Stefania Della Vecchia1, Alessandra Tessa2, Claudia Dosi3, Jacopo Baldacci4, Rosa Pasquariello1, Antonella Antenora5, Guja Astrea1, Maria Teresa Bassi6, Roberta Battini1,7, Carlo Casali8, Ettore Cioffi8, Greta Conti9, Giovanna De Michele5, Anna Rita Ferrari1, Alessandro Filla5, Chiara Fiorillo10, Carlo Fusco11, Salvatore Gallone12, Chiara Germiniasi13, Renzo Guerrini9, Shalom Haggiag14, Diego Lopergolo1,15, Andrea Martinuzzi16, Federico Melani9, Andrea Mignarri15, Elena Panzeri6, Antonella Pini17, Anna Maria Pinto18, Francesca Pochiero19, Guido Primiano20, Elena Procopio19, Alessandra Renieri18, Romina Romaniello21, Cristina Sancricca20, Serenella Servidei20,22, Carlotta Spagnoli11, Chiara Ticci1,19, Anna Rubegni1, Filippo Maria Santorelli23. 1. IRCCS Stella Maris Foundation, Calambrone, via dei Giacinti 2, 56128, Pisa, Italy. 2. IRCCS Stella Maris Foundation, Calambrone, via dei Giacinti 2, 56128, Pisa, Italy. aletessa@gmail.com. 3. Child Neurology, Fondazione IRCCS Istituto Neurologico Carlo Besta, 20133, Milan, Italy. 4. Kode Solutions, Lungarno Galileo Galilei 1, 56125, Pisa, Italy. 5. Department of Neurosciences, Reproductive and Odontostomatological Sciences, Federico II University, 80131, Naples, Italy. 6. Laboratory of Molecular Biology, Scientific Institute IRCCS Eugenio Medea, Bosisio Parini, 23842, Lecco, Italy. 7. Department of Clinical and Experimental Medicine, Neurological Institute, University of Pisa, 56125, Pisa, Italy. 8. Department of Medical and Surgical Sciences and Biotechnologies, Sapienza University of Rome, 40100, Latina, Italy. 9. Neurology Unit and Neurogenetics Laboratories, Meyer Children University Hospital, University of Florence, 50139, Florence, Italy. 10. Neuromuscular Disorders Unit, IRCCS Istituto Giannina Gaslini, DINOGMI, University of Genoa, Genoa, Italy. 11. Child Neurology Unit, Pediatric Neurophysiology Laboratory, Department of Pediatrics, Azienda USL-IRCCS Di Reggio Emilia, 42122, Reggio Emilia, Italy. 12. Clinical Neurogenetics, Department Neurosciences, Az. Osp. Città della Salute e della Scienza di Torino, 1026, Torino, Italy. 13. Neuromuscular Unit, Scientific Institute IRCCS E. Medea, Bosisio Parini, 23842, Lecco, Italy. 14. Department of Neurology, Azienda Ospedaliera San Camillo Forlanini, 00152, Rome, Italy. 15. Unit of Neurology and Neurometabolic Disorders, Department of Medicine, Surgery and Neurosciences, University of Siena, 53100, Siena, Italy. 16. Scientific Institute IRCCS E. Medea, Unità Operativa Conegliano, 31015, Treviso, Italy. 17. Neuromuscular Pediatric Unit, IRRCS Istituto delle Scienze Neurologiche di Bologna, 40139, Bologna, Italy. 18. Medical Genetics Unit, University of Siena, Azienda Ospedaliera Universitaria Senese, 53100, Siena, Italy. 19. Department of Metabolic and Muscular, Meyer Children's University Hospital, 50139, Florence, Italy. 20. Neurofisiopathology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168, Rome, Italy. 21. Neuropsychiatry and Neurorehabilitation Unit, Scientific Institute, IRCCS Eugenio Medea, Bosisio Parini, 23842, Lecco, Italy. 22. Dipartimento Universitario di Neuroscienze, Università Cattolica del Sacro Cuore, 00168, Rome, Italy. 23. IRCCS Stella Maris Foundation, Calambrone, via dei Giacinti 2, 56128, Pisa, Italy. filippo3364@gmail.com.
Abstract
BACKGROUND: Monoallelic variants in the KIF1A gene are associated with a large set of clinical phenotypes including neurodevelopmental and neurodegenerative disorders, underpinned by a broad spectrum of central and peripheral nervous system involvement. METHODS: In a multicenter study conducted in patients presenting spastic gait or complex neurodevelopmental disorders, we analyzed the clinical, genetic and neuroradiological features of 28 index cases harboring heterozygous variants in KIF1A. We conducted a literature systematic review with the aim to comparing our findings with previously reported KIF1A-related phenotypes. RESULTS: Among 28 patients, we identified nine novel monoallelic variants, and one a copy number variation encompassing KIF1A. Mutations arose de novo in most patients and were prevalently located in the motor domain. Most patients presented features of a continuum ataxia-spasticity spectrum with only five cases showing a prevalently pure spastic phenotype and six presenting congenital ataxias. Seventeen mutations occurred in the motor domain of the Kinesin-1A protein, but location of mutation did not correlate with neurological and imaging presentations. When tested in 15 patients, muscle biopsy showed oxidative metabolism alterations (6 cases), impaired respiratory chain complexes II + III activity (3/6) and low CoQ10 levels (6/9). Ubiquinol supplementation (1gr/die) was used in 6 patients with subjective benefit. CONCLUSIONS: This study broadened our clinical, genetic, and neuroimaging knowledge of KIF1A-related disorders. Although highly heterogeneous, it seems that manifestations of ataxia-spasticity spectrum disorders seem to occur in most patients. Some patients also present secondary impairment of oxidative metabolism; in this subset, ubiquinol supplementation therapy might be appropriate.
BACKGROUND: Monoallelic variants in the KIF1A gene are associated with a large set of clinical phenotypes including neurodevelopmental and neurodegenerative disorders, underpinned by a broad spectrum of central and peripheral nervous system involvement. METHODS: In a multicenter study conducted in patients presenting spastic gait or complex neurodevelopmental disorders, we analyzed the clinical, genetic and neuroradiological features of 28 index cases harboring heterozygous variants in KIF1A. We conducted a literature systematic review with the aim to comparing our findings with previously reported KIF1A-related phenotypes. RESULTS: Among 28 patients, we identified nine novel monoallelic variants, and one a copy number variation encompassing KIF1A. Mutations arose de novo in most patients and were prevalently located in the motor domain. Most patients presented features of a continuum ataxia-spasticity spectrum with only five cases showing a prevalently pure spastic phenotype and six presenting congenital ataxias. Seventeen mutations occurred in the motor domain of the Kinesin-1A protein, but location of mutation did not correlate with neurological and imaging presentations. When tested in 15 patients, muscle biopsy showed oxidative metabolism alterations (6 cases), impaired respiratory chain complexes II + III activity (3/6) and low CoQ10 levels (6/9). Ubiquinol supplementation (1gr/die) was used in 6 patients with subjective benefit. CONCLUSIONS: This study broadened our clinical, genetic, and neuroimaging knowledge of KIF1A-related disorders. Although highly heterogeneous, it seems that manifestations of ataxia-spasticity spectrum disorders seem to occur in most patients. Some patients also present secondary impairment of oxidative metabolism; in this subset, ubiquinol supplementation therapy might be appropriate.
Authors: Fadi F Hamdan; Julie Gauthier; Yoichi Araki; Da-Ting Lin; Yuhki Yoshizawa; Kyohei Higashi; A-Reum Park; Dan Spiegelman; Sylvia Dobrzeniecka; Amélie Piton; Hideyuki Tomitori; Hussein Daoud; Christine Massicotte; Edouard Henrion; Ousmane Diallo; Masoud Shekarabi; Claude Marineau; Michael Shevell; Bruno Maranda; Grant Mitchell; Amélie Nadeau; Guy D'Anjou; Michel Vanasse; Myriam Srour; Ronald G Lafrenière; Pierre Drapeau; Jean Claude Lacaille; Eunjoon Kim; Jae-Ran Lee; Kazuei Igarashi; Richard L Huganir; Guy A Rouleau; Jacques L Michaud Journal: Am J Hum Genet Date: 2011-03-03 Impact factor: 11.025