Skip to main content

Advertisement

SpringerLink
Log in

PMP22 Gene–Associated Neuropathies: Phenotypic Spectrum in a Cohort from India

  • Published:
Journal of Molecular Neuroscience Aims and scope Submit manuscript

Abstract

Reports of spectrum of clinical manifestations in PMP22 gene–associated neuropathies (duplication/mutations) are scarce. To identify the frequency of PMP22 gene variations and establish their genotype-phenotype correlation. Patients with suspected genetic demyelinating neuropathy (n = 128) underwent evaluation for copy number variations and point mutations in PMP22 gene by multiplex ligation-dependent probe amplification (MLPA) and direct sequencing respectively. Of these, only 27 patients (M:F:19:8) from 18 families had PMP22 gene–associated neuropathy; they were subsequently analyzed for genotype-phenotype correlation. Twenty-five patients had PMP22 duplication while two patients had PMP22 missense mutations (p.A114V and p.L80P). Age at onset of neuropathy ranged from infancy to 63 years and symptom duration ranged from 2 to 32 years. Cranial nerve dysfunction in the form of ptosis, ophthalmoplegia, bifacial weakness, and sensorineural hearing loss was observed in addition to a number of systemic features. Three patients were asymptomatic. All except one patient were ambulant. Velocity of median nerve and amplitude of evoked motor responses from common peroneal nerve were significantly reduced in male patients. There was significantly worse disability in the late-onset group as compared with the early-onset group. Otherwise, the mean age at onset, frequency of skeletal deformities, patterns of motor weakness, muscle stretch reflexes, sensory impairment, disability rating scales, and electrophysiological parameters were comparable irrespective of gender, onset age, family history and ulnar nerve conduction velocities. The relatively low frequency of PMP22 duplication in the present cohort warrants a more comprehensive search to establish the genetic etiology. Further research into the role of other genetic variants as well as modifier genes and their effect on phenotypic heterogeneity is indicated.

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

Similar content being viewed by others

References

  • Abe A, Numakura C, Kijima K, Hayashi M, Hashimoto T, Hayasaka K (2011) Molecular diagnosis and clinical onset of Charcot-Marie-Tooth disease in Japan. J Hum Genet 56(5):364–368

    CAS  PubMed  Google Scholar 

  • Aho TR, Wallace RC, Pitt AM, Sivakumar K (2004) Charcot-Marie-Tooth disease: extensive cranial nerve involvement on CT and MR imaging. AJNR Am J Neuroradiol 25(3):494–497

    PubMed  Google Scholar 

  • Azevedo H, Pupe C, Pereira R, Nascimento OJM (2018) Pain in Charcot-Marie-Tooth disease: an update. ArqNeuropsiquiatr. 76(4):273–276

    Google Scholar 

  • Barreto LC, Oliveira FS, Nunes PS, de França Costa IM, Garcez CA, Goes GM, Neves EL, de Souza Siqueira Quintans J, de Souza Araújo AA (2016) Epidemiologic Study of Charcot-Marie-Tooth disease: a systematic review. Neuroepidemiology. 46(3):157–165

    PubMed  Google Scholar 

  • Boerkoel CF, Takashima H, Garcia CA, Olney RK, Johnson J, Berry K, Russo P, Kennedy S, Teebi AS, Scavina M, Williams LL, Mancias P, Butler IJ, Krajewski K, Shy M, Lupski JR (2002) Charcot-Marie-Tooth disease and related neuropathies: mutation distribution and genotype-phenotype correlation. Ann Neurol 51(2):190–201

    CAS  PubMed  Google Scholar 

  • Botsford B, Vuong LN, Hedges TR III, Mendoza-Santiesteban CE (2017) Characterization of Charcot-Marie-Tooth optic neuropathy. J Neurol 264(12):2431–2435

    PubMed  Google Scholar 

  • Chanson JB, Echaniz-Laguna A, Blanc F, Lacour A, Ballonzoli L, Kremer S, Namer IJ, Lannes B, Tranchant C, Vermersch P, de Seze J (2013) Central nervous system abnormalities in patients with PMP22 gene mutations: a prospective study. J Neurol Neurosurg Psychiatry 84(4):392–397

    PubMed  Google Scholar 

  • Choi BO, Lee MS, Shin SH, Hwang JH, Choi KG, Kim WK, Sunwoo IN, Kim NK, Chung KW (2004) Mutational analysis of PMP22, MPZ, GJB1, EGR2 and NEFL in Korean Charcot-Marie-Tooth neuropathy patients. Hum Mutat 24(2):185–186

    PubMed  Google Scholar 

  • Choi JE, Seok JM, Ahn J, Ji YS, Lee KM, Hong SH, Choi BO, Moon IJ (2018) Hidden hearing loss in patients with Charcot-Marie-Tooth disease type 1A. Sci Rep 8(1):10335

    PubMed  PubMed Central  Google Scholar 

  • Coffey RJ, Fromm GH (1991) Familial trigeminal neuralgia and Charcot-Marie-Tooth neuropathy. Report of two families and review. Surg Neurol 35(1):49–53

    CAS  PubMed  Google Scholar 

  • Colomban C, Micallef J, Lefebvre MN, Dubourg O, Gonnaud PM, Stojkovic T, Jouve E, Blin O, Pouget J, Attarian S (2014) Clinical spectrum and gender differences in a large cohort of Charcot-Marie-Tooth type 1A patients. J Neurol Sci 336(1–2):155–160

    PubMed  Google Scholar 

  • Das N, Kandalaft S, Wu X, Malhotra A (2017) Cranial nerve involvement inCharcot-Marie-Tooth disease. J Clin Neurosci 37:59–62

    PubMed  Google Scholar 

  • Deymeer F, Matur Z, Poyraz M, Battaloglu E, Oflazer-Serdaroglu P, Parman Y (2011) Nerve conduction studies in Charcot-Marie-Tooth disease in a cohort from Turkey. Muscle Nerve 43(5):657–664

    CAS  PubMed  Google Scholar 

  • DiVincenzo C, Elzinga CD, Medeiros AC, Karbassi I, Jones JR, Evans MC, Braastad CD, Bishop CM, Jaremko M, Wang Z, Liaquat K, Hoffman CA, York MD, Batish SD, Lupski JR, Higgins JJ (2014) The allelic spectrum of Charcot-Marie-Tooth disease in over 17,000 individuals with neuropathy. Mol Genet Genomic Med 2(6):522–529

    CAS  PubMed  PubMed Central  Google Scholar 

  • Gabreëls-Festen AA, Bolhuis PA, Hoogendijk JE, Valentijn LJ, Eshuis EJ, Gabreëls FJ (1995) Charcot-Marie-Tooth disease type 1A: morphological phenotype of the 17p duplication versus PMP22 point mutations. Acta Neuropathol 90(6):645–649

    PubMed  Google Scholar 

  • Gadoth N, Gordon CR, Bleich N, Pratt H (1991) Three modality evoked potentials in Charcot-Marie-Tooth disease (HMSN-1). Brain Dev 13(2):91–94

    CAS  PubMed  Google Scholar 

  • Hermans G, Clerckx B, Vanhullebusch T, Segers J, Vanpee G, Robbeets C, Casaer MP, Wouters P, Gosselink R, Van Den Berghe G (2012) Interobserver agreement of Medical Research Council sum-score and handgrip strength in the intensive care unit. Muscle Nerve 45(1):18–25

    PubMed  Google Scholar 

  • Joo IS, Ki CS, Joo SY, Huh K, Kim JW (2004) A novel point mutation in PMP22 gene associated with a familial case of Charcot-Marie-Tooth disease type 1A withsensorineural deafness. Neuromuscul Disord 14(5):325–328

    PubMed  Google Scholar 

  • Khadilkar SV, Patil ND, Kadam ND, Mansukhani KA, Patel BA (2017) Clinico-electrophysiological and genetic overlaps and magnetic resonance imaging findings in Charcot-Marie- Tooth disease: a pilot study from Western India. Ann Indian Acad Neurol 20(4):425–429

    PubMed  PubMed Central  Google Scholar 

  • Knopp M, Leese RJ, Martin-Lamb D, Rajabally YA (2014) Optic and auditory pathway dysfunction in demyelinating neuropathies. Acta Neurol Scand 130(1):53–57

    CAS  PubMed  Google Scholar 

  • Kovach MJ, Lin JP, Boyadjiev S, Campbell K, Mazzeo L, Herman K, Rimer LA, Frank W, Llewellyn B, Jabs EW, Gelber D, Kimonis VE (1999) A unique point mutation in the PMP22 gene is associated with Charcot-Marie-Tooth disease and deafness. Am J Hum Genet 64(6):1580–1593

    CAS  PubMed  PubMed Central  Google Scholar 

  • Kumagai-Eto R, Kaseda Y, Tobimatsu S, Uozumi T, Tsuji S, Nakamura S (2004) Subclinical cranial nerve involvement in hereditary motor and sensory neuropathy: a combined conduction study with electrical and magnetic stimulation. ClinNeurophysiol. 115(7):1689–1696

    Google Scholar 

  • Li J, Parker B, Martyn C, Natarajan C, Guo J (2013) The PMP22 gene and its related diseases. Mol Neurobiol 47(2):673–698

    CAS  PubMed  Google Scholar 

  • Liu P, Gelowani V, Zhang F, Drory VE, Ben-Shachar S, Roney E, Medeiros AC, Moore RJ, DiVincenzo C, Burnette WB, Higgins JJ, Li J, Orr-Urtreger A, Lupski JR (2014) Mechanism, prevalence, and more severe neuropathy phenotype of the Charcot-Marie-Tooth type 1A triplication. Am J Hum Genet 94(3):462–469

    CAS  PubMed  PubMed Central  Google Scholar 

  • Manganelli F, Pisciotta C, Reilly MM, Tozza S, Schenone A, Fabrizi GM, Cavallaro T, Vita G, Padua L, Gemignani F, Laurà M, Hughes RA, Solari A, Pareyson D, Santoro L, CMT-TRIAAL and CMT-TRAUK Group (2016) Nerve conduction velocity in CMT1A: what else can we tell? Eur J Neurol 23(10):1566–1571

    CAS  PubMed  PubMed Central  Google Scholar 

  • Marlin S, Jonard L, Loundon N, Bonnet C, Leboulanger N, Van Maldergem L, Gherbi S, Louha M, Deltenre P, Collette JL, Couderc R, Garabedian EN, Denoyelle F (2011) Genetic update on auditory neuropathy. Audiol Neurotol Extra 1:20–29

    Google Scholar 

  • Mathis S, Corcia P, Tazir M, Camu W, Magdelaine C, Latour P, Biberon J, Guennoc AM, Richard L, Magy L, Funalot B, Vallat JM (2014) Peripheral myelin protein 22 gene duplication with atypical presentations: a new example of the wide spectrum of Charcot-Marie-Tooth 1A disease. Neuromuscul Disord 24(6):524–528

    PubMed  Google Scholar 

  • Mersiyanova IV, Ismailov SM, Polyakov AV, Dadali EL, Fedotov VP, Nelis E, Löfgren A, Timmerman V, van Broeckhoven C, Evgrafov OV (2000) Screening for mutations in the peripheral myelin genes PMP22, MPZ and Cx32 (GJB1) in Russian Charcot-Marie-Tooth neuropathy patients. Hum Mutat 15(4):340–347

    CAS  PubMed  Google Scholar 

  • Milley GM, Varga ET, Grosz Z, Nemes C, Arányi Z, Boczán J, Diószeghy P, Molnár MJ, Gál A (2018) Genotypic and phenotypic spectrum of the most common causative genesof Charcot-Marie-Tooth disease in Hungarian patients. Neuromuscul Disord 28(1):38–43

    PubMed  Google Scholar 

  • Murphy SM, Laura M, Fawcett K, Pandraud A, Liu YT, Davidson GL, Rossor AM, Polke JM, Castleman V, Manji H, Lunn MP, Bull K, Ramdharry G, Davis M, Blake JC, Houlden H, Reilly MM (2012) Charcot-Marie-Tooth disease: frequency of genetic subtypes and guidelines for genetic testing. J Neurol Neurosurg Psychiatry 83(7):706–710

    PubMed  PubMed Central  Google Scholar 

  • Numakura C, Lin C, Ikegami T, Guldberg P, Hayasaka K (2002) Molecular analysis in Japanese patients with Charcot-Marie-Tooth disease: DGGE analysis for PMP22,MPZ,and Cx32/GJB1 mutations. Hum Mutat 20(5):392–398

    CAS  PubMed  Google Scholar 

  • Pareyson D, Scaioli V, Laurà M (2006) Clinical and electrophysiological aspects of Charcot-Marie-Tooth disease. Neuromolecular Med 8(1-2):3–22

  • Piantino JA, Torres A (2007) Myoclonic seizures in a patient with Charcot-Marie-tooth disease. Pediatr Neurol 36(2):118–120

    PubMed  Google Scholar 

  • Posa A, Emmer A, Kornhuber ME (2017) Unilateral oculomotor palsy in Charcot-Marie-Tooth disease 1A (CMT 1A). Clin Neurol Neurosurg 155:20–21

    CAS  PubMed  Google Scholar 

  • Rajabally YA, Adams D, Latour P, Attarian S (2016) Hereditary and inflammatory neuropathies: a review of reported associations, mimics and misdiagnoses. J Neurol Neurosurg Psychiatry 87(10):1051–1060

    PubMed  Google Scholar 

  • Ramchandren S (2017) Charcot-Marie-Tooth Disease and Other Genetic Polyneuropathies. Continuum (MinneapMinn) 23(5, Peripheral Nerve and Motor Neuron Disorders):1360–1377

    Google Scholar 

  • Ribiere C, Bernardin M, Sacconi S, Delmont E, Fournier-Mehouas M, Rauscent H, Benchortane M, Staccini P, Lantéri-Minet M, Desnuelle C (2012) Pain assessment inCharcot-Marie-Tooth (CMT) disease. Ann Phys Rehabil Med 55(3):160–173

    CAS  PubMed  Google Scholar 

  • Russo M, Laurá M, Polke JM, Davis MB, Blake J, Brandner S, Hughes RA, Houlden H, Bennett DL, Lunn MP, Reilly MM (2011) Variable phenotypes are associated with PMP22 missense mutations. Neuromuscul Disord 21(2):106–114

    CAS  PubMed  Google Scholar 

  • Sambuughin N, de Bantel A, McWilliams S, Sivakumar K (2003) Deafness and CMT disease associated with a novel four amino acid deletion in the PMP22 gene. Neurology. 60(3):506–508

    CAS  PubMed  Google Scholar 

  • Saporta AS, Sottile SL, Miller LJ, Feely SM, Siskind CE, Shy ME (2011) Charcot-Marie-tooth disease subtypes and genetic testing strategies. Ann Neurol 69(1):22–33

    PubMed  PubMed Central  Google Scholar 

  • Seeman P, Mazanec R, Huehne K, Suslíková P, Keller O, Rautenstrauss B (2004) Hearing loss as the first feature of late-onset axonal CMT disease due to a novel P0 mutation. Neurology. 63(4):733–735

    CAS  PubMed  Google Scholar 

  • Shy ME, Blake J, Krajewski K, Fuerst DR, Laura M, Hahn AF, Li J, Lewis RA, Reilly M (2005) Reliability and validity of the CMT neuropathy score as a measure of disability. Neurology. 64(7):1209–1214

    CAS  PubMed  Google Scholar 

  • Street VA, Meekins G, Lipe HP, Seltzer WK, Carter GT, Kraft GH, Bird TD (2002) Charcot-Marie-Tooth neuropathy: clinical phenotypes of four novel mutations inthe MPZ and Cx 32 genes. Neuromuscul Disord 12(7–8):643–650

    CAS  PubMed  Google Scholar 

  • Stuppia L, Antonucci I, Palka G, Gatta V (2012) Use of the MLPA assay in the molecular diagnosis of gene copy number alterations in human genetic diseases. Int J Mol Sci 13(3):3245–3276

    CAS  PubMed  PubMed Central  Google Scholar 

  • Swan ER, Fuerst DR, Shy ME (2007) Women and men are equally disabled byCharcot-Marie-Tooth disease type 1A. Neurology. 68(11):873

    PubMed  Google Scholar 

  • Tsao CY (2011) Intractable epilepsy, audio-visual hallucinations and Charcot-Marie-Tooth disease 1A in an African-American boy. Clin EEG Neurosci 42(3):206–208

    PubMed  Google Scholar 

  • Tyson J, Ellis D, Fairbrother U, King RH, Muntoni F, Jacobs J, Malcolm S, Harding AE, Thomas PK (1997) Hereditary demyelinating neuropathy of infancy. A genetically complex syndrome. Brain 120(Pt 1):47–63

    PubMed  Google Scholar 

  • Vaeth S, Christensen R, Dunø M, Lildballe DL, Thorsen K, Vissing J, Svenstrup K, Hertz JM, Andersen H, Jensen UB (2019) Genetic analysis of Charcot-Marie-Tooth disease in Denmark and the implementation of a next generation sequencingplatform. Eur J Med Genet 62(1):1–8

    PubMed  Google Scholar 

  • van Paassen BW, van der Kooi AJ, van Spaendonck-Zwarts KY, Verhamme C, Baas F, de Visser M (2014) PMP22 related neuropathies: Charcot-Marie-Tooth disease type 1A and hereditary neuropathy with liability to pressure palsies. Orphanet J Rare Dis 9:38

    PubMed  PubMed Central  Google Scholar 

  • Verhagen WI, Huygen PL, Gabreëls-Festen AA, Engelhart M, van Mierlo PJ, van Engelen BG (2005) Sensorineural hearing impairment in patients with Pmp22 duplication,deletion, and frameshift mutations. Otol Neurotol 26(3):405–414

    CAS  PubMed  Google Scholar 

  • Verhamme C, van Schaik IN, Koelman JH, de Haan RJ, de Visser M (2009) The natural history of Charcot-Marie-Tooth type 1A in adults: a 5-year follow-up study. Brain 132(Pt 12):3252–3262

    PubMed  Google Scholar 

  • Watila MM, Balarabe SA (2015) Molecular and clinical features of inheritedneuropathies due to PMP22 duplication. J Neurol Sci 355(1–2):18–24

    CAS  PubMed  Google Scholar 

  • Werheid F, Azzedine H, Zwerenz E, Bozkurt A, Moeller MJ, Lin L, Mull M, Häusler M, Schulz JB, Weis J, Claeys KG (2016) Underestimated associated features in CMT neuropathies: clinical indicators for the causative gene? Brain Behav 6(4):e00451

    PubMed  PubMed Central  Google Scholar 

  • Wong RH, Farhat HI (2013) Charcot-Marie-tooth and trigeminal neuralgia. Clin Neurol Neurosurg 115(10):2234–2235

    PubMed  Google Scholar 

  • Zhan Y, Zi X, Hu Z, Peng Y, Wu L, Li X, Jiang M, Liu L, Xie Y, Xia K, Tang B, Zhang R (2015) PMP22-Related neuropathies and other clinical manifestations in Chinese Han patients with Charcot-Marie-Tooth disease type 1. Muscle Nerve 52(1):69–75

    CAS  PubMed  Google Scholar 

Download references

Sources of Funding

The study is a part of a larger study funded by a grant from the Indian Council of Medical Research (BMS/TF/Trans-Neuro/2014-3389/July-15/16/KA/Govt dated 25th July 2016).

Author information

Authors and Affiliations

  1. Department of Neurology, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, 560029, India

    Madhu Nagappa, Shivani Sharma, Ramesh Siram, Akhilesh Shroti, Sanjib Sinha, Parayil S. Bindu & Arun B. Taly

  2. Neuromuscular Laboratory, Neurobiology Research Centre, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, 560029, India

    Madhu Nagappa, Shivani Sharma, Periyasamy Govindaraj, Yasha T. Chickabasaviah, Parayil S. Bindu & Arun B. Taly

  3. Department of Neuropathology, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, 560029, India

    Shivani Sharma, Periyasamy Govindaraj & Yasha T. Chickabasaviah

  4. Department of Human Genetics, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, 560029, India

    Monojit Debnath

Authors
  1. Madhu Nagappa
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Shivani Sharma
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Periyasamy Govindaraj
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yasha T. Chickabasaviah
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ramesh Siram
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Akhilesh Shroti
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Monojit Debnath
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Sanjib Sinha
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Parayil S. Bindu
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Arun B. Taly
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Madhu Nagappa.

Ethics declarations

The study was approved by the Institute Ethics Committee (NIMHANS/DO/103RDIEC/2016).

Conflict of Interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic Supplementary Material

ESM 1

(DOCX 30 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Nagappa, M., Sharma, S., Govindaraj, P. et al. PMP22 Gene–Associated Neuropathies: Phenotypic Spectrum in a Cohort from India. J Mol Neurosci 70, 778–789 (2020). https://doi.org/10.1007/s12031-020-01488-w

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12031-020-01488-w

Keywords

Search

Navigation