mohammed IN, Elseed MA, Hamad MHA, Babai AM, Siddig RA, Abd Allah ASI, Mohamed M, El-Amin M, Esteves T, Altmüller J, Toliat MR, Thiele H, Nürnberg P, Salih MA, Ahmed AE, Lerche H, and Stevanin G
Subjects: Child, Child, Preschool, Consanguinity, Female, Haplotypes, Homozygote, Humans, Introns, Male, Pedigree, Phenotype, RNA Splice Sites, Sudan, Exome Sequencing, Dystonia genetics, Hypokinesia genetics, Neurodevelopmental Disorders genetics, Phosphoric Monoester Hydrolases genetics, RNA Splicing
Abstract: PRUNE1 is linked to a wide range of neurodevelopmental and neurodegenerative phenotypes. Multiple pathogenic missense and stop-gain PRUNE1 variants were identified in its DHH and DHHA2 phosphodiesterase domains. Conversely, a single splice alteration was previously reported. We investigated five patients from two unrelated consanguineous Sudanese families with an inherited severe neurodevelopmental disorder using whole-exome sequencing coupled with homozygosity mapping, segregation, and haplotype analysis. We identified a founder haplotype transmitting a homozygous canonical splice-donor variant (NM_021222.3:c.132+2T > C) in intron 2 of PRUNE1 segregated with the phenotype in all the patients. This splice variant possibly results in an in-frame deletion in the DHH domain or premature truncation of the protein. The phenotypes of the affected individuals showed phenotypic similarities characterized by remarkable pyramidal dysfunction and prominent extrapyramidal features (severe dystonia and bradykinesia). In conclusion, we identified a novel founder variant in PRUNE1 and corroborated abnormal splicing events as a disease mechanism in PRUNE1-related disorders. Given the phenotypes' consistency coupled with the founder effect, canonical and cryptic PRUNE1 splice-site variants should be carefully evaluated in patients presenting with prominent dystonia and pyramidal dysfunction., (© 2021 John Wiley & Sons Ltd/University College London.)
Published: 2021
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50. Pathogenic Variants in ABHD16A Cause a Novel Psychomotor Developmental Disorder With Spastic Paraplegia.

Author: Yahia A, Elsayed LEO, Valter R, Hamed AAA, Mohammed IN, Elseed MA, Salih MA, Esteves T, Auger N, Abubaker R, Koko M, Abozar F, Malik H, Adil R, Emad S, Musallam MA, Idris R, Eltazi IZM, Babai A, Ahmed EAA, Abd Allah ASI, Mairey M, Ahmed AKMA, Elbashir MI, Brice A, Ibrahim ME, Ahmed AE, Lamari F, and Stevanin G
Abstract: Introduction: Hereditary spastic paraplegia is a clinically and genetically heterogeneous neurological entity that includes more than 80 disorders which share lower limb spasticity as a common feature. Abnormalities in multiple cellular processes are implicated in their pathogenesis, including lipid metabolism; but still 40% of the patients are undiagnosed. Our goal was to identify the disease-causing variants in Sudanese families excluded for known genetic causes and describe a novel clinico-genetic entity. Methods: We studied four patients from two unrelated consanguineous Sudanese families who manifested a neurological phenotype characterized by spasticity, psychomotor developmental delay and/or regression, and intellectual impairment. We applied next-generation sequencing, bioinformatics analysis, and Sanger sequencing to identify the genetic culprit. We then explored the consequences of the identified variants in patients-derived fibroblasts using targeted-lipidomics strategies. Results and Discussion: Two homozygous variants in ABHD16A segregated with the disease in the two studied families. ABHD16A encodes the main brain phosphatidylserine hydrolase. In vitro , we confirmed that ABHD16A loss of function reduces the levels of certain long-chain lysophosphatidylserine species while increases the levels of multiple phosphatidylserine species in patient's fibroblasts. Conclusion: ABHD16A loss of function is implicated in the pathogenesis of a novel form of complex hereditary spastic paraplegia., Competing Interests: GS declares to have received funding support from Biogen, unrelated to this work. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Yahia, Elsayed, Valter, Hamed, Mohammed, Elseed, Salih, Esteves, Auger, Abubaker, Koko, Abozar, Malik, Adil, Emad, Musallam, Idris, Eltazi, Babai, Ahmed, Abd Allah, Mairey, Ahmed, Elbashir, Brice, Ibrahim, Ahmed, Lamari and Stevanin.)
Published: 2021
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