Advertisement

Neurological Sciences

, Volume 37, Issue 7, pp 1063–1070 | Cite as

CNS involvement in CMTX1 caused by a novel connexin 32 mutation: a 6-year follow-up in neuroimaging and nerve conduction

  • Chong Xie
  • Xiajun Zhou
  • Desheng Zhu
  • Wei Liu
  • Xiaoqing Wang
  • Hong Yang
  • Zezhi Li
  • Yong Hao
  • Guang-Xian ZhangEmail author
  • Yangtai Guan
Original Article

Abstract

X-linked Charcot-Marie-Tooth disease, type 1 (CMTX1) is one of the most common inherited neurological disorders. Obvious CNS involvement is relatively rare in CMTX1 patients. A 24-year-old male with CMTX1 presented with three transient stroke-like attacks, and was followed up regularly for 6 years with brain MRI and electrophysiological examination. Transient symmetrical high signals on T2 imaging and restricted diffusion were found in bilateral deep white matter. Electrophysiological measurement revealed a sensorimotor peripheral neuropathy with slightly reduced nerve conduction velocities. A novel thymine to cytosine mutation at nucleotide position 445 in the connexin 32 allele of the GJB1 gene was identified. During the 6-year longitudinal study, patient’s motor and sensory function did not worsen; radiological abnormalities correlated with episodes of CNS dysfunction and resolved after clinical recovery; electrophysiological records showed no obvious change. Little change in the patient’s clinical, radiological and electrophysiological results over the follow-up reflected a slow disease progression.

Keywords

X-linked Charcot-Marie-Tooth disease CNS involvement Symmetrical white matter abnormalities Nerve conduction velocity Cx32 gene mutation 

Abbreviations

CMAP

Compound muscle action potential

CMT

Charcot-Marie-Tooth disease

CMTX

X-linked Charcot-Marie-Tooth disease

CMTX1

X-linked Charcot-Marie-Tooth disease, type 1

CNS

Central nervous system

Cx32

Connexin 32

DWI

Diffusion-weighted imaging

FLAIR

Fluid attenuated inversion recovery

GJBI

Gap junction beta 1

SNAP

Sensory nerve action potential

Notes

Acknowledgments

This work was supported by the National Natural Science Foundations of China (81230027, 81070959) and Key Scientific and Technological Project of Shanghai (11411950300). We thank the patients for their participation. We also thank Katherine Regan for editorial assistance.

Compliance with ethical standards

Conflict of interest

On behalf of all authors, we state that there is no conflict of interest.

Supplementary material

10072_2016_2537_MOESM1_ESM.tif (6 mb)
The CT angiography showed no abnormalities. (TIFF 6100 kb)
10072_2016_2537_MOESM2_ESM.tif (17.8 mb)
The CT perfusion showed no abnormalities. (TIFF 18219 kb)
10072_2016_2537_MOESM3_ESM.docx (31 kb)
Supplementary material 3 (DOCX 31 kb)

References

  1. 1.
    Skre H (1974) Genetic and clinical aspects of Charcot-Marie-Tooth’s disease. Clin Genet 6(2):98–118CrossRefPubMedGoogle Scholar
  2. 2.
    Pareyson D, Marchesi C (2009) Diagnosis, natural history, and management of Charcot-Marie-Tooth disease. Lancet Neurol 8(7):654–667. doi: 10.1016/S1474-4422(09)70110-3 CrossRefPubMedGoogle Scholar
  3. 3.
    Bergoffen J, Scherer SS, Wang S, Scott MO, Bone LJ, Paul DL, Chen K, Lensch MW, Chance PF, Fischbeck KH (1993) Connexin mutations in X-linked Charcot-Marie-Tooth disease. Science 262(5142):2039–2042CrossRefPubMedGoogle Scholar
  4. 4.
    Bahr M, Andres F, Timmerman V, Nelis ME, Van Broeckhoven C, Dichgans J (1999) Central visual, acoustic, and motor pathway involvement in a Charcot-Marie-Tooth family with an Asn205Ser mutation in the connexin 32 gene. J Neurol Neurosurg Psychiatry 66(2):202–206CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Chen SD, Li ZX, Guan YT, Zhou XJ, Jiang JM, Hao Y (2011) A novel mutation of gap junction protein beta 1 gene in X-linked Charcot-Marie-Tooth disease. Muscle Nerve 43(6):887–892. doi: 10.1002/mus.21992 CrossRefPubMedGoogle Scholar
  6. 6.
    Birouk N, LeGuern E, Maisonobe T, Rouger H, Gouider R, Tardieu S, Gugenheim M, Routon MC, Leger JM, Agid Y, Brice A, Bouche P (1998) X-linked Charcot-Marie-Tooth disease with connexin 32 mutations: clinical and electrophysiologic study. Neurology 50(4):1074–1082CrossRefPubMedGoogle Scholar
  7. 7.
    Dubourg O, Tardieu S, Birouk N, Gouider R, Leger JM, Maisonobe T, Brice A, Bouche P, LeGuern E (2001) Clinical, electrophysiological and molecular genetic characteristics of 93 patients with X-linked Charcot-Marie-Tooth disease. Brain J Neurol 124(Pt 10):1958–1967CrossRefGoogle Scholar
  8. 8.
    Sato K, Kubo S, Fujii H, Okamoto M, Takahashi K, Takamatsu K, Tanaka A, Kuriyama M (2012) Diffusion tensor imaging and magnetic resonance spectroscopy of transient cerebral white matter lesions in X-linked Charcot-Marie-Tooth disease. J Neurol Sci 316(1–2):178–180. doi: 10.1016/j.jns.2012.01.017 CrossRefPubMedGoogle Scholar
  9. 9.
    Siskind C, Feely SM, Bernes S, Shy ME, Garbern JY (2009) Persistent CNS dysfunction in a boy with CMT1X. J Neurol Sci 279(1–2):109–113. doi: 10.1016/j.jns.2008.12.031 CrossRefPubMedGoogle Scholar
  10. 10.
    Sakaguchi H, Yamashita S, Miura A, Hirahara T, Kimura E, Maeda Y, Terasaki T, Hirano T, Uchino M (2011) A novel GJB1 frameshift mutation produces a transient CNS symptom of X-linked Charcot-Marie-Tooth disease. J Neurol 258(2):284–290. doi: 10.1007/s00415-010-5752-8 CrossRefPubMedGoogle Scholar
  11. 11.
    Zhong L, Yan K, Liu C, Xue J, Wu L, Yin F (2012) Clinical reasoning: a young man with reversible paralysis, cerebral white matter lesions, and peripheral neuropathy. Neurology 79(8):e70–e72. doi: 10.1212/WNL.0b013e3182661eca CrossRefPubMedGoogle Scholar
  12. 12.
    Al-Mateen M, Craig AK, Chance PF (2014) The central nervous system phenotype of X-linked Charcot-Marie-Tooth disease: a transient disorder of children and young adults. J Child Neurol 29(3):342–348. doi: 10.1177/0883073812474343 CrossRefPubMedGoogle Scholar
  13. 13.
    Panas M, Kalfakis N, Karadimas C, Vassilopoulos D (2001) Episodes of generalized weakness in two sibs with the C164T mutation of the connexin 32 gene. Neurology 57(10):1906–1908CrossRefPubMedGoogle Scholar
  14. 14.
    Paulson HL, Garbern JY, Hoban TF, Krajewski KM, Lewis RA, Fischbeck KH, Grossman RI, Lenkinski R, Kamholz JA, Shy ME (2002) Transient central nervous system white matter abnormality in X-linked Charcot-Marie-Tooth disease. Ann Neurol 52(4):429–434. doi: 10.1002/ana.10305 CrossRefPubMedGoogle Scholar
  15. 15.
    Schelhaas HJ, Van Engelen BG, Gabreels-Festen AA, Hageman G, Vliegen JH, Van Der Knaap MS, Zwarts MJ (2002) Transient cerebral white matter lesions in a patient with connexin 32 missense mutation. Neurology 59(12):2007–2008CrossRefPubMedGoogle Scholar
  16. 16.
    Taylor RA, Simon EM, Marks HG, Scherer SS (2003) The CNS phenotype of X-linked Charcot-Marie-Tooth disease: more than a peripheral problem. Neurology 61(11):1475–1478CrossRefPubMedGoogle Scholar
  17. 17.
    Hanemann CO, Bergmann C, Senderek J, Zerres K, Sperfeld AD (2003) Transient, recurrent, white matter lesions in X-linked Charcot-Marie-Tooth disease with novel connexin 32 mutation. Arch Neurol 60(4):605–609. doi: 10.1001/archneur.60.4.605 CrossRefPubMedGoogle Scholar
  18. 18.
    Isoardo G, Di Vito N, Nobile M, Benetton G, Fassio F (2005) X-linked Charcot-Marie-Tooth disease and progressive-relapsing central demyelinating disease. Neurology 65(10):1672–1673. doi: 10.1212/01.wnl.0000186032.06791.94 CrossRefPubMedGoogle Scholar
  19. 19.
    Kassubek J, Bretschneider V, Sperfeld AD (2005) Corticospinal tract MRI hyperintensity in X-linked Charcot-Marie-Tooth Disease. J Clin Neurosci Off J Neurosurg Soc Australas 12(5):588–589. doi: 10.1016/j.jocn.2004.07.020 Google Scholar
  20. 20.
    Halbrich M, Barnes J, Bunge M, Joshi C (2008) A V139M mutation also causes the reversible CNS phenotype in CMTX. Can J Neurol Sci Le J Can des Sci Neurol 35(3):372–374CrossRefGoogle Scholar
  21. 21.
    Srinivasan J, Leventer RJ, Kornberg AJ, Dahl HH, Ryan MM (2008) Central nervous system signs in X-linked Charcot-Marie-Tooth disease after hyperventilation. Pediatr Neurol 38(4):293–295. doi: 10.1016/j.pediatrneurol.2007.12.003 CrossRefPubMedGoogle Scholar
  22. 22.
    Anand G, Maheshwari N, Roberts D, Padeniya A, Hamilton-Ayers M, van der Knaap M, Fratter C, Jayawant S (2010) X-linked hereditary motor sensory neuropathy (type 1) presenting with a stroke-like episode. Dev Med Child Neurol 52(7):677–679. doi: 10.1111/j.1469-8749.2010.03674.x CrossRefPubMedGoogle Scholar
  23. 23.
    Fusco C, Frattini D, Pisani F, Spaggiari F, Ferlini A, Della Giustina E (2010) Coexistent central and peripheral nervous system involvement in a Charcot-Marie-Tooth syndrome X-linked patient. J Child Neurol 25(6):759–763. doi: 10.1177/0883073809344119 CrossRefPubMedGoogle Scholar
  24. 24.
    Rosser T, Muir J, Panigrahy A, Baldwin EE, Boles RG (2010) Transient leukoencephalopathy associated with X-linked Charcot-Marie-Tooth disease. J Child Neurol 25(8):1013–1016. doi: 10.1177/0883073809352378 CrossRefPubMedGoogle Scholar
  25. 25.
    Basu A, Horvath R, Esisi B, Birchall D, Chinnery PF (2011) Recurrent stroke-like episodes in X-linked Charcot-Marie-Tooth disease. Neurology 77(12):1205–1206. doi: 10.1212/WNL.0b013e31822f046e CrossRefPubMedGoogle Scholar
  26. 26.
    Uk-I JM, Yiu E, Donner EJ, Shroff M (2011) MRI findings in X-linked Charcot-Marie-Tooth disease associated with a novel connexin 32 mutation. Clin Radiol 66(5):471–474. doi: 10.1016/j.crad.2010.11.009 CrossRefGoogle Scholar
  27. 27.
    Weishaupt JH, Ganser C, Bahr M (2012) Inflammatory demyelinating CNS disorder in a case of X-linked Charcot-Marie-Tooth disease: positive response to natalizumab. J Neurol 259(9):1967–1969. doi: 10.1007/s00415-012-6467-9 CrossRefPubMedGoogle Scholar
  28. 28.
    Kulkarni GB, Mailankody P, Isnwara PP, Prasad C, Mustare V (2015) Episodic neurological dysfunction in hereditary peripheral neuropathy. Ann Indian Acad Neurol 18(1):111–114. doi: 10.4103/0972-2327.144314 PubMedPubMedCentralGoogle Scholar
  29. 29.
    McKinney JL, De Los Reyes EC, Lo WD, Flanigan KM (2014) Recurrent central nervous system white matter changes in Charcot-Marie-tooth type X disease. Muscle Nerve 49(3):451–454. doi: 10.1002/mus.24108 CrossRefPubMedGoogle Scholar
  30. 30.
    3rd workshop of the European CMT consortium: 54th ENMC International workshop on genotype/phenotype correlations in Charcot-Marie-Tooth type 1 and hereditary neuropathy with liability to pressure palsies 28–30 November 1997, Naarden, The Netherlands (1998). Neuromuscular disorders: NMD 8(8):591–603Google Scholar
  31. 31.
    Williams MM, Tyfield LA, Jardine P, Lunt PW, Stevens DL, Turnpenny PD (1999) HMSN and HNPP. Laboratory service provision in the south west of England—two years’ experience. Ann N Y Acad Sci 883:500–503CrossRefPubMedGoogle Scholar
  32. 32.
    Li QH, Liu KX, Feng JL, Zeng AY, Li H, Wu L, Tang YG, Chen ML, Lin XH, Jiang JZ (2010) A new mutation in the GJB1 gene of a Chinese family with Charcot-Marie-Tooth disease associated with vocal cord paresis. Zhonghua yi xue yi chuan xue za zhi Zhonghua yixue yichuanxue zazhi Chin J Med Genet 27(5):497–500. doi: 10.3760/cma.j.issn.1003-9406.2010.05.005 Google Scholar
  33. 33.
    Lin P, Mao F, Liu Q, Yang W, Shao C, Yan C, Gong Y (2010) A novel deletion mutation in GJB1 causes X-linked Charcot-Marie-Tooth disease in a Han Chinese family. Muscle Nerve 42(6):922–926. doi: 10.1002/mus.21790 CrossRefPubMedGoogle Scholar
  34. 34.
    Shahrizaila N, Samulong S, Tey S, Suan LC, Meng LK, Goh KJ, Ahmad-Annuar A (2014) X-linked Charcot-Marie-Tooth disease predominates in a cohort of multiethnic Malaysian patients. Muscle Nerve 49(2):198–201. doi: 10.1002/mus.23892 CrossRefPubMedGoogle Scholar
  35. 35.
    Shy ME, Siskind C, Swan ER, Krajewski KM, Doherty T, Fuerst DR, Ainsworth PJ, Lewis RA, Scherer SS, Hahn AF (2007) CMT1X phenotypes represent loss of GJB1 gene function. Neurology 68(11):849–855. doi: 10.1212/01.wnl.0000256709.08271.4d CrossRefPubMedGoogle Scholar
  36. 36.
    Abrams CK, Freidin M, Bukauskas F, Dobrenis K, Bargiello TA, Verselis VK, Bennett MV, Chen L, Sahenk Z (2003) Pathogenesis of X-linked Charcot-Marie-Tooth disease: differential effects of two mutations in connexin 32. J Neurosci Off J Soc Neurosci 23(33):10548–10558Google Scholar
  37. 37.
    Kleopa KA, Abrams CK, Scherer SS (2012) How do mutations in GJB1 cause X-linked Charcot-Marie-Tooth disease? Brain Res 1487:198–205. doi: 10.1016/j.brainres.2012.03.068 CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Hahn AF, Ainsworth PJ, Naus CC, Mao J, Bolton CF (2000) Clinical and pathological observations in men lacking the gap junction protein connexin 32. Muscle Nerve Suppl 9:S39–S48CrossRefGoogle Scholar

Copyright information

© Springer-Verlag Italia 2016

Authors and Affiliations

  • Chong Xie
    • 1
  • Xiajun Zhou
    • 4
  • Desheng Zhu
    • 2
  • Wei Liu
    • 1
  • Xiaoqing Wang
    • 1
  • Hong Yang
    • 3
  • Zezhi Li
    • 4
  • Yong Hao
    • 4
  • Guang-Xian Zhang
    • 5
    Email author
  • Yangtai Guan
    • 1
    • 4
  1. 1.Department of Neurology, Changhai HospitalSecond Military Medical UniversityShanghaiChina
  2. 2.Department of Neurology, Huashan HospitalFudan UniversityShanghaiChina
  3. 3.Department of NeurologyShanghai Yangpu Geriatric HospitalShanghaiChina
  4. 4.Department of Neurology, Renji HospitalShanghai Jiaotong UniversityShanghaiChina
  5. 5.Department of NeurologyThomas Jefferson UniversityPhiladelphiaUSA

Personalised recommendations