title: Genetic heterogeneity of motor neuropathies.
abstract: OBJECTIVE
  To study the prevalence, molecular cause, and clinical presentation of hereditary motor neuropathies in a large cohort of patients from the North of England.
  
  
  METHODS
  Detailed neurologic and electrophysiologic assessments and next-generation panel testing or whole exome sequencing were performed in 105 patients with clinical symptoms of distal hereditary motor neuropathy (dHMN, 64 patients), axonal motor neuropathy (motor Charcot-Marie-Tooth disease [CMT2], 16 patients), or complex neurologic disease predominantly affecting the motor nerves (hereditary motor neuropathy plus, 25 patients).
  
  
  RESULTS
  The prevalence of dHMN is 2.14 affected individuals per 100,000 inhabitants (95% confidence interval 1.62-2.66) in the North of England. Causative mutations were identified in 26 out of 73 index patients (35.6%). The diagnostic rate in the dHMN subgroup was 32.5%, which is higher than previously reported (20%). We detected a significant defect of neuromuscular transmission in 7 cases and identified potentially causative mutations in 4 patients with multifocal demyelinating motor neuropathy.
  
  
  CONCLUSIONS
  Many of the genes were shared between dHMN and motor CMT2, indicating identical disease mechanisms; therefore, we suggest changing the classification and including dHMN also as a subcategory of Charcot-Marie-Tooth disease. Abnormal neuromuscular transmission in some genetic forms provides a treatable target to develop therapies.
authors.affiliation: From the MRC Centre for Neuromuscular Diseases and John Walton Muscular Dystrophy Research Centre, Institute of Genetic Medicine (B.B., H.G., T.E., J.D., A.B., V.B., H.S., E.F., A.P., H.L., P.F.C., R.H.), and Institute of Neuroscience (R.G.W., J.M.), Newcastle University, Newcastle upon Tyne; Bristol Genetics Laboratory (T.A., M.G., N.F.), Pathology Sciences, North Bristol NHS Trust, Southmead Hospital; Medical Genetic Center (S.K.), Munich, Germany; Department of Paediatric Neurology (V.R.), Royal Victoria Infirmary, Newcastle upon Tyne Foundation Hospitals NHS Trust; Nuffield Department of Clinical Neurosciences (E.F.), University of Oxford; and Department of Clinical Neurosciences (P.F.C.), Cambridge Biomedical Campus, University of Cambridge, UK.
authors.forename: Boglarka
authors.initials: B
authors.lastname: Bansagi
authors.affiliation: From the MRC Centre for Neuromuscular Diseases and John Walton Muscular Dystrophy Research Centre, Institute of Genetic Medicine (B.B., H.G., T.E., J.D., A.B., V.B., H.S., E.F., A.P., H.L., P.F.C., R.H.), and Institute of Neuroscience (R.G.W., J.M.), Newcastle University, Newcastle upon Tyne; Bristol Genetics Laboratory (T.A., M.G., N.F.), Pathology Sciences, North Bristol NHS Trust, Southmead Hospital; Medical Genetic Center (S.K.), Munich, Germany; Department of Paediatric Neurology (V.R.), Royal Victoria Infirmary, Newcastle upon Tyne Foundation Hospitals NHS Trust; Nuffield Department of Clinical Neurosciences (E.F.), University of Oxford; and Department of Clinical Neurosciences (P.F.C.), Cambridge Biomedical Campus, University of Cambridge, UK.
authors.forename: Helen
authors.initials: H
authors.lastname: Griffin
authors.affiliation: From the MRC Centre for Neuromuscular Diseases and John Walton Muscular Dystrophy Research Centre, Institute of Genetic Medicine (B.B., H.G., T.E., J.D., A.B., V.B., H.S., E.F., A.P., H.L., P.F.C., R.H.), and Institute of Neuroscience (R.G.W., J.M.), Newcastle University, Newcastle upon Tyne; Bristol Genetics Laboratory (T.A., M.G., N.F.), Pathology Sciences, North Bristol NHS Trust, Southmead Hospital; Medical Genetic Center (S.K.), Munich, Germany; Department of Paediatric Neurology (V.R.), Royal Victoria Infirmary, Newcastle upon Tyne Foundation Hospitals NHS Trust; Nuffield Department of Clinical Neurosciences (E.F.), University of Oxford; and Department of Clinical Neurosciences (P.F.C.), Cambridge Biomedical Campus, University of Cambridge, UK.
authors.forename: Roger G
authors.initials: RG
authors.lastname: Whittaker
authors.affiliation: From the MRC Centre for Neuromuscular Diseases and John Walton Muscular Dystrophy Research Centre, Institute of Genetic Medicine (B.B., H.G., T.E., J.D., A.B., V.B., H.S., E.F., A.P., H.L., P.F.C., R.H.), and Institute of Neuroscience (R.G.W., J.M.), Newcastle University, Newcastle upon Tyne; Bristol Genetics Laboratory (T.A., M.G., N.F.), Pathology Sciences, North Bristol NHS Trust, Southmead Hospital; Medical Genetic Center (S.K.), Munich, Germany; Department of Paediatric Neurology (V.R.), Royal Victoria Infirmary, Newcastle upon Tyne Foundation Hospitals NHS Trust; Nuffield Department of Clinical Neurosciences (E.F.), University of Oxford; and Department of Clinical Neurosciences (P.F.C.), Cambridge Biomedical Campus, University of Cambridge, UK.
authors.forename: Thalia
authors.initials: T
authors.lastname: Antoniadi
authors.affiliation: From the MRC Centre for Neuromuscular Diseases and John Walton Muscular Dystrophy Research Centre, Institute of Genetic Medicine (B.B., H.G., T.E., J.D., A.B., V.B., H.S., E.F., A.P., H.L., P.F.C., R.H.), and Institute of Neuroscience (R.G.W., J.M.), Newcastle University, Newcastle upon Tyne; Bristol Genetics Laboratory (T.A., M.G., N.F.), Pathology Sciences, North Bristol NHS Trust, Southmead Hospital; Medical Genetic Center (S.K.), Munich, Germany; Department of Paediatric Neurology (V.R.), Royal Victoria Infirmary, Newcastle upon Tyne Foundation Hospitals NHS Trust; Nuffield Department of Clinical Neurosciences (E.F.), University of Oxford; and Department of Clinical Neurosciences (P.F.C.), Cambridge Biomedical Campus, University of Cambridge, UK.
authors.forename: Teresinha
authors.initials: T
authors.lastname: Evangelista
authors.affiliation: From the MRC Centre for Neuromuscular Diseases and John Walton Muscular Dystrophy Research Centre, Institute of Genetic Medicine (B.B., H.G., T.E., J.D., A.B., V.B., H.S., E.F., A.P., H.L., P.F.C., R.H.), and Institute of Neuroscience (R.G.W., J.M.), Newcastle University, Newcastle upon Tyne; Bristol Genetics Laboratory (T.A., M.G., N.F.), Pathology Sciences, North Bristol NHS Trust, Southmead Hospital; Medical Genetic Center (S.K.), Munich, Germany; Department of Paediatric Neurology (V.R.), Royal Victoria Infirmary, Newcastle upon Tyne Foundation Hospitals NHS Trust; Nuffield Department of Clinical Neurosciences (E.F.), University of Oxford; and Department of Clinical Neurosciences (P.F.C.), Cambridge Biomedical Campus, University of Cambridge, UK.
authors.forename: James
authors.initials: J
authors.lastname: Miller
authors.affiliation: From the MRC Centre for Neuromuscular Diseases and John Walton Muscular Dystrophy Research Centre, Institute of Genetic Medicine (B.B., H.G., T.E., J.D., A.B., V.B., H.S., E.F., A.P., H.L., P.F.C., R.H.), and Institute of Neuroscience (R.G.W., J.M.), Newcastle University, Newcastle upon Tyne; Bristol Genetics Laboratory (T.A., M.G., N.F.), Pathology Sciences, North Bristol NHS Trust, Southmead Hospital; Medical Genetic Center (S.K.), Munich, Germany; Department of Paediatric Neurology (V.R.), Royal Victoria Infirmary, Newcastle upon Tyne Foundation Hospitals NHS Trust; Nuffield Department of Clinical Neurosciences (E.F.), University of Oxford; and Department of Clinical Neurosciences (P.F.C.), Cambridge Biomedical Campus, University of Cambridge, UK.
authors.forename: Mark
authors.initials: M
authors.lastname: Greenslade
authors.affiliation: From the MRC Centre for Neuromuscular Diseases and John Walton Muscular Dystrophy Research Centre, Institute of Genetic Medicine (B.B., H.G., T.E., J.D., A.B., V.B., H.S., E.F., A.P., H.L., P.F.C., R.H.), and Institute of Neuroscience (R.G.W., J.M.), Newcastle University, Newcastle upon Tyne; Bristol Genetics Laboratory (T.A., M.G., N.F.), Pathology Sciences, North Bristol NHS Trust, Southmead Hospital; Medical Genetic Center (S.K.), Munich, Germany; Department of Paediatric Neurology (V.R.), Royal Victoria Infirmary, Newcastle upon Tyne Foundation Hospitals NHS Trust; Nuffield Department of Clinical Neurosciences (E.F.), University of Oxford; and Department of Clinical Neurosciences (P.F.C.), Cambridge Biomedical Campus, University of Cambridge, UK.
authors.forename: Natalie
authors.initials: N
authors.lastname: Forester
authors.affiliation: From the MRC Centre for Neuromuscular Diseases and John Walton Muscular Dystrophy Research Centre, Institute of Genetic Medicine (B.B., H.G., T.E., J.D., A.B., V.B., H.S., E.F., A.P., H.L., P.F.C., R.H.), and Institute of Neuroscience (R.G.W., J.M.), Newcastle University, Newcastle upon Tyne; Bristol Genetics Laboratory (T.A., M.G., N.F.), Pathology Sciences, North Bristol NHS Trust, Southmead Hospital; Medical Genetic Center (S.K.), Munich, Germany; Department of Paediatric Neurology (V.R.), Royal Victoria Infirmary, Newcastle upon Tyne Foundation Hospitals NHS Trust; Nuffield Department of Clinical Neurosciences (E.F.), University of Oxford; and Department of Clinical Neurosciences (P.F.C.), Cambridge Biomedical Campus, University of Cambridge, UK.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Duff
authors.affiliation: From the MRC Centre for Neuromuscular Diseases and John Walton Muscular Dystrophy Research Centre, Institute of Genetic Medicine (B.B., H.G., T.E., J.D., A.B., V.B., H.S., E.F., A.P., H.L., P.F.C., R.H.), and Institute of Neuroscience (R.G.W., J.M.), Newcastle University, Newcastle upon Tyne; Bristol Genetics Laboratory (T.A., M.G., N.F.), Pathology Sciences, North Bristol NHS Trust, Southmead Hospital; Medical Genetic Center (S.K.), Munich, Germany; Department of Paediatric Neurology (V.R.), Royal Victoria Infirmary, Newcastle upon Tyne Foundation Hospitals NHS Trust; Nuffield Department of Clinical Neurosciences (E.F.), University of Oxford; and Department of Clinical Neurosciences (P.F.C.), Cambridge Biomedical Campus, University of Cambridge, UK.
authors.forename: Anna
authors.initials: A
authors.lastname: Bradshaw
authors.affiliation: From the MRC Centre for Neuromuscular Diseases and John Walton Muscular Dystrophy Research Centre, Institute of Genetic Medicine (B.B., H.G., T.E., J.D., A.B., V.B., H.S., E.F., A.P., H.L., P.F.C., R.H.), and Institute of Neuroscience (R.G.W., J.M.), Newcastle University, Newcastle upon Tyne; Bristol Genetics Laboratory (T.A., M.G., N.F.), Pathology Sciences, North Bristol NHS Trust, Southmead Hospital; Medical Genetic Center (S.K.), Munich, Germany; Department of Paediatric Neurology (V.R.), Royal Victoria Infirmary, Newcastle upon Tyne Foundation Hospitals NHS Trust; Nuffield Department of Clinical Neurosciences (E.F.), University of Oxford; and Department of Clinical Neurosciences (P.F.C.), Cambridge Biomedical Campus, University of Cambridge, UK.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Kleinle
authors.affiliation: From the MRC Centre for Neuromuscular Diseases and John Walton Muscular Dystrophy Research Centre, Institute of Genetic Medicine (B.B., H.G., T.E., J.D., A.B., V.B., H.S., E.F., A.P., H.L., P.F.C., R.H.), and Institute of Neuroscience (R.G.W., J.M.), Newcastle University, Newcastle upon Tyne; Bristol Genetics Laboratory (T.A., M.G., N.F.), Pathology Sciences, North Bristol NHS Trust, Southmead Hospital; Medical Genetic Center (S.K.), Munich, Germany; Department of Paediatric Neurology (V.R.), Royal Victoria Infirmary, Newcastle upon Tyne Foundation Hospitals NHS Trust; Nuffield Department of Clinical Neurosciences (E.F.), University of Oxford; and Department of Clinical Neurosciences (P.F.C.), Cambridge Biomedical Campus, University of Cambridge, UK.
authors.forename: Veronika
authors.initials: V
authors.lastname: Boczonadi
authors.affiliation: From the MRC Centre for Neuromuscular Diseases and John Walton Muscular Dystrophy Research Centre, Institute of Genetic Medicine (B.B., H.G., T.E., J.D., A.B., V.B., H.S., E.F., A.P., H.L., P.F.C., R.H.), and Institute of Neuroscience (R.G.W., J.M.), Newcastle University, Newcastle upon Tyne; Bristol Genetics Laboratory (T.A., M.G., N.F.), Pathology Sciences, North Bristol NHS Trust, Southmead Hospital; Medical Genetic Center (S.K.), Munich, Germany; Department of Paediatric Neurology (V.R.), Royal Victoria Infirmary, Newcastle upon Tyne Foundation Hospitals NHS Trust; Nuffield Department of Clinical Neurosciences (E.F.), University of Oxford; and Department of Clinical Neurosciences (P.F.C.), Cambridge Biomedical Campus, University of Cambridge, UK.
authors.forename: Hannah
authors.initials: H
authors.lastname: Steele
authors.affiliation: From the MRC Centre for Neuromuscular Diseases and John Walton Muscular Dystrophy Research Centre, Institute of Genetic Medicine (B.B., H.G., T.E., J.D., A.B., V.B., H.S., E.F., A.P., H.L., P.F.C., R.H.), and Institute of Neuroscience (R.G.W., J.M.), Newcastle University, Newcastle upon Tyne; Bristol Genetics Laboratory (T.A., M.G., N.F.), Pathology Sciences, North Bristol NHS Trust, Southmead Hospital; Medical Genetic Center (S.K.), Munich, Germany; Department of Paediatric Neurology (V.R.), Royal Victoria Infirmary, Newcastle upon Tyne Foundation Hospitals NHS Trust; Nuffield Department of Clinical Neurosciences (E.F.), University of Oxford; and Department of Clinical Neurosciences (P.F.C.), Cambridge Biomedical Campus, University of Cambridge, UK.
authors.forename: Venkateswaran
authors.initials: V
authors.lastname: Ramesh
authors.affiliation: From the MRC Centre for Neuromuscular Diseases and John Walton Muscular Dystrophy Research Centre, Institute of Genetic Medicine (B.B., H.G., T.E., J.D., A.B., V.B., H.S., E.F., A.P., H.L., P.F.C., R.H.), and Institute of Neuroscience (R.G.W., J.M.), Newcastle University, Newcastle upon Tyne; Bristol Genetics Laboratory (T.A., M.G., N.F.), Pathology Sciences, North Bristol NHS Trust, Southmead Hospital; Medical Genetic Center (S.K.), Munich, Germany; Department of Paediatric Neurology (V.R.), Royal Victoria Infirmary, Newcastle upon Tyne Foundation Hospitals NHS Trust; Nuffield Department of Clinical Neurosciences (E.F.), University of Oxford; and Department of Clinical Neurosciences (P.F.C.), Cambridge Biomedical Campus, University of Cambridge, UK.
authors.forename: Edit
authors.initials: E
authors.lastname: Franko
authors.affiliation: From the MRC Centre for Neuromuscular Diseases and John Walton Muscular Dystrophy Research Centre, Institute of Genetic Medicine (B.B., H.G., T.E., J.D., A.B., V.B., H.S., E.F., A.P., H.L., P.F.C., R.H.), and Institute of Neuroscience (R.G.W., J.M.), Newcastle University, Newcastle upon Tyne; Bristol Genetics Laboratory (T.A., M.G., N.F.), Pathology Sciences, North Bristol NHS Trust, Southmead Hospital; Medical Genetic Center (S.K.), Munich, Germany; Department of Paediatric Neurology (V.R.), Royal Victoria Infirmary, Newcastle upon Tyne Foundation Hospitals NHS Trust; Nuffield Department of Clinical Neurosciences (E.F.), University of Oxford; and Department of Clinical Neurosciences (P.F.C.), Cambridge Biomedical Campus, University of Cambridge, UK.
authors.forename: Angela
authors.initials: A
authors.lastname: Pyle
authors.affiliation: From the MRC Centre for Neuromuscular Diseases and John Walton Muscular Dystrophy Research Centre, Institute of Genetic Medicine (B.B., H.G., T.E., J.D., A.B., V.B., H.S., E.F., A.P., H.L., P.F.C., R.H.), and Institute of Neuroscience (R.G.W., J.M.), Newcastle University, Newcastle upon Tyne; Bristol Genetics Laboratory (T.A., M.G., N.F.), Pathology Sciences, North Bristol NHS Trust, Southmead Hospital; Medical Genetic Center (S.K.), Munich, Germany; Department of Paediatric Neurology (V.R.), Royal Victoria Infirmary, Newcastle upon Tyne Foundation Hospitals NHS Trust; Nuffield Department of Clinical Neurosciences (E.F.), University of Oxford; and Department of Clinical Neurosciences (P.F.C.), Cambridge Biomedical Campus, University of Cambridge, UK.
authors.forename: Hanns
authors.initials: H
authors.lastname: Lochmüller
authors.affiliation: From the MRC Centre for Neuromuscular Diseases and John Walton Muscular Dystrophy Research Centre, Institute of Genetic Medicine (B.B., H.G., T.E., J.D., A.B., V.B., H.S., E.F., A.P., H.L., P.F.C., R.H.), and Institute of Neuroscience (R.G.W., J.M.), Newcastle University, Newcastle upon Tyne; Bristol Genetics Laboratory (T.A., M.G., N.F.), Pathology Sciences, North Bristol NHS Trust, Southmead Hospital; Medical Genetic Center (S.K.), Munich, Germany; Department of Paediatric Neurology (V.R.), Royal Victoria Infirmary, Newcastle upon Tyne Foundation Hospitals NHS Trust; Nuffield Department of Clinical Neurosciences (E.F.), University of Oxford; and Department of Clinical Neurosciences (P.F.C.), Cambridge Biomedical Campus, University of Cambridge, UK.
authors.forename: Patrick F
authors.initials: PF
authors.lastname: Chinnery
authors.affiliation: From the MRC Centre for Neuromuscular Diseases and John Walton Muscular Dystrophy Research Centre, Institute of Genetic Medicine (B.B., H.G., T.E., J.D., A.B., V.B., H.S., E.F., A.P., H.L., P.F.C., R.H.), and Institute of Neuroscience (R.G.W., J.M.), Newcastle University, Newcastle upon Tyne; Bristol Genetics Laboratory (T.A., M.G., N.F.), Pathology Sciences, North Bristol NHS Trust, Southmead Hospital; Medical Genetic Center (S.K.), Munich, Germany; Department of Paediatric Neurology (V.R.), Royal Victoria Infirmary, Newcastle upon Tyne Foundation Hospitals NHS Trust; Nuffield Department of Clinical Neurosciences (E.F.), University of Oxford; and Department of Clinical Neurosciences (P.F.C.), Cambridge Biomedical Campus, University of Cambridge, UK. Rita.Horvath@ncl.ac.uk.
authors.forename: Rita
authors.initials: R
authors.lastname: Horvath
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000704:Analysis of Variance; D002607:Charcot-Marie-Tooth Disease / Q000453:epidemiology* / Q000235:genetics / Q000503:physiopathology; D015331:Cohort Studies; D017630:Connexins / Q000235:genetics; D004252:DNA Mutational Analysis; D004576:Electromyography; D004739:England / Q000453:epidemiology; D005192:Family Health; D005260:Female; D020558:GTP Phosphohydrolases / Q000235:genetics; D018740:Genetic Heterogeneity; D015417:Hereditary Sensory and Motor Neuropathy / Q000453:epidemiology* / Q000235:genetics* / Q000503:physiopathology; D006801:Humans; D008297:Male; D008875:Middle Aged; D024101:Mitochondrial Proteins / Q000235:genetics; D009154:Mutation / Q000235:genetics*; D009185:Myelin Proteins / Q000235:genetics; D009431:Neural Conduction / Q000235:genetics; D055815:Young Adult; D000097002:Gap Junction beta-1 Protein
chemical_list: D017630:Connexins; D020558:GTP Phosphohydrolases; D024101:Mitochondrial Proteins; D009185:Myelin Proteins; D000097002:Gap Junction beta-1 Protein; C073687:PMP22 protein, human; C470018:MFN2 protein, human