Short communication| Volume 279, ISSUE 1-2, P109-113, April 15, 2009

Persistent CNS dysfunction in a boy with CMT1X

Published:February 04, 2009DOI:



      X-linked Charcot Marie Tooth disease (CMT1X) is a hereditary demyelinating neuropathy caused by mutations in the GJB1 gene encoding the gap junction protein connexin 32 (Cx32). Some GJB1 mutations have been reported to cause transient clinical CNS dysfunction. We report a boy with persistent CNS abnormalities possibly caused by CMT1X.


      A five year old boy was evaluated by clinical, electrophysiological, MRI and genetic testing.


      The patient's early motor milestones were normal to age 5 months. His subsequent course was one of slow improvement punctuated by brief periods of loss of ability to sit between age 5 and 10 months, loss of language between 12 months and 2 years and 1 episode of non-clinically observed resolved left-sided facial weakness. At age 5, he had truncal instability, appendicular ataxia, and dysarthric speech. Cognition was normal. He had mild toe weakness and intrinsic muscle atrophy. MRI evaluation was abnormal. Electrophysiologic testing revealed slowed motor conduction velocities and sensory responses of low amplitude. Genetic workup was normal excepting a novel missense mutation in GJB1, causing a p.54N>H substitution.


      The patient has persistent CNS abnormalities characterized by dysarthria and ataxia. These are similar to transient CNS abnormalities reported in patients with CMT1X. These CNS findings may be the direct result of his novel Cx32 mutation.


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Journal of the Neurological Sciences
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Skre H.
        Genetic and clinical aspects of Charcot-Marie-Tooth's disease.
        Clin Genet. 1974; 6: 98-118
        • Szigteti K.
        • Garcia C.
        • Lupski J.R.
        Charcot-Marie-Tooth disease and related hereditary polyneuropathies: Molecular diagnostics determine aspects of medical management.
        Genet Med. 2006; 8: 86-92
        • Nelis E.
        • Van Broeckhoven C.
        • De Jonghe P.
        • Lofgren A.
        • Vandenberghe A.
        • Latour P.
        • et al.
        Estimation of the mutation frequencies in Charcot-Marie-Tooth disease type 1 and hereditary neuropathy with liability to pressure palsies: a European collaborative study.
        Eur J Hum Genet. 1996; 4: 25-33
        • Bergoffen J.
        • Scherer S.S.
        • Wang S.
        • Scott M.O.
        • Bone L.J.
        • Paul D.L.
        • et al.
        Connexin mutations in X-linked Charcot-Marie-Tooth disease.
        Science. 1993; 262: 2039-2042
        • Balice-Gordon R.J.
        • Bone L.
        • Scherer S.S.
        Functional gap junctions in the Schwann cell myelin sheath.
        J Cell Biol. 1998; 142: 1095-104
        • Rash J.E.
        • Yasumura T.
        • Dudek F.E.
        • Nagy J.I.
        Cell-specific expression of connexins and evidence of restricted gap junctional coupling between glial cells and between neurons.
        J Neurosci. 2001; 21: 1983-2000
        • Shy M.E.
        • Siskind C.
        • Swan E.R.
        • Krajewski K.M.
        • Doherty T.
        • Fuerst D.R.
        • et al.
        CMT1X phenotypes represent loss of GJB1 gene function.
        Neurology. 2007; 68: 849-855
        • Nicholson G.
        • Corbett A.
        Slowing of central conduction in X-linked Charcot-Marie-Tooth neuropathy shown by brain auditory evoked responses.
        J Neurol Neurosurg Psychiatry. 1996; 61: 43-46
        • Murru M.R.
        • Vannelli A.
        • Marrosu G.
        • Cocco E.
        • Corongiu D.
        • Tranquilli S.
        • et al.
        A novel Cx32 mutation causes X-linked Charcot-Marie-Tooth disease with brainstem involvement and brain magnetic resonance spectroscopy abnormalities.
        Neurol Sci. 2006; 27: 18-23
        • Panas M.
        • Karadimas C.
        • Avramopoulos D.
        • Vassilopoulos D.
        Central nervous system involvement in four patients with Charcot-Marie-Tooth disease with connexin 32 extracellular mutations.
        J Neurol Neurosurg Psychiatry. 1998; 65: 947-948
        • Panas M.
        • Kalfakis N.
        • Karadimas C.
        • Vassilopoulos D.
        Episodes of generalized weakness in two sibs with the C164T mutation of the connexin 32 gene.
        Neurology. 2001; 57: 1906-1908
        • Lee M.–J.
        • Nelson I.
        • Houlden H.
        • Sweeney M.G.
        • Hilton-Jones D.
        • Blake J.
        • et al.
        Six novel connexin32 (GJB1) mutations in X-linked Charcot-Marie-Tooth disease.
        J Neurol Neurosurg Psychiatry. 2002; 73: 304-306
        • Hanemann C.O.
        • Bergmann C.
        • Senderek J.
        • Zerres K.
        • Sperfeld A.–D.
        Transient, Recurrent, White Matter Lesions in X-linked Charcot-Marie-Tooth Disease With Novel Connexin 32 Mutation.
        Arch Neurol. 2003; 60: 605-609
        • Schelhaas H.J.
        • van Engelen B.G.M.
        • Gabreels-Festen A.A.W.M.
        • Hageman G.
        • Vliegen J.H.R.
        • van der Knaap M.S.
        • et al.
        Transient cerebral white matter lesions in a patient with connexin 32 missense mutation.
        Neurology. 2002; 59: 2007-2008
        • Paulson H.L.
        • Garbern J.Y.
        • Hoban T.F.
        • Krajewski K.M.
        • Lewis R.A.
        • Fischbeck K.H.
        • et al.
        Transient Central Nervous System White Matter Abnormality in X-Linked Charcot-Marie-Tooth disease.
        Ann Neurol. 2002; 52: 429-434
        • Taylor R.A.
        • Simon E.M.
        • Marks H.G.
        • Scherer S.S.
        The CNS phenotype of X-linked Charcot-Marie-Tooth disease.
        Neurology. 2003; 61: 1475-1478
        • Lewis R.A.
        • Shy M.E.
        Electrodiagnostic findings in CMTX: a disorder of the Schwann cell and peripheral nerve myelin.
        Ann NY Acad Sci. 1999; 883: 504-507
        • Hudson L.D.
        • Puckett C.
        • Berndt J.
        • Chan J.
        • Gencic S.
        Mutation of the proteolipid protein gene PLP in a human X chromosome-linked myelin disorder.
        Proc Natl Acad Sci USA. 1989; 86: 8128-8131
        • Uhlenberg B.
        • Schuelke M.
        • Ruschendorf F.
        • Ruf N.
        • Kaindl A.M.
        • Henneke M.
        • et al.
        Mutations in the gene encoding gap junction protein alpha 12 (connexin 46.6) cause Pelizaeus-Merzbacher-like disease.
        Am J Hum Genet. 2004; 75: 251-260
        • Kleopa K.A.
        • Zamba-Papanicolaou E.
        • Alevra X.
        • Nicolaou P.
        • Georgiou D.M.
        • Hadjisavvas A.
        • et al.
        Phenotypic and cellular expression of two novel connexin32 mutations causing CMT1X.
        Neurology. 2006; 66: 396-402
        • Wise R.P.
        • Salive M.E.
        • Braun M.M.
        • Mootrey G.T.
        • Seward J.F.
        • Rider L.G.
        • et al.
        Postlicensure Safety Surveillance for Varicella Vaccine.
        JAMA. 2000; 284: 1271-1279
        • Nakagawa H.
        • Iwasaki S.
        • Kichikawa K.
        • Fukusumi A.
        • Taoka T.
        • Ohishi H.
        • et al.
        Normal myelination of anatomic nerve fiber bundles: MR analysis.
        Am J Neuroradiol. 1998; 19: 1129-1136
        • Barkovich A.J.
        • Kjos B.O.
        • Jackson D.E.
        • Norman D.
        Normal maturation of the neonatal and infant brain: MR imaging at 1.5 T.
        Radiology. 1988; 166: 173-180
        • Kawakami H.
        • Inoue K.
        • Sakakihara I.
        • Nakamura S.
        Novel mutation in X-linked Charcot-Marie-Tooth disease associated with CNS impairment.
        Neurology. 2002; 59: 923-926