title: CNTNAP1mutations cause CNS hypomyelination and neuropathy with or without arthrogryposis.
abstract: OBJECTIVE
  To explore the phenotypic spectrum and pathophysiology of human disease deriving from mutations in theCNTNAP1gene.
  
  
  METHODS
  In a field study on consanguineous Palestinian families, we identified 3 patients carrying homozygous mutations in theCNTNAP1gene using whole-exome sequencing. An unrelated Irish family was detected by screening the GENESIS database for furtherCNTNAP1mutations. Neurophysiology, MRI, and nerve biopsy including electron microscopy were performed for deep phenotyping.
  
  
  RESULTS
  We identified 3 novelCNTNAP1mutations in 5 patients from 2 families: c.2015G>A:p.(Trp672*) in a homozygous state in family 1 and c.2011C>T:p.(Gln671*) in a compound heterozygous state with c.2290C>T:p.(Arg764Cys) in family 2. Affected patients suffered from a severe CNS disorder with hypomyelinating leukodystrophy and peripheral neuropathy of sensory-motor type. Arthrogryposis was present in 2 patients but absent in 3 patients. Brain MRI demonstrated severe hypomyelination and secondary cerebral and cerebellar atrophy as well as a mega cisterna magna and corpus callosum hypoplasia. Nerve biopsy revealed very distinct features with lack of transverse bands at the paranodes and widened paranodal junctional gaps.
  
  
  CONCLUSIONS
  CNTNAP1mutations have recently been linked to patients with arthrogryposis multiplex congenita. However, we show that arthrogryposis is not an obligate feature.CNTNAP1-related disorders are foremost severe hypomyelinating disorders of the CNS and the peripheral nervous system. The pathology is partly explained by the involvement of CNTNAP1 in the proper formation and preservation of paranodal junctions and partly by the assumed role of CNTNAP1 as a key regulator in the development of the cerebral cortex.
authors.affiliation: Department of Neurology and Hertie-Institute for Clinical Brain Research (H.H., R. Schüle, L.S.), University of Tübingen, Germany; German Center of Neurodegenerative Diseases (DZNE) (H.H., R.S., L.S.), Tübingen, Germany; Northern Ireland Regional Genetics Service (A.M.), Belfast City Hospital, Belfast; Department of Neurology (J.-M.V.), National Reference Center for Rare Peripheral Neuropathies, University Hospital, Limoges, France; Institute for Neuroscience and Muscle Research (R.O.), The Children's Hospital at Westmead, Sydney, New South Wales, Australia; The Triangle Regional Research and Development Center (R. Sharkia), Kfar Qari' Israel; Beit-Berl Academic College (R. Sharkia), Israel; Child Neurology and Development Center (M.M.), Hillel-Yaffe Medical Center, Hadera, Israel; Rappaport Faculty of Medicine (M.M.), Technion, Haifa, Israel; Institute of Medical Genetics and Applied Genomics (M.S.), University of Tübingen, Germany; Department of Pediatric Neurology (I.K.-M.), University Medical Center Tübingen, Germany; Hussman Institute for Human Genomics (S.Z.), University of Miami Miller School of Medicine, FL; Clalit Health Services (M.A.-R.), Haifa, Israel; and Meuhedet Health Services (J.M.), North District, Israel.
authors.forename: Holger
authors.initials: H
authors.lastname: Hengel
authors.affiliation: Department of Neurology and Hertie-Institute for Clinical Brain Research (H.H., R. Schüle, L.S.), University of Tübingen, Germany; German Center of Neurodegenerative Diseases (DZNE) (H.H., R.S., L.S.), Tübingen, Germany; Northern Ireland Regional Genetics Service (A.M.), Belfast City Hospital, Belfast; Department of Neurology (J.-M.V.), National Reference Center for Rare Peripheral Neuropathies, University Hospital, Limoges, France; Institute for Neuroscience and Muscle Research (R.O.), The Children's Hospital at Westmead, Sydney, New South Wales, Australia; The Triangle Regional Research and Development Center (R. Sharkia), Kfar Qari' Israel; Beit-Berl Academic College (R. Sharkia), Israel; Child Neurology and Development Center (M.M.), Hillel-Yaffe Medical Center, Hadera, Israel; Rappaport Faculty of Medicine (M.M.), Technion, Haifa, Israel; Institute of Medical Genetics and Applied Genomics (M.S.), University of Tübingen, Germany; Department of Pediatric Neurology (I.K.-M.), University Medical Center Tübingen, Germany; Hussman Institute for Human Genomics (S.Z.), University of Miami Miller School of Medicine, FL; Clalit Health Services (M.A.-R.), Haifa, Israel; and Meuhedet Health Services (J.M.), North District, Israel.
authors.forename: Alex
authors.initials: A
authors.lastname: Magee
authors.affiliation: Department of Neurology and Hertie-Institute for Clinical Brain Research (H.H., R. Schüle, L.S.), University of Tübingen, Germany; German Center of Neurodegenerative Diseases (DZNE) (H.H., R.S., L.S.), Tübingen, Germany; Northern Ireland Regional Genetics Service (A.M.), Belfast City Hospital, Belfast; Department of Neurology (J.-M.V.), National Reference Center for Rare Peripheral Neuropathies, University Hospital, Limoges, France; Institute for Neuroscience and Muscle Research (R.O.), The Children's Hospital at Westmead, Sydney, New South Wales, Australia; The Triangle Regional Research and Development Center (R. Sharkia), Kfar Qari' Israel; Beit-Berl Academic College (R. Sharkia), Israel; Child Neurology and Development Center (M.M.), Hillel-Yaffe Medical Center, Hadera, Israel; Rappaport Faculty of Medicine (M.M.), Technion, Haifa, Israel; Institute of Medical Genetics and Applied Genomics (M.S.), University of Tübingen, Germany; Department of Pediatric Neurology (I.K.-M.), University Medical Center Tübingen, Germany; Hussman Institute for Human Genomics (S.Z.), University of Miami Miller School of Medicine, FL; Clalit Health Services (M.A.-R.), Haifa, Israel; and Meuhedet Health Services (J.M.), North District, Israel.
authors.forename: Muhammad
authors.initials: M
authors.lastname: Mahanjah
authors.affiliation: Department of Neurology and Hertie-Institute for Clinical Brain Research (H.H., R. Schüle, L.S.), University of Tübingen, Germany; German Center of Neurodegenerative Diseases (DZNE) (H.H., R.S., L.S.), Tübingen, Germany; Northern Ireland Regional Genetics Service (A.M.), Belfast City Hospital, Belfast; Department of Neurology (J.-M.V.), National Reference Center for Rare Peripheral Neuropathies, University Hospital, Limoges, France; Institute for Neuroscience and Muscle Research (R.O.), The Children's Hospital at Westmead, Sydney, New South Wales, Australia; The Triangle Regional Research and Development Center (R. Sharkia), Kfar Qari' Israel; Beit-Berl Academic College (R. Sharkia), Israel; Child Neurology and Development Center (M.M.), Hillel-Yaffe Medical Center, Hadera, Israel; Rappaport Faculty of Medicine (M.M.), Technion, Haifa, Israel; Institute of Medical Genetics and Applied Genomics (M.S.), University of Tübingen, Germany; Department of Pediatric Neurology (I.K.-M.), University Medical Center Tübingen, Germany; Hussman Institute for Human Genomics (S.Z.), University of Miami Miller School of Medicine, FL; Clalit Health Services (M.A.-R.), Haifa, Israel; and Meuhedet Health Services (J.M.), North District, Israel.
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Vallat
authors.affiliation: Department of Neurology and Hertie-Institute for Clinical Brain Research (H.H., R. Schüle, L.S.), University of Tübingen, Germany; German Center of Neurodegenerative Diseases (DZNE) (H.H., R.S., L.S.), Tübingen, Germany; Northern Ireland Regional Genetics Service (A.M.), Belfast City Hospital, Belfast; Department of Neurology (J.-M.V.), National Reference Center for Rare Peripheral Neuropathies, University Hospital, Limoges, France; Institute for Neuroscience and Muscle Research (R.O.), The Children's Hospital at Westmead, Sydney, New South Wales, Australia; The Triangle Regional Research and Development Center (R. Sharkia), Kfar Qari' Israel; Beit-Berl Academic College (R. Sharkia), Israel; Child Neurology and Development Center (M.M.), Hillel-Yaffe Medical Center, Hadera, Israel; Rappaport Faculty of Medicine (M.M.), Technion, Haifa, Israel; Institute of Medical Genetics and Applied Genomics (M.S.), University of Tübingen, Germany; Department of Pediatric Neurology (I.K.-M.), University Medical Center Tübingen, Germany; Hussman Institute for Human Genomics (S.Z.), University of Miami Miller School of Medicine, FL; Clalit Health Services (M.A.-R.), Haifa, Israel; and Meuhedet Health Services (J.M.), North District, Israel.
authors.forename: Robert
authors.initials: R
authors.lastname: Ouvrier
authors.affiliation: Department of Neurology and Hertie-Institute for Clinical Brain Research (H.H., R. Schüle, L.S.), University of Tübingen, Germany; German Center of Neurodegenerative Diseases (DZNE) (H.H., R.S., L.S.), Tübingen, Germany; Northern Ireland Regional Genetics Service (A.M.), Belfast City Hospital, Belfast; Department of Neurology (J.-M.V.), National Reference Center for Rare Peripheral Neuropathies, University Hospital, Limoges, France; Institute for Neuroscience and Muscle Research (R.O.), The Children's Hospital at Westmead, Sydney, New South Wales, Australia; The Triangle Regional Research and Development Center (R. Sharkia), Kfar Qari' Israel; Beit-Berl Academic College (R. Sharkia), Israel; Child Neurology and Development Center (M.M.), Hillel-Yaffe Medical Center, Hadera, Israel; Rappaport Faculty of Medicine (M.M.), Technion, Haifa, Israel; Institute of Medical Genetics and Applied Genomics (M.S.), University of Tübingen, Germany; Department of Pediatric Neurology (I.K.-M.), University Medical Center Tübingen, Germany; Hussman Institute for Human Genomics (S.Z.), University of Miami Miller School of Medicine, FL; Clalit Health Services (M.A.-R.), Haifa, Israel; and Meuhedet Health Services (J.M.), North District, Israel.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Abu-Rashid
authors.affiliation: Department of Neurology and Hertie-Institute for Clinical Brain Research (H.H., R. Schüle, L.S.), University of Tübingen, Germany; German Center of Neurodegenerative Diseases (DZNE) (H.H., R.S., L.S.), Tübingen, Germany; Northern Ireland Regional Genetics Service (A.M.), Belfast City Hospital, Belfast; Department of Neurology (J.-M.V.), National Reference Center for Rare Peripheral Neuropathies, University Hospital, Limoges, France; Institute for Neuroscience and Muscle Research (R.O.), The Children's Hospital at Westmead, Sydney, New South Wales, Australia; The Triangle Regional Research and Development Center (R. Sharkia), Kfar Qari' Israel; Beit-Berl Academic College (R. Sharkia), Israel; Child Neurology and Development Center (M.M.), Hillel-Yaffe Medical Center, Hadera, Israel; Rappaport Faculty of Medicine (M.M.), Technion, Haifa, Israel; Institute of Medical Genetics and Applied Genomics (M.S.), University of Tübingen, Germany; Department of Pediatric Neurology (I.K.-M.), University Medical Center Tübingen, Germany; Hussman Institute for Human Genomics (S.Z.), University of Miami Miller School of Medicine, FL; Clalit Health Services (M.A.-R.), Haifa, Israel; and Meuhedet Health Services (J.M.), North District, Israel.
authors.forename: Jamal
authors.initials: J
authors.lastname: Mahamid
authors.affiliation: Department of Neurology and Hertie-Institute for Clinical Brain Research (H.H., R. Schüle, L.S.), University of Tübingen, Germany; German Center of Neurodegenerative Diseases (DZNE) (H.H., R.S., L.S.), Tübingen, Germany; Northern Ireland Regional Genetics Service (A.M.), Belfast City Hospital, Belfast; Department of Neurology (J.-M.V.), National Reference Center for Rare Peripheral Neuropathies, University Hospital, Limoges, France; Institute for Neuroscience and Muscle Research (R.O.), The Children's Hospital at Westmead, Sydney, New South Wales, Australia; The Triangle Regional Research and Development Center (R. Sharkia), Kfar Qari' Israel; Beit-Berl Academic College (R. Sharkia), Israel; Child Neurology and Development Center (M.M.), Hillel-Yaffe Medical Center, Hadera, Israel; Rappaport Faculty of Medicine (M.M.), Technion, Haifa, Israel; Institute of Medical Genetics and Applied Genomics (M.S.), University of Tübingen, Germany; Department of Pediatric Neurology (I.K.-M.), University Medical Center Tübingen, Germany; Hussman Institute for Human Genomics (S.Z.), University of Miami Miller School of Medicine, FL; Clalit Health Services (M.A.-R.), Haifa, Israel; and Meuhedet Health Services (J.M.), North District, Israel.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Schüle
authors.affiliation: Department of Neurology and Hertie-Institute for Clinical Brain Research (H.H., R. Schüle, L.S.), University of Tübingen, Germany; German Center of Neurodegenerative Diseases (DZNE) (H.H., R.S., L.S.), Tübingen, Germany; Northern Ireland Regional Genetics Service (A.M.), Belfast City Hospital, Belfast; Department of Neurology (J.-M.V.), National Reference Center for Rare Peripheral Neuropathies, University Hospital, Limoges, France; Institute for Neuroscience and Muscle Research (R.O.), The Children's Hospital at Westmead, Sydney, New South Wales, Australia; The Triangle Regional Research and Development Center (R. Sharkia), Kfar Qari' Israel; Beit-Berl Academic College (R. Sharkia), Israel; Child Neurology and Development Center (M.M.), Hillel-Yaffe Medical Center, Hadera, Israel; Rappaport Faculty of Medicine (M.M.), Technion, Haifa, Israel; Institute of Medical Genetics and Applied Genomics (M.S.), University of Tübingen, Germany; Department of Pediatric Neurology (I.K.-M.), University Medical Center Tübingen, Germany; Hussman Institute for Human Genomics (S.Z.), University of Miami Miller School of Medicine, FL; Clalit Health Services (M.A.-R.), Haifa, Israel; and Meuhedet Health Services (J.M.), North District, Israel.
authors.forename: Martin
authors.initials: M
authors.lastname: Schulze
authors.affiliation: Department of Neurology and Hertie-Institute for Clinical Brain Research (H.H., R. Schüle, L.S.), University of Tübingen, Germany; German Center of Neurodegenerative Diseases (DZNE) (H.H., R.S., L.S.), Tübingen, Germany; Northern Ireland Regional Genetics Service (A.M.), Belfast City Hospital, Belfast; Department of Neurology (J.-M.V.), National Reference Center for Rare Peripheral Neuropathies, University Hospital, Limoges, France; Institute for Neuroscience and Muscle Research (R.O.), The Children's Hospital at Westmead, Sydney, New South Wales, Australia; The Triangle Regional Research and Development Center (R. Sharkia), Kfar Qari' Israel; Beit-Berl Academic College (R. Sharkia), Israel; Child Neurology and Development Center (M.M.), Hillel-Yaffe Medical Center, Hadera, Israel; Rappaport Faculty of Medicine (M.M.), Technion, Haifa, Israel; Institute of Medical Genetics and Applied Genomics (M.S.), University of Tübingen, Germany; Department of Pediatric Neurology (I.K.-M.), University Medical Center Tübingen, Germany; Hussman Institute for Human Genomics (S.Z.), University of Miami Miller School of Medicine, FL; Clalit Health Services (M.A.-R.), Haifa, Israel; and Meuhedet Health Services (J.M.), North District, Israel.
authors.forename: Ingeborg
authors.initials: I
authors.lastname: Krägeloh-Mann
authors.affiliation: Department of Neurology and Hertie-Institute for Clinical Brain Research (H.H., R. Schüle, L.S.), University of Tübingen, Germany; German Center of Neurodegenerative Diseases (DZNE) (H.H., R.S., L.S.), Tübingen, Germany; Northern Ireland Regional Genetics Service (A.M.), Belfast City Hospital, Belfast; Department of Neurology (J.-M.V.), National Reference Center for Rare Peripheral Neuropathies, University Hospital, Limoges, France; Institute for Neuroscience and Muscle Research (R.O.), The Children's Hospital at Westmead, Sydney, New South Wales, Australia; The Triangle Regional Research and Development Center (R. Sharkia), Kfar Qari' Israel; Beit-Berl Academic College (R. Sharkia), Israel; Child Neurology and Development Center (M.M.), Hillel-Yaffe Medical Center, Hadera, Israel; Rappaport Faculty of Medicine (M.M.), Technion, Haifa, Israel; Institute of Medical Genetics and Applied Genomics (M.S.), University of Tübingen, Germany; Department of Pediatric Neurology (I.K.-M.), University Medical Center Tübingen, Germany; Hussman Institute for Human Genomics (S.Z.), University of Miami Miller School of Medicine, FL; Clalit Health Services (M.A.-R.), Haifa, Israel; and Meuhedet Health Services (J.M.), North District, Israel.
authors.forename: Peter
authors.initials: P
authors.lastname: Bauer
authors.affiliation: Department of Neurology and Hertie-Institute for Clinical Brain Research (H.H., R. Schüle, L.S.), University of Tübingen, Germany; German Center of Neurodegenerative Diseases (DZNE) (H.H., R.S., L.S.), Tübingen, Germany; Northern Ireland Regional Genetics Service (A.M.), Belfast City Hospital, Belfast; Department of Neurology (J.-M.V.), National Reference Center for Rare Peripheral Neuropathies, University Hospital, Limoges, France; Institute for Neuroscience and Muscle Research (R.O.), The Children's Hospital at Westmead, Sydney, New South Wales, Australia; The Triangle Regional Research and Development Center (R. Sharkia), Kfar Qari' Israel; Beit-Berl Academic College (R. Sharkia), Israel; Child Neurology and Development Center (M.M.), Hillel-Yaffe Medical Center, Hadera, Israel; Rappaport Faculty of Medicine (M.M.), Technion, Haifa, Israel; Institute of Medical Genetics and Applied Genomics (M.S.), University of Tübingen, Germany; Department of Pediatric Neurology (I.K.-M.), University Medical Center Tübingen, Germany; Hussman Institute for Human Genomics (S.Z.), University of Miami Miller School of Medicine, FL; Clalit Health Services (M.A.-R.), Haifa, Israel; and Meuhedet Health Services (J.M.), North District, Israel.
authors.forename: Stephan
authors.initials: S
authors.lastname: Züchner
authors.affiliation: Department of Neurology and Hertie-Institute for Clinical Brain Research (H.H., R. Schüle, L.S.), University of Tübingen, Germany; German Center of Neurodegenerative Diseases (DZNE) (H.H., R.S., L.S.), Tübingen, Germany; Northern Ireland Regional Genetics Service (A.M.), Belfast City Hospital, Belfast; Department of Neurology (J.-M.V.), National Reference Center for Rare Peripheral Neuropathies, University Hospital, Limoges, France; Institute for Neuroscience and Muscle Research (R.O.), The Children's Hospital at Westmead, Sydney, New South Wales, Australia; The Triangle Regional Research and Development Center (R. Sharkia), Kfar Qari' Israel; Beit-Berl Academic College (R. Sharkia), Israel; Child Neurology and Development Center (M.M.), Hillel-Yaffe Medical Center, Hadera, Israel; Rappaport Faculty of Medicine (M.M.), Technion, Haifa, Israel; Institute of Medical Genetics and Applied Genomics (M.S.), University of Tübingen, Germany; Department of Pediatric Neurology (I.K.-M.), University Medical Center Tübingen, Germany; Hussman Institute for Human Genomics (S.Z.), University of Miami Miller School of Medicine, FL; Clalit Health Services (M.A.-R.), Haifa, Israel; and Meuhedet Health Services (J.M.), North District, Israel.
authors.forename: Rajech
authors.initials: R
authors.lastname: Sharkia
authors.affiliation: Department of Neurology and Hertie-Institute for Clinical Brain Research (H.H., R. Schüle, L.S.), University of Tübingen, Germany; German Center of Neurodegenerative Diseases (DZNE) (H.H., R.S., L.S.), Tübingen, Germany; Northern Ireland Regional Genetics Service (A.M.), Belfast City Hospital, Belfast; Department of Neurology (J.-M.V.), National Reference Center for Rare Peripheral Neuropathies, University Hospital, Limoges, France; Institute for Neuroscience and Muscle Research (R.O.), The Children's Hospital at Westmead, Sydney, New South Wales, Australia; The Triangle Regional Research and Development Center (R. Sharkia), Kfar Qari' Israel; Beit-Berl Academic College (R. Sharkia), Israel; Child Neurology and Development Center (M.M.), Hillel-Yaffe Medical Center, Hadera, Israel; Rappaport Faculty of Medicine (M.M.), Technion, Haifa, Israel; Institute of Medical Genetics and Applied Genomics (M.S.), University of Tübingen, Germany; Department of Pediatric Neurology (I.K.-M.), University Medical Center Tübingen, Germany; Hussman Institute for Human Genomics (S.Z.), University of Miami Miller School of Medicine, FL; Clalit Health Services (M.A.-R.), Haifa, Israel; and Meuhedet Health Services (J.M.), North District, Israel.
authors.forename: Ludger
authors.initials: L
authors.lastname: Schöls