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Case Reports
. 2022 Jan 7;22(1):17.
doi: 10.1186/s12883-021-02538-5.

Coexistence of Charcot-Marie-Tooth 1A and nondystrophic myotonia due to PMP22 duplication and SCN4A pathogenic variants: a case report

Haitian Nan #  1 , Yunqing Wu #  2 , Shilei Cui  2 , Houliang Sun  2 , Jiawei Wang  2 , Ying Li  3 , Lingchao Meng  3 , Takamura Nagasaka  4 , Liyong Wu  5
Affiliations
Case Reports

Coexistence of Charcot-Marie-Tooth 1A and nondystrophic myotonia due to PMP22 duplication and SCN4A pathogenic variants: a case report

Haitian Nan et al. BMC Neurol. .

Abstract

Background: Charcot-Marie-Tooth disease (CMT) is a genetically heterogeneous hereditary neuropathy, and CMT1A is the most common form; it is caused by a duplication of the peripheral myelin protein 22 (PMP22) gene. Mutations in the transient sodium channel Nav1.4 alpha subunit (SCN4A) gene underlie a diverse group of dominantly inherited nondystrophic myotonias that run the spectrum from subclinical myopathy to severe muscle stiffness, disabling weakness, or frank episodes of paralysis.

Case presentation: We describe a Chinese family affected by both CMT1A and myotonia with concomitant alterations in both the PMP22 and SCN4A genes. In this family, the affected proband inherited the disease from his father in an autosomal dominant manner. Genetic analysis confirmed duplication of the PMP22 gene and a missense c.3917G > C (p. Gly1306Ala) mutation in SCN4A in both the proband and his father. The clinical phenotype in the proband showed the combined involvement of skeletal muscle and peripheral nerves. Electromyography showed myopathic changes, including myotonic discharges. MRI revealed the concurrence of neurogenic and myogenic changes in the lower leg muscles. Sural nerve biopsies revealed a chronic demyelinating and remyelinating process with onion bulb formations in the proband. The proband's father presented with confirmed subclinical myopathy, very mild distal atrophy and proximal hypertrophy of the lower leg muscles, pes cavus, and areflexia.

Conclusion: This study reports the coexistence of PMP22 duplication and SCN4A mutation. The presenting features in this family suggested that both neuropathy and myopathy were inherited in an autosomal dominant manner. The proband had a typical phenotype of sodium channel myotonia (SCM) and CMT1A. However, his father with the same mutations presented a much milder clinical phenotype. Our study might expand the genetic and phenotypic spectra of neuromuscular disorders with concomitant mutations.

Keywords: Case report; Charcot-Marie-Tooth disease; Nondystrophic myotonia; PMP22; SCN4A.

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Conflict of interest statement

The authors declare that they have no conflict of interest.

Figures

Fig. 1
Fig. 1
A Pedigree of the present family. The proband is indicated (arrow). Individuals evaluated both clinically and genetically in this study are denoted by asterisks. B Serial photographs of the proband taken at age 29. The proband presented hand deformities characterized by curvature of the fingers. There was mild atrophy of the distal muscles of the hands, particularly of the thenar eminence. C Appearance of the legs of the proband. There was mild quadriceps wasting and simultaneous mild calf hypertrophy. D Fat-saturated MRI of the lower legs in the coronal plane and T2-weighted image in the axial plane of the lower third of the calves of the proband. High-intensity regions manifesting as neurogenic changes can be easily observed in the bilateral triceps surae muscles, with proximal dominant hypertrophy in the coronal plane (white arrowhead). There was moderate fatty atrophy involving bilateral tibialis anterior muscles in the axial plane (blue arrowhead), which predominated on the right side. Conversely, there was very slight hypertrophy in the posterior compartment muscles (yellow arrowhead), including the soleus, gastrocnemius, and tibialis posterior. R and L indicate right and left. E Electrophysiologic findings in the proband recorded from the left extensor digitorum communis. The insertion activity of needle electromyography at rest shows myotonic discharges (timebase set to 40 ms/division). F Appearance of the legs of the proband’s father at age 57. Pes cavus is pronounced. Mild proximal hypertrophy and distal atrophy of bilateral lower leg muscles were observed
Fig. 2
Fig. 2
A Sanger sequencing revealed that the c.3917G > C mutation in SCN4A was heterozygous in the proband. B The results of MLPA study in the proband. A heterozygous 1.5-Mb duplication in 17p11.2-p12, including the coding regions of the COX10, PMP22, and TEKT3 genes, was found. Data were analyzed by Coffalyser software. The cutoff value for duplication was > 1.2. C Sanger sequencing revealed that the c.3917G > C mutation in SCN4A was heterozygous in the proband’s father. D The results of MLPA study in the proband’s father. A heterozygous 1.5-Mb duplication in 17p11.2-p12, including the coding regions of the COX10, PMP22, and TEKT3 genes, was found. E The c.3917G > C mutation in SCN4A was not detected in the proband’s mother. F The results of MLPA study in the proband’s mother. No duplication in the coding regions of the COX10, PMP22, or TEKT3 genes was found. G The sural nerve biopsy of the proband was examined by light microscopy. Toluidine blue staining revealed severe loss of myelinated fibers and regenerating clusters of myelinated fibers, with frequent onion bulb formations
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References

    1. Lupski JR, de Oca-Luna RM, Slaugenhaupt S, Pentao L, Guzzetta V, Trask BJ, et al. DNA duplication associated with Charcot-Marie-tooth disease type 1A. Cell. 1991;66(2):219–232. doi: 10.1016/0092-8674(91)90613-4. - DOI - PubMed
    1. Matthews E, Fialho D, Tan SV, Venance SL, Cannon SC, Sternberg D, et al. The non-dystrophic myotonias: molecular pathogenesis, diagnosis and treatment. Brain. 2010;133(Pt 1):9–22. doi: 10.1093/brain/awp294. - DOI - PMC - PubMed
    1. Heatwole CR, Moxley RT., 3rd The nondystrophic myotonias. Neurotherapeutics. 2007;4(2):238–251. doi: 10.1016/j.nurt.2007.01.012. - DOI - PubMed
    1. Horga A, Raja Rayan DL, Matthews E, Sud R, Fialho D, Durran SC, et al. Prevalence study of genetically defined skeletal muscle channelopathies in England. Neurology. 2013;80(16):1472–1475. doi: 10.1212/WNL.0b013e31828cf8d0. - DOI - PMC - PubMed
    1. van Paassen BW, van der Kooi AJ, van Spaendonck-Zwarts KY, Verhamme C, Baas F, de Visser M. PMP22 related neuropathies: Charcot-Marie-tooth disease type 1A and hereditary neuropathy with liability to pressure palsies. Orphanet J Rare Dis. 2014;9:38. doi: 10.1186/1750-1172-9-38. - DOI - PMC - PubMed

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