Skip to main content

Advertisement

SpringerLink
Log in

Reduced penetrance in hereditary motor neuropathy caused by TRPV4 Arg269Cys mutation

  • Original Communication
  • Published:
Journal of Neurology Aims and scope Submit manuscript

Abstract

Incomplete penetrance has rarely been reported in Charcot–Marie–Tooth disease. Our aim is to describe reduced penetrance in a hereditary motor neuropathy pedigree due to mutation in the transient receptor potential vallinoid 4 (TRPV4) gene. The pedigree comprised two affected members, the proband aged 44 years and her affected daughter aged 7 years, and seven additional related subjects, three of whom were subclinical gene mutation carriers aged 9, 40 and 70 years. Clinico-electrophysiological studies, MRI of lower-limb musculature and genetic testing of the TRPV4 were performed. The proband presented with a moderate facio-scapulo-peroneal syndrome, whereas her symptomatic daughter suffered from severe congenital spinal muscular atrophy with arthrogryposis, laryngomalacia, and vocal cord paresis. Electrophysiological evaluation revealed a pure motor axonal neuropathy. In the proband, MRI showed extensive and widespread fatty atrophy of lower-leg musculature, whereas in thigh musculature there was just mild distal fatty infiltration of vastus lateralis. Genetic testing revealed a heterozygous Arg269Cys mutation in the TPRV4 gene. In all three mutation carriers results from clinical and electrophysiological examination, and MRI of foot and lower-leg musculature were normal. We conclude that non-penetrance may be an integral feature of neuropathic syndromes associated with TRPV4 gene mutation.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Auer-Grumbach M, Schlotter-Weigel B, Lochmüller H, Strobl-Wildemann G, Auer-Grumbach P, Fischer R, Offenbacher H, Zwick EB, Robl T, Hartl G, Hartung HP, Wagner K, Windpassinger C, Austrian Peripheral Neuropathy Study Group (2005) Phenotypes of the N88S Berardinelli-Seip congenital lipodystrophy 2 mutation. Ann Neurol 57:415–424

    Article  PubMed  CAS  Google Scholar 

  2. Auer-Grumbach M, Olschewski A, Papić L, Kremer H, McEntagart ME, Uhrig S, Fischer C, Fröhlich E, Bálint Z, Tang B, Strohmaier H, Lochmüller H, Schlotter-Weigel B, Senderek J, Krebs A, Dick KJ, Petty R, Longman C, Anderson NE, Padberg GW, Schelhaas HJ, van Ravenswaaij-Arts CM, Pieber TR, Crosby AH, Guelly C (2010) Alterations in the ankyrin domain of TRPV4 cause congenital distal SMA, scapuloperoneal SMA and HMSN2C. Nat Genet 42:160–164

    Article  PubMed  CAS  Google Scholar 

  3. Berciano J, Gallardo E, García A, Ramón C, Mateo I, Infante J, Rodríguez-Rodríguez E, Combarros O (2008) CMT1A duplication: refining the minimal adult phenotype. J Peripher Nerv Syst 13:310–312

    Article  PubMed  Google Scholar 

  4. Boltshauser E, Lang W, Spillmann T, Hof E (1989) Hereditary distal muscular atrophy with vocal cord paralysis and sensorineural hearing loss: a dominant form of spinal muscular atrophy? J Med Genet 26:105–158

    Article  PubMed  CAS  Google Scholar 

  5. Chen DH, Sul Y, Weiss M, Hillel A, Lipe H, Wolff J, Matsushita M, Raskind W, Bird T (2010) CMT2C with vocal cord paresis associated with short stature and mutations in the TRPV4 gene. Neurology 75:1968–1975

    Article  PubMed  Google Scholar 

  6. Chung KW, Suh BC, Shy ME, Cho SY, Yoo JH, Park SW, Moon H, Park KD, Choi KG, Kim S, Kim SB, Shim DS, Kim SM, Sunwoo IN, Choi BO (2008) Different clinical and magnetic resonance imaging features between Charcot–Marie–Tooth disease type 1A and 2A. Neuromuscul Disord 18:610–618

    Article  PubMed  CAS  Google Scholar 

  7. Dai J, Cho TJ, Unger S, Lausch E, Nishimura G, Kim OH, Superti-Furga A, Ikegawa S (2010) TRPV4-pathy, a novel channelopathy affecting diverse systems. J Hum Genet 55:400–402

    Article  PubMed  Google Scholar 

  8. Davies DV, Coupland RE (1967) Gray’s anatomy descriptive and applied. Longmans, Glasgow

    Google Scholar 

  9. De Jonghe P, Timmerman V, Ceuterick C, Nelis E, De Vriendt E, Löfgren A, Vercruyssen A, Verellen C, Van Maldergem L, Martin JJ, Van Broeckhoven C (1999) The Thr124Met mutation in the peripheral myelin protein zero (MPZ) gene is associated with a clinically distinct Charcot–Marie–Tooth phenotype. Brain 122:281–290

    Article  PubMed  Google Scholar 

  10. Deng HX, Klein CJ, Yan J, Shi Y, Wu Y, Fecto F, Yau HJ, Yang Y, Zhai H, Siddique N, Hedley-Whyte ET, Delong R, Martina M, Dyck PJ, Siddique T (2010) Scapuloperoneal spinal muscular atrophy and CMT2C are allelic disorders caused by alterations in TRPV4. Nat Genet 42:165–169

    Article  PubMed  CAS  Google Scholar 

  11. Donaghy M, Kennett R (1999) Varying occurrence of vocal cord paralysis in a family with autosomal dominant hereditary motor and sensory neuropathy. J Neurol 246:552–555

    Article  PubMed  CAS  Google Scholar 

  12. Dubourg O, Azzedine H, Yaou RB, Pouget J, Barois A, Meininger V, Bouteiller D, Ruberg M, Brice A, LeGuern E (2006) The G526R glycyl-tRNA synthetase gene mutation in distal hereditary motor neuropathy type V. Neurology 66:1721–1726

    Article  PubMed  CAS  Google Scholar 

  13. Dyck PJ, Litchy WJ, Minnerath S, Bird TD, Chance PF, Schaid DJ, Aronson AE (1994) Hereditary motor and sensory neuropathy with diaphragm and vocal cord paresis. Ann Neurol 35:608–615

    Article  PubMed  CAS  Google Scholar 

  14. Fleury P, Hageman G (1985) A dominantly inherited lower motor neuron disorder presenting at birth with associated arthrogryposis. J Neurol Neurosurg Psychiatry 48:1037–1048

    Article  PubMed  CAS  Google Scholar 

  15. Gallardo E, García A, Combarros O, Berciano J (2006) Charcot–Marie–Tooth disease type 1A duplication: spectrum of clinical and magnetic resonance imaging features in leg and foot muscles. Brain 129:426–437

    Article  PubMed  Google Scholar 

  16. Gallardo E, García A, Ramón C, Maraví E, Infante J, Gastón I, Alonso A, Combarros O, De Jonghe P, Berciano J (2009) Charcot–Marie–Tooth disease type 2J with MPZ Thr124Met mutation: clinico-electrophysiological and MRI study of a family. J Neurol 256:2061–2071

    Article  PubMed  Google Scholar 

  17. García A, Combarros O, Calleja J, Berciano J (1998) Charcot–Marie–Tooth disease type 1A with 17p duplication in infancy and early childhood: a longitudinal clinical and electrophysiologic study. Neurology 50:1061–1067

    PubMed  Google Scholar 

  18. García A, Calleja J, Antolín FM, Berciano J (2000) Peripheral motor and sensory nerve conduction studies in normal infants and children. Clin Neurophysiol 111:513–520

    Article  PubMed  Google Scholar 

  19. Guilak F, Leddy HA, Liedtke W (2010) Transient receptor potential vanilloid 4: The sixth sense of the musculoskeletal system? Ann N Y Acad Sci 1192:404–409

    Article  PubMed  CAS  Google Scholar 

  20. Houlden H, King R, Blake J, Groves M, Love S, Woodward C, Hammans S, Nicoll J, Lennox G, O’Donovan DG, Gabriel C, Thomas PK, Reilly MM (2006) Clinical, pathological and genetic characterization of hereditary sensory and autonomic neuropathy type 1 (HSAN I). Brain 129:411–425

    Article  PubMed  Google Scholar 

  21. Klein CJ, Cunningham JM, Atkinson EJ, Schaid DJ, Hebbring SJ, Anderson SA, Klein DM, Dyck PJ, Litchy WJ, Thibodeau SN, Dyck PJ (2003) The gene for HMSN2C maps to 12q23-24: a region of neuromuscular disorders. Neurology 60:1151–1156

    PubMed  CAS  Google Scholar 

  22. Landouré G, Zdebik AA, Martinez TL, Burnett BG, Stanescu HC, Inada H, Shi Y, Taye AA, Kong L, Munns CH, Choo SS, Phelps CB, Paudel R, Houlden H, Ludlow CL, Caterina MJ, Gaudet R, Kleta R, Fischbeck KH, Sumner CJ (2010) Mutations in TRPV4 cause Charcot–Marie–Tooth disease type 2C. Nat Genet 42:170–174

    Article  PubMed  Google Scholar 

  23. Lawson VH, Graham BV, Flanigan KM (2005) Clinical and electrophysiologic features of CMT2A with mutations in the mitofusin 2 gene. Neurology 65:197–204

    Article  PubMed  CAS  Google Scholar 

  24. McEntagart ME, Reid SL, Irrthum A, Douglas JB, Eyre KE, Donaghy MJ, Anderson NE, Rahman N (2005) Confirmation of a hereditary motor and sensory neuropathy IIC locus at chromosome 12q23-q24. Ann Neurol 57:293–297

    Article  PubMed  CAS  Google Scholar 

  25. Nilius B, Owsianik G (2010) Channelopathies converge on TRPV4. Nat Genet 42:98–100

    Article  PubMed  CAS  Google Scholar 

  26. Santoro L, Manganelli F, Di Maio L, Barbieri F, Carella M, D’Adamo P, Casari G (2002) Charcot–Marie–Tooth disease type 2C: a distinct genetic entity. Clinical and molecular characterization of the first European family. Neuromuscul Disord 12:399–404

    Article  PubMed  CAS  Google Scholar 

  27. Sivakumar K, Kyriakides T, Puls I, Nicholson GA, Funalot B, Antonellis A, Sambuughin N, Christodoulou K, Beggs JL, Zamba-Papanicolaou E, Ionasescu V, Dalakas MC, Green ED, Fischbeck KH, Goldfarb LG (2005) Phenotypic spectrum of disorders associated with glycyl-tRNA synthetase mutations. Brain 128:2304–2314

    Article  PubMed  Google Scholar 

  28. Sowden JE, Logigian EL, Malik K, Herrmann DN (2005) Genotype-phenotype correlation in a family with late onset CMT and an MPZ lys236del mutation. J Neurol Neurosurg Psychiatry 76:442–444

    Article  PubMed  CAS  Google Scholar 

  29. Voo I, Allf BE, Udar N, Silva-Garcia R, Vance J, Small KW (2003) Hereditary motor and sensory neuropathy type VI with optic atrophy. Am J Ophthalmol 136:670–677

    Article  PubMed  Google Scholar 

  30. Windpassinger C, Auer-Grumbach M, Irobi J, Patel H, Petek E, Hörl G, Malli R, Reed JA, Dierick I, Verpoorten N, Warner TT, Proukakis C, Van den Bergh P, Verellen C, Van Maldergem L, Merlini L, De Jonghe P, Timmerman V, Crosby AH, Wagner K (2004) Heterozygous missense mutations in BSCL2 are associated with distal hereditary motor neuropathy and Silver syndrome. Nat Genet 36:271–276

    Article  PubMed  CAS  Google Scholar 

  31. Zimoń M, Baets J, Auer-Grumbach M, Berciano J, Garcia A, Lopez-Laso E, Merlini L, Hilton-Jones D, McEntagart M, Crosby AH, Barisic N, Boltshauser E, Shaw CE, Landouré G, Ludlow CL, Gaudet R, Houlden H, Reilly MM, Fischbeck KH, Sumner CJ, Timmerman V, Jordanova A, Jonghe PD (2010) Dominant mutations in the cation channel gene transient receptor potential vanilloid 4 cause an unusual spectrum of neuropathies. Brain 133:1798–1809

    Article  PubMed  Google Scholar 

  32. Züchner S, De Jonghe P, Jordanova A, Claeys KG, Guergueltcheva V, Cherninkova S, Hamilton SR, Van Stavern G, Krajewski KM, Stajich J, Tournev I, Verhoeven K, Langerhorst CT, de Visser M, Baas F, Bird T, Timmerman V, Shy M, Vance JM (2006) Axonal neuropathy with optic atrophy is caused by mutations in mitofusin 2. Ann Neurol 59:276–281

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

We are grateful to the patients and family members for their willingness to participate in this study. Patient consent was obtained to publish the figures in this paper. This study was supported by CIBERNED and FIS grant PI07/132E, the University of Antwerp, the Fund for Scientific Research (FWO-Flanders), the Medical Foundation Queen Elisabeth (GSKE), the ‘Association Belge contre les Maladies Neuromusculaires’ (ABMM), the Interuniversity Attraction Poles P6/43 program of the Belgian Federal Science Policy Office (BELSPO), the “Methusalem excellence grant” of the Flemish Government. MZ and JB are supported by PhD fellowships of the FWO-Flanders.

Conflict of interest

None.

Author information

Authors and Affiliations

  1. Service of Neurology, University Hospital “Marqués de Valdecilla” (IFIMAV), “Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas” (CIBERNED), University of Cantabria (UC), 39008, Santander, Spain

    José Berciano, Onofre Combarros & Jon Infante

  2. Service of Radiology, University Hospital “Marqués de Valdecilla” (IFIMAV), “Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas” (CIBERNED), University of Cantabria (UC), Santander, Spain

    Elena Gallardo

  3. Service of Clinical Neurophysiology, University Hospital “Marqués de Valdecilla” (IFIMAV), “Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas” (CIBERNED), University of Cantabria (UC), Santander, Spain

    Antonio García

  4. Neurogenetics Group, Neurogenetics Laboratory, Institute Born-Bunge, University of Antwerp, Antwerpen, Belgium

    Jonathan Baets, Magdalena Zimoń, Vincent Timmerman, Albena Jordanova & Peter De Jonghe

  5. Paediatric Neurology Unit, Department of Paediatrics, University Hospital “Reina Sofía”, University of Córdoba, Córdoba, Spain

    Eduardo López-Laso

Authors
  1. José Berciano
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jonathan Baets
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Elena Gallardo
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Magdalena Zimoń
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Antonio García
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Eduardo López-Laso
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Onofre Combarros
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Jon Infante
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Vincent Timmerman
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Albena Jordanova
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Peter De Jonghe
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to José Berciano.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOC 1962 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Berciano, J., Baets, J., Gallardo, E. et al. Reduced penetrance in hereditary motor neuropathy caused by TRPV4 Arg269Cys mutation. J Neurol 258, 1413–1421 (2011). https://doi.org/10.1007/s00415-011-5947-7

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00415-011-5947-7

Keywords

Search

Navigation