Abstract
Charcot-Marie-Tooth disease type 1E (CMT1E) is a demyelinating motor and sensory neuropathy with peripheral myelin protein 22 (PMP22) point mutations. The objective of this study was to identify genetic causes and determine genotype–phenotype correlation in two Korean demyelinating CMT patients based on whole exome sequencing (WES), histological examination of distal sural nerve, and magnetic resonance imaging (MRI) of leg. WES revealed two de novo PMP22 mutations in the two demyelinating CMT patients, including one novel p.Leu82Pro (c.245T>A) mutation in one patient and one previously reported p.Ser72Leu (c.215C>T) mutation in the other patient. Both mutation sites were located in the well conserved second transmembrane domain. No control had the same mutations. The affected individual with the novel p.Leu82Pro mutation showed early onset, scoliosis, and sensory ataxia with ability to walk without assistance. Histopathological examination showed severe damage of myelin and axons. No compound muscle action potentials (CMAPs) were evoked in the upper or lower limb nerves. Leg MRIs revealed mild fatty infiltration of the bilateral peronei muscles consistent with clinical manifestations. The patient with the p.Ser72Leu mutation showed developmental delay in infancy. No CMAPs were elicited. However, she was also able to walk without assistance. In spite of markedly severe electrophysiological defects, leg MRIs showed almost normal findings except slight muscle atrophies of the lower legs. Both patients presented similar clinical features including no CMAPs in electrophysiological tests and mild fatty replacement in the lower leg MRI. Therefore, there was a good genotype–phenotype correlation in both cases.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Birouk N, LeGuern E, Maisonobe T, Rouger H, Gouider R, Tardieu S et al (1998) X-linked Charcot-Marie-Tooth disease with connexin 32 mutations: clinical and electrophysilogic study. Neurology 50:1074–1082
Chance PF, Alderson MK, Leppig KA, Lensch MW, Matsunami N, Smith B et al (1993) DNA deletion associated with hereditary neuropathy with liability to pressure palsies. Cell 72:143–151
Choi BO, Koo SK, Park MH, Rhee HS, Yang SJ, Choi KG et al (2012) Exome sequencing is an efficient tool for genetic screening of Charcot-Marie-Tooth disease. Hum Mutat 33:1610–1615
Chow CY, Zhang Y, Dowling JJ, Jin N, Adamska M, Shiga K et al (2007) Mutation of FIG4 causes neurodegeneration in the pale tremor mouse and patients with CMT4J. Nature 448:68–72
Chung KW, Suh BC, Shy ME, Cho SY, Yoo JH, Park SW et al (2008) Different clinical and magnetic resonance imaging features between Charcot-Marie-Tooth disease type 1A and 2A. Neuromuscul Disord 18:610–618
Fabrizi GM, Simonati A, Taioli F, Cavallaro T, Ferrarini M, Rigatelli F et al (2001) PMP22 related congenital hypomyelination neuropathy. J Neurol Neurosurg Psychiatry 70:123–126
Fridman V, Bundy B, Reilly MM, Pareyson D, Bacon C, Burns J et al (2015) CMT subtypes and disease burden in patients enrolled in the Inherited Neuropathies Consortium natural history study: a cross-sectional analysis. J Neurol Neurosurg Psychiatry 86:873–878
Gallardo E, Garcia 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
Harding AE, Thomas PK (1980) The clinical features of hereditary motor and sensory neuropathy types I and II. Brain 103:259–280
Ionasescu VV, Searby C, Greenberg SA (1996) Dejerine-Sottas disease with sensorineural hearing loss, nystagmus, and peripheral facial nerve weakness: de novo dominant point mutation of the PMP22 gene. J Med Genet 33:1048–1049
Kleopa KA, Georgiou D-M, Nicolaou P, Koutsou P, Papathanasiou E, Kyriakides T et al (2004) A novel PMP22 mutation ser22phe in a family with hereditary neuropathy with liability to pressure palsies and CMT1A phenotypes. Neurogenetics 5:171–175
Li J, Parker B, Martyn C, Natarajan C, Guo J (2013) The PMP22 gene and its related diseases. Mol Neurobiol 47:673–698
Lupski JR, Montes de Oca-Luna R, Slaugenhaupt S, Pentao L, Guzzetta V, Trask BJ et al (1991) DNA duplication associated with Charcot-Marie-Tooth disease type 1A. Cell 66:219–232
Marques W Jr, Pina Neto JM, Barreira AA (2004) Dejerine-Sottas’ neuropathy caused by the missense mutation PMP22 Ser72Leu. Acta Neurol Scand 110:196–199
Marques W Jr, Thomas PK, Sweeney MG, Carr L, Wood NW (1998) Dejerine-Sottas neuropathy and PMP22 point mutations: a new base pair substitution and a possible “Hot spot” on Ser72. Ann Neurol 43:680–683
Montenegro G, Powell E, Huang J, Speziani F, Edwards YJ, Beecham G et al (2011) Exome sequencing allows for rapid gene identification in a Charcot-Marie-Tooth family. Ann Neurol 69:464–470
Nam SH, Hong YB, Hyun YS, Nam DE, Kwak G, Hwang SH et al (2016) Identification of genetic causes of inherited peripheral neuropathies by targeted gene panel sequencing. Mol Cells. doi:10.14348/molcells.2016.2288
Nicholson G, Myers S (2006) Intermediate forms of Charcot-Marie-Tooth neuropathy: a review. Neuromol Med 8:123–130
Paternostro-Sluga T, Grim-Stieger M, Posch M, Schuhfried O, Vacariu G, Mittermaier C et al (2008) Reliability and validity of the Medical Research Council (MRC) scale and a modified scale for testing muscle strength in patients with radial palsy. J Rehabil Med 40:665–671
Planté-Bordeneuve V, Parman Y, Guiochon-Mantel A, Alj Y, Dyemeer F, Serdaroglu P et al (2001) The range of chronic demyelinating neuropathy of infancy: a clinico-pathological and genetic study of 15 unrelated cases. J Neurol 248:795–803
Reilly MM (2007) Sorting out the inherited neuropathies. Pract Neurol 7:93–105
Roa BB, Dyck PJ, Marks HG, Chance PF, Lupski JR (1993) Dejerine-Sottas syndrome associated with point mutation in the peripheral myelin protein 22 (PMP22) gene. Nat Genet 5:269–273
Rossor AM, Polke JM, Houlden H, Reilly MM (2013) Clinical implications of genetic advances in Charcot-Marie-Tooth disease. Nat Rev Neurol 9:562–571
Russo M, Laurá M, Polke JM, Davis MB, Blake J, Brandner S et al (2011) Variable phenotypes are associated with PMP22 missense mutations. Neuromuscul Disord 21:106–114
Shy ME, Blake J, Krajewski K, Fuerst DR, Laura M, Hahn AF et al (2005) Reliability and validity of the CMT neuropathy score as a measure of disability. Neurology 64:1209–1214
Simonati A, Fabrizi GM, Pasquinelli A, Taioli F, Cavallaro T, Morbin M et al (1999) Congenital hypomyelination neuropathy with Ser72Leu substitution in PMP22. Neuromuscul Disord 9:257–261
Valentijn LJ, Baas F, Wolterman RA, Hoogendijk JE, van den Bosch NH, Zorn I et al (1992) Identical point mutations of PMP-22 in Trembler-J mouse and Charcot-Marie-Tooth disease type 1A. Nat Genet 2:288–291
Vital A, Sole G, Casenave P, Magdelaine C, Ferrer X, Vital C et al (2013) Severe Charcot-Marie-Tooth disease type 1E caused by a novel p.Phe84Leufs*24 PMP22 point mutation. J Peripher Nerv Syst 18:181–184
Acknowledgments
The authors would like to thank the patients and their families for their essential help with this work. This study was supported by Grants (HI12C0135 and HI14C3484) of Korean Health Technology R&D Project funded by the Ministry of Health & Welfare, and Grants (NRF-2014R1A2A2A01004240 and NRF-2014R1A2A2A01003164) of the National Research Foundation of Korea (NRF) funded by the Korean government, Republic of Korea.
Author information
Authors and Affiliations
Corresponding authors
Ethics declarations
Conflict of interest
All authors declare that they have no conflict of interest.
Informed consent
Written informed consent was obtained from all participants or parents of those younger than 18 years of age according to the protocol approved by the Institutional Review Board for Sungkyunkwan University, Samsung Medical Center (SMC 2013-10-066).
Rights and permissions
About this article
Cite this article
Kim, J.Y., Koo, H., Park, KD. et al. Genotype–phenotype correlation of Charcot-Marie-Tooth type 1E patients with PMP22 mutations. Genes Genom 38, 659–667 (2016). https://doi.org/10.1007/s13258-016-0423-5
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s13258-016-0423-5