title: Extended phenotypic spectrum of KIF5A mutations: From spastic paraplegia to axonal neuropathy.
abstract: OBJECTIVE
  To establish the phenotypic spectrum of KIF5A mutations and to investigate whether KIF5A mutations cause axonal neuropathy associated with hereditary spastic paraplegia (HSP) or typical Charcot-Marie-Tooth disease type 2 (CMT2).
  
  
  METHODS
  KIF5A sequencing of the motor-domain coding exons was performed in 186 patients with the clinical diagnosis of HSP and in 215 patients with typical CMT2. Another 66 patients with HSP or CMT2 with pyramidal signs were sequenced for all exons of KIF5A by targeted resequencing. One additional patient was genetically diagnosed by whole-exome sequencing.
  
  
  RESULTS
  Five KIF5A mutations were identified in 6 unrelated patients: R204W and D232N were novel mutations; R204Q, R280C, and R280H have been previously reported. Three patients had CMT2 as the predominant and presenting phenotype; 2 of them also had pyramidal signs. The other 3 patients presented with HSP but also had significant axonal neuropathy or other additional features.
  
  
  CONCLUSIONS
  This is currently the largest study investigating KIF5A mutations. By combining next-generation sequencing and conventional sequencing, we confirm that KIF5A mutations can cause variable phenotypes ranging from HSP to CMT2. The identification of mutations in CMT2 broadens the phenotypic spectrum and underlines the importance of KIF5A mutations, which involve degeneration of both the central and peripheral nervous systems and should be tested in HSP and CMT2.
authors.affiliation: From the MRC Centre for Neuromuscular Diseases (Y.-T.L., M.L., A.H., M.M.R., H.H.) and Departments of Molecular Neuroscience (Y.-T.L., J.H., A.H., A.P., D.H., M.M.R., H.H.) and Clinical Neuroscience (C.P.), UCL Institute of Neurology; National Hospital for Neurology and Neurosurgery and UCLH (M.L., J.H., A.H., K.G.S., M.M.R., H.H.), London, UK; Section of Epilepsy (Y.-T.L.), Department of Neurology, Neurological Institute, Taipei Veterans General Hospital; National Yang-Ming University School of Medicine (Y.-T.L.), Taipei, Taiwan; Division of Neuropathology (Z.J., S.B.) and Neurogenetics Unit (J.M.P, M.G.S.), National Hospital for Neurology and Neurosurgery; Department of Neurology (J.C.J.), Chelsea and Westminster Hospital, London, UK; Department of Orthopaedics (M.A.-G.), Medical University Vienna, Austria; and Dr. John T. MacDonald Department of Human Genetics and Hussman Institute for Human Genomics (S.Z.), Miller School of Medicine, University of Miami, FL.
authors.forename: Yo-Tsen
authors.initials: YT
authors.lastname: Liu
authors.affiliation: From the MRC Centre for Neuromuscular Diseases (Y.-T.L., M.L., A.H., M.M.R., H.H.) and Departments of Molecular Neuroscience (Y.-T.L., J.H., A.H., A.P., D.H., M.M.R., H.H.) and Clinical Neuroscience (C.P.), UCL Institute of Neurology; National Hospital for Neurology and Neurosurgery and UCLH (M.L., J.H., A.H., K.G.S., M.M.R., H.H.), London, UK; Section of Epilepsy (Y.-T.L.), Department of Neurology, Neurological Institute, Taipei Veterans General Hospital; National Yang-Ming University School of Medicine (Y.-T.L.), Taipei, Taiwan; Division of Neuropathology (Z.J., S.B.) and Neurogenetics Unit (J.M.P, M.G.S.), National Hospital for Neurology and Neurosurgery; Department of Neurology (J.C.J.), Chelsea and Westminster Hospital, London, UK; Department of Orthopaedics (M.A.-G.), Medical University Vienna, Austria; and Dr. John T. MacDonald Department of Human Genetics and Hussman Institute for Human Genomics (S.Z.), Miller School of Medicine, University of Miami, FL.
authors.forename: Matilde
authors.initials: M
authors.lastname: Laurá
authors.affiliation: From the MRC Centre for Neuromuscular Diseases (Y.-T.L., M.L., A.H., M.M.R., H.H.) and Departments of Molecular Neuroscience (Y.-T.L., J.H., A.H., A.P., D.H., M.M.R., H.H.) and Clinical Neuroscience (C.P.), UCL Institute of Neurology; National Hospital for Neurology and Neurosurgery and UCLH (M.L., J.H., A.H., K.G.S., M.M.R., H.H.), London, UK; Section of Epilepsy (Y.-T.L.), Department of Neurology, Neurological Institute, Taipei Veterans General Hospital; National Yang-Ming University School of Medicine (Y.-T.L.), Taipei, Taiwan; Division of Neuropathology (Z.J., S.B.) and Neurogenetics Unit (J.M.P, M.G.S.), National Hospital for Neurology and Neurosurgery; Department of Neurology (J.C.J.), Chelsea and Westminster Hospital, London, UK; Department of Orthopaedics (M.A.-G.), Medical University Vienna, Austria; and Dr. John T. MacDonald Department of Human Genetics and Hussman Institute for Human Genomics (S.Z.), Miller School of Medicine, University of Miami, FL.
authors.forename: Joshua
authors.initials: J
authors.lastname: Hersheson
authors.affiliation: From the MRC Centre for Neuromuscular Diseases (Y.-T.L., M.L., A.H., M.M.R., H.H.) and Departments of Molecular Neuroscience (Y.-T.L., J.H., A.H., A.P., D.H., M.M.R., H.H.) and Clinical Neuroscience (C.P.), UCL Institute of Neurology; National Hospital for Neurology and Neurosurgery and UCLH (M.L., J.H., A.H., K.G.S., M.M.R., H.H.), London, UK; Section of Epilepsy (Y.-T.L.), Department of Neurology, Neurological Institute, Taipei Veterans General Hospital; National Yang-Ming University School of Medicine (Y.-T.L.), Taipei, Taiwan; Division of Neuropathology (Z.J., S.B.) and Neurogenetics Unit (J.M.P, M.G.S.), National Hospital for Neurology and Neurosurgery; Department of Neurology (J.C.J.), Chelsea and Westminster Hospital, London, UK; Department of Orthopaedics (M.A.-G.), Medical University Vienna, Austria; and Dr. John T. MacDonald Department of Human Genetics and Hussman Institute for Human Genomics (S.Z.), Miller School of Medicine, University of Miami, FL.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Horga
authors.affiliation: From the MRC Centre for Neuromuscular Diseases (Y.-T.L., M.L., A.H., M.M.R., H.H.) and Departments of Molecular Neuroscience (Y.-T.L., J.H., A.H., A.P., D.H., M.M.R., H.H.) and Clinical Neuroscience (C.P.), UCL Institute of Neurology; National Hospital for Neurology and Neurosurgery and UCLH (M.L., J.H., A.H., K.G.S., M.M.R., H.H.), London, UK; Section of Epilepsy (Y.-T.L.), Department of Neurology, Neurological Institute, Taipei Veterans General Hospital; National Yang-Ming University School of Medicine (Y.-T.L.), Taipei, Taiwan; Division of Neuropathology (Z.J., S.B.) and Neurogenetics Unit (J.M.P, M.G.S.), National Hospital for Neurology and Neurosurgery; Department of Neurology (J.C.J.), Chelsea and Westminster Hospital, London, UK; Department of Orthopaedics (M.A.-G.), Medical University Vienna, Austria; and Dr. John T. MacDonald Department of Human Genetics and Hussman Institute for Human Genomics (S.Z.), Miller School of Medicine, University of Miami, FL.
authors.forename: Zane
authors.initials: Z
authors.lastname: Jaunmuktane
authors.affiliation: From the MRC Centre for Neuromuscular Diseases (Y.-T.L., M.L., A.H., M.M.R., H.H.) and Departments of Molecular Neuroscience (Y.-T.L., J.H., A.H., A.P., D.H., M.M.R., H.H.) and Clinical Neuroscience (C.P.), UCL Institute of Neurology; National Hospital for Neurology and Neurosurgery and UCLH (M.L., J.H., A.H., K.G.S., M.M.R., H.H.), London, UK; Section of Epilepsy (Y.-T.L.), Department of Neurology, Neurological Institute, Taipei Veterans General Hospital; National Yang-Ming University School of Medicine (Y.-T.L.), Taipei, Taiwan; Division of Neuropathology (Z.J., S.B.) and Neurogenetics Unit (J.M.P, M.G.S.), National Hospital for Neurology and Neurosurgery; Department of Neurology (J.C.J.), Chelsea and Westminster Hospital, London, UK; Department of Orthopaedics (M.A.-G.), Medical University Vienna, Austria; and Dr. John T. MacDonald Department of Human Genetics and Hussman Institute for Human Genomics (S.Z.), Miller School of Medicine, University of Miami, FL.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Brandner
authors.affiliation: From the MRC Centre for Neuromuscular Diseases (Y.-T.L., M.L., A.H., M.M.R., H.H.) and Departments of Molecular Neuroscience (Y.-T.L., J.H., A.H., A.P., D.H., M.M.R., H.H.) and Clinical Neuroscience (C.P.), UCL Institute of Neurology; National Hospital for Neurology and Neurosurgery and UCLH (M.L., J.H., A.H., K.G.S., M.M.R., H.H.), London, UK; Section of Epilepsy (Y.-T.L.), Department of Neurology, Neurological Institute, Taipei Veterans General Hospital; National Yang-Ming University School of Medicine (Y.-T.L.), Taipei, Taiwan; Division of Neuropathology (Z.J., S.B.) and Neurogenetics Unit (J.M.P, M.G.S.), National Hospital for Neurology and Neurosurgery; Department of Neurology (J.C.J.), Chelsea and Westminster Hospital, London, UK; Department of Orthopaedics (M.A.-G.), Medical University Vienna, Austria; and Dr. John T. MacDonald Department of Human Genetics and Hussman Institute for Human Genomics (S.Z.), Miller School of Medicine, University of Miami, FL.
authors.forename: Alan
authors.initials: A
authors.lastname: Pittman
authors.affiliation: From the MRC Centre for Neuromuscular Diseases (Y.-T.L., M.L., A.H., M.M.R., H.H.) and Departments of Molecular Neuroscience (Y.-T.L., J.H., A.H., A.P., D.H., M.M.R., H.H.) and Clinical Neuroscience (C.P.), UCL Institute of Neurology; National Hospital for Neurology and Neurosurgery and UCLH (M.L., J.H., A.H., K.G.S., M.M.R., H.H.), London, UK; Section of Epilepsy (Y.-T.L.), Department of Neurology, Neurological Institute, Taipei Veterans General Hospital; National Yang-Ming University School of Medicine (Y.-T.L.), Taipei, Taiwan; Division of Neuropathology (Z.J., S.B.) and Neurogenetics Unit (J.M.P, M.G.S.), National Hospital for Neurology and Neurosurgery; Department of Neurology (J.C.J.), Chelsea and Westminster Hospital, London, UK; Department of Orthopaedics (M.A.-G.), Medical University Vienna, Austria; and Dr. John T. MacDonald Department of Human Genetics and Hussman Institute for Human Genomics (S.Z.), Miller School of Medicine, University of Miami, FL.
authors.forename: Deborah
authors.initials: D
authors.lastname: Hughes
authors.affiliation: From the MRC Centre for Neuromuscular Diseases (Y.-T.L., M.L., A.H., M.M.R., H.H.) and Departments of Molecular Neuroscience (Y.-T.L., J.H., A.H., A.P., D.H., M.M.R., H.H.) and Clinical Neuroscience (C.P.), UCL Institute of Neurology; National Hospital for Neurology and Neurosurgery and UCLH (M.L., J.H., A.H., K.G.S., M.M.R., H.H.), London, UK; Section of Epilepsy (Y.-T.L.), Department of Neurology, Neurological Institute, Taipei Veterans General Hospital; National Yang-Ming University School of Medicine (Y.-T.L.), Taipei, Taiwan; Division of Neuropathology (Z.J., S.B.) and Neurogenetics Unit (J.M.P, M.G.S.), National Hospital for Neurology and Neurosurgery; Department of Neurology (J.C.J.), Chelsea and Westminster Hospital, London, UK; Department of Orthopaedics (M.A.-G.), Medical University Vienna, Austria; and Dr. John T. MacDonald Department of Human Genetics and Hussman Institute for Human Genomics (S.Z.), Miller School of Medicine, University of Miami, FL.
authors.forename: James M
authors.initials: JM
authors.lastname: Polke
authors.affiliation: From the MRC Centre for Neuromuscular Diseases (Y.-T.L., M.L., A.H., M.M.R., H.H.) and Departments of Molecular Neuroscience (Y.-T.L., J.H., A.H., A.P., D.H., M.M.R., H.H.) and Clinical Neuroscience (C.P.), UCL Institute of Neurology; National Hospital for Neurology and Neurosurgery and UCLH (M.L., J.H., A.H., K.G.S., M.M.R., H.H.), London, UK; Section of Epilepsy (Y.-T.L.), Department of Neurology, Neurological Institute, Taipei Veterans General Hospital; National Yang-Ming University School of Medicine (Y.-T.L.), Taipei, Taiwan; Division of Neuropathology (Z.J., S.B.) and Neurogenetics Unit (J.M.P, M.G.S.), National Hospital for Neurology and Neurosurgery; Department of Neurology (J.C.J.), Chelsea and Westminster Hospital, London, UK; Department of Orthopaedics (M.A.-G.), Medical University Vienna, Austria; and Dr. John T. MacDonald Department of Human Genetics and Hussman Institute for Human Genomics (S.Z.), Miller School of Medicine, University of Miami, FL.
authors.forename: Mary G
authors.initials: MG
authors.lastname: Sweeney
authors.affiliation: From the MRC Centre for Neuromuscular Diseases (Y.-T.L., M.L., A.H., M.M.R., H.H.) and Departments of Molecular Neuroscience (Y.-T.L., J.H., A.H., A.P., D.H., M.M.R., H.H.) and Clinical Neuroscience (C.P.), UCL Institute of Neurology; National Hospital for Neurology and Neurosurgery and UCLH (M.L., J.H., A.H., K.G.S., M.M.R., H.H.), London, UK; Section of Epilepsy (Y.-T.L.), Department of Neurology, Neurological Institute, Taipei Veterans General Hospital; National Yang-Ming University School of Medicine (Y.-T.L.), Taipei, Taiwan; Division of Neuropathology (Z.J., S.B.) and Neurogenetics Unit (J.M.P, M.G.S.), National Hospital for Neurology and Neurosurgery; Department of Neurology (J.C.J.), Chelsea and Westminster Hospital, London, UK; Department of Orthopaedics (M.A.-G.), Medical University Vienna, Austria; and Dr. John T. MacDonald Department of Human Genetics and Hussman Institute for Human Genomics (S.Z.), Miller School of Medicine, University of Miami, FL.
authors.forename: Christos
authors.initials: C
authors.lastname: Proukakis
authors.affiliation: From the MRC Centre for Neuromuscular Diseases (Y.-T.L., M.L., A.H., M.M.R., H.H.) and Departments of Molecular Neuroscience (Y.-T.L., J.H., A.H., A.P., D.H., M.M.R., H.H.) and Clinical Neuroscience (C.P.), UCL Institute of Neurology; National Hospital for Neurology and Neurosurgery and UCLH (M.L., J.H., A.H., K.G.S., M.M.R., H.H.), London, UK; Section of Epilepsy (Y.-T.L.), Department of Neurology, Neurological Institute, Taipei Veterans General Hospital; National Yang-Ming University School of Medicine (Y.-T.L.), Taipei, Taiwan; Division of Neuropathology (Z.J., S.B.) and Neurogenetics Unit (J.M.P, M.G.S.), National Hospital for Neurology and Neurosurgery; Department of Neurology (J.C.J.), Chelsea and Westminster Hospital, London, UK; Department of Orthopaedics (M.A.-G.), Medical University Vienna, Austria; and Dr. John T. MacDonald Department of Human Genetics and Hussman Institute for Human Genomics (S.Z.), Miller School of Medicine, University of Miami, FL.
authors.forename: John C
authors.initials: JC
authors.lastname: Janssen
authors.affiliation: From the MRC Centre for Neuromuscular Diseases (Y.-T.L., M.L., A.H., M.M.R., H.H.) and Departments of Molecular Neuroscience (Y.-T.L., J.H., A.H., A.P., D.H., M.M.R., H.H.) and Clinical Neuroscience (C.P.), UCL Institute of Neurology; National Hospital for Neurology and Neurosurgery and UCLH (M.L., J.H., A.H., K.G.S., M.M.R., H.H.), London, UK; Section of Epilepsy (Y.-T.L.), Department of Neurology, Neurological Institute, Taipei Veterans General Hospital; National Yang-Ming University School of Medicine (Y.-T.L.), Taipei, Taiwan; Division of Neuropathology (Z.J., S.B.) and Neurogenetics Unit (J.M.P, M.G.S.), National Hospital for Neurology and Neurosurgery; Department of Neurology (J.C.J.), Chelsea and Westminster Hospital, London, UK; Department of Orthopaedics (M.A.-G.), Medical University Vienna, Austria; and Dr. John T. MacDonald Department of Human Genetics and Hussman Institute for Human Genomics (S.Z.), Miller School of Medicine, University of Miami, FL.
authors.forename: Michaela
authors.initials: M
authors.lastname: Auer-Grumbach
authors.affiliation: From the MRC Centre for Neuromuscular Diseases (Y.-T.L., M.L., A.H., M.M.R., H.H.) and Departments of Molecular Neuroscience (Y.-T.L., J.H., A.H., A.P., D.H., M.M.R., H.H.) and Clinical Neuroscience (C.P.), UCL Institute of Neurology; National Hospital for Neurology and Neurosurgery and UCLH (M.L., J.H., A.H., K.G.S., M.M.R., H.H.), London, UK; Section of Epilepsy (Y.-T.L.), Department of Neurology, Neurological Institute, Taipei Veterans General Hospital; National Yang-Ming University School of Medicine (Y.-T.L.), Taipei, Taiwan; Division of Neuropathology (Z.J., S.B.) and Neurogenetics Unit (J.M.P, M.G.S.), National Hospital for Neurology and Neurosurgery; Department of Neurology (J.C.J.), Chelsea and Westminster Hospital, London, UK; Department of Orthopaedics (M.A.-G.), Medical University Vienna, Austria; and Dr. John T. MacDonald Department of Human Genetics and Hussman Institute for Human Genomics (S.Z.), Miller School of Medicine, University of Miami, FL.
authors.forename: Stephan
authors.initials: S
authors.lastname: Zuchner
authors.affiliation: From the MRC Centre for Neuromuscular Diseases (Y.-T.L., M.L., A.H., M.M.R., H.H.) and Departments of Molecular Neuroscience (Y.-T.L., J.H., A.H., A.P., D.H., M.M.R., H.H.) and Clinical Neuroscience (C.P.), UCL Institute of Neurology; National Hospital for Neurology and Neurosurgery and UCLH (M.L., J.H., A.H., K.G.S., M.M.R., H.H.), London, UK; Section of Epilepsy (Y.-T.L.), Department of Neurology, Neurological Institute, Taipei Veterans General Hospital; National Yang-Ming University School of Medicine (Y.-T.L.), Taipei, Taiwan; Division of Neuropathology (Z.J., S.B.) and Neurogenetics Unit (J.M.P, M.G.S.), National Hospital for Neurology and Neurosurgery; Department of Neurology (J.C.J.), Chelsea and Westminster Hospital, London, UK; Department of Orthopaedics (M.A.-G.), Medical University Vienna, Austria; and Dr. John T. MacDonald Department of Human Genetics and Hussman Institute for Human Genomics (S.Z.), Miller School of Medicine, University of Miami, FL.
authors.forename: Kevin G
authors.initials: KG
authors.lastname: Shields
authors.affiliation: From the MRC Centre for Neuromuscular Diseases (Y.-T.L., M.L., A.H., M.M.R., H.H.) and Departments of Molecular Neuroscience (Y.-T.L., J.H., A.H., A.P., D.H., M.M.R., H.H.) and Clinical Neuroscience (C.P.), UCL Institute of Neurology; National Hospital for Neurology and Neurosurgery and UCLH (M.L., J.H., A.H., K.G.S., M.M.R., H.H.), London, UK; Section of Epilepsy (Y.-T.L.), Department of Neurology, Neurological Institute, Taipei Veterans General Hospital; National Yang-Ming University School of Medicine (Y.-T.L.), Taipei, Taiwan; Division of Neuropathology (Z.J., S.B.) and Neurogenetics Unit (J.M.P, M.G.S.), National Hospital for Neurology and Neurosurgery; Department of Neurology (J.C.J.), Chelsea and Westminster Hospital, London, UK; Department of Orthopaedics (M.A.-G.), Medical University Vienna, Austria; and Dr. John T. MacDonald Department of Human Genetics and Hussman Institute for Human Genomics (S.Z.), Miller School of Medicine, University of Miami, FL.
authors.forename: Mary M
authors.initials: MM
authors.lastname: Reilly
authors.affiliation: From the MRC Centre for Neuromuscular Diseases (Y.-T.L., M.L., A.H., M.M.R., H.H.) and Departments of Molecular Neuroscience (Y.-T.L., J.H., A.H., A.P., D.H., M.M.R., H.H.) and Clinical Neuroscience (C.P.), UCL Institute of Neurology; National Hospital for Neurology and Neurosurgery and UCLH (M.L., J.H., A.H., K.G.S., M.M.R., H.H.), London, UK; Section of Epilepsy (Y.-T.L.), Department of Neurology, Neurological Institute, Taipei Veterans General Hospital; National Yang-Ming University School of Medicine (Y.-T.L.), Taipei, Taiwan; Division of Neuropathology (Z.J., S.B.) and Neurogenetics Unit (J.M.P, M.G.S.), National Hospital for Neurology and Neurosurgery; Department of Neurology (J.C.J.), Chelsea and Westminster Hospital, London, UK; Department of Orthopaedics (M.A.-G.), Medical University Vienna, Austria; and Dr. John T. MacDonald Department of Human Genetics and Hussman Institute for Human Genomics (S.Z.), Miller School of Medicine, University of Miami, FL. h.houlden@ucl.ac.uk.
authors.forename: Henry
authors.initials: H
authors.lastname: Houlden
mesh_terms: D000328:Adult; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics*; D002648:Child; D005091:Exons; D005190:Family; D005260:Female; D006801:Humans; D016547:Kinesins / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009410:Nerve Degeneration / Q000235:genetics; D010375:Pedigree; D010641:Phenotype; D017422:Sequence Analysis, DNA; D015419:Spastic Paraplegia, Hereditary / Q000235:genetics*
chemical_list: C500506:KIF5A protein, human; D016547:Kinesins