Course of Atypical Manifestations of a Case of Charcot-Marie-Tooth Disease over 35 Years of Clinical Observation


Introduction: Atypical manifestations of peripheral neuropathy are not rare, challenging the differential diagnosis. In the past, the diagnosis of hereditary neuropathy was mainly based on the clinical and electromyographic (EMG) findings and, occasionally, biopsy. Nowadays, the genetic tests allow us to identify more than 40 different genes/loci associated with Charcot-Marie-Tooth (CMT) disease, although some subtypes are clinically indistinguishable. We have followed a patient with a clinical diagnosis of apparent sporadic and atypical CMT and recently diagnosed genetically as distal hereditary motor neuropathy, type V (dHMN-V). Case Report: Thirty-five years ago, a 16 years old patient complained muscular weakness and wasting at the hands small muscles. Sporadic fasciculations were observed whereas deep tendon reflexes and sensation were normal. EMG examination revealed neurogenic muscular denervation in the distribution of C7, C8 and T1 segments bilaterally. Muscular biopsy of the left Biceps Brachii showed rare atrophic fibers and some cellular atypia. The disease has undergone a clinical and EMG progression and diffusion over the years, involving the lower limbs and leading to a bilateral steppage. A more slight diffuse axonal motor neuropathy was also identified in the proband’s son and second cousin. The genetic study found a known missense mutation in BSCL2 gene related to a dHMN-V. Interestingly, there was a remarkable intra-familiar phenotypic variability, especially in the clinical onset and severity. Discussion: Atypical manifestations of hereditary neuropathies often overlap with other conditions. The present case highlights how a comprehensive clinical evaluation and a careful follow-up have led to a correct diagnosis even 35 years later and have allowed to identify other affected family members. The apparent lack of familiarity was probably due to the very soft presentation in the proband’s relatives. Although the genetic study was not available at that time, the first clinical diagnosis was not disavowed. The main differential diagnoses and a brief review of similar reported cases are discussed.

Share and Cite:

G. Lanza, L. Vinciguerra, V. Puglisi, D. Modica, A. Catalano, G. Zelante, R. Ricceri, L. Lupo, S. Giuffrida and M. Pennisi, "Course of Atypical Manifestations of a Case of Charcot-Marie-Tooth Disease over 35 Years of Clinical Observation," Neuroscience and Medicine, Vol. 4 No. 3, 2013, pp. 145-149. doi: 10.4236/nm.2013.43023.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] J. Irobi, P. De Jonghe and V. Timmerman, “Molecular Genetics of Distal Hereditary Motor Neuropathies,” Human Molecular Genetics, Vol. 13, No. 2, 2004, pp. R195-R202.
[2] C. Windpassinger, M. Auer-Grumbach, J. Irobi, H. Patel, E. Petek, G. Horl, et al., “Heterozygous Missense Mutations in BSCL2 Are Associated with Distal Hereditary Motor Neuropathy and Silver Syndrome,” Nature Genetics, Vol. 36, No. 3, 2004, pp. 271-276. doi:10.1038/ng1313
[3] D. Ito and N. Suzuki, “Seipinopathy: A Novel Endoplasmic Reticulum Stress-Associated Disease,” Brain, Vol. 132, 2009, pp. 8-15.
[4] M. Bonduelle, “Aran-Duchenne? Duchenne-Aran? The Quarrel around Progressive Muscular Atrophy,” Revue Neurologique Société de Neurologie de Paris, Vol. 146, No. 2, 1990, pp. 97-106.
[5] J. Magrè, M. Delépine, E. Khallout, T. Gedde-Dahl, L. Van Maldergem, E. Sobel, et al., “Identification of the Gene Altered in Berardinelli-Seip Congenital Lipodystrophy on Chromosome 11q13,” Nature Genetics, Vol. 28, No. 4, 2001, pp. 365-370. doi:10.1038/ng585
[6] K. Sivakumar, T. Kyriakides, I. Puls, G. A. Nicholson, B. Funalot, A. Antonellis, et al., “Phenotypic Spectrum of Disorders Associated with Glycyl-tRNA Synthetase Mutations,” Brain, Vol. 128, No. 10, 2005, pp. 2304-2314. doi:10.1093/brain/awh590
[7] V. Rakocevic-Stojanovic, V. Milic-Rasic, S. Peric, J. Baets, V. Timmerman, I. Dierick, et al., “N88S Mutation in the BSCL2 Gene in a Serbian Family with Distal Hereditary Motor Neuropathy Type V or Silver Syndrome,” Journal of the Neurological Sciences, Vol. 296, No. 1-2, 2010, pp. 107-109. doi:10.1016/j.jns.2010.06.015
[8] B. P. van de Warrenburg, H. Scheffer, J. J. van Eijk, M. H. Versteeg, H. Kremer, M. J. Zwarts, et al., “BSCL2 Mutations in Two Dutch Families with Overlapping Silver Syndrome-Distal Hereditary Motor Neuropathy,” Neuromuscular Disorders, Vol. 16, No. 2, 2006, pp. 122-125. doi:10.1016/j.nmd.2005.11.003
[9] M. Auer-Grumbach, B. Schlotter-Weigel, H. Lochmüller, G. Strobl-Wildemann, P. Auer-Grumbach, R. Fischer, et al., “Phenotypes of the N88S Berardinelli-Seip Congenital Lipodystrophy 2 Mutation,” Annals of Neurology, Vol. 57, No. 3, 2005, pp. 415-424. doi:10.1002/ana.20410
[10] B. Chen, R. Zheng, X. Luan, W. Zhang, Z. Wang and Y. Yuan, “Clinical and Pathological Study of Distal Motor Neuropathy with N88S Mutation in BSCL2,” Neuropathology, Vol. 29, No. 5, 2009, pp. 543-547. doi:10.1111/j.1440-1789.2009.01011.x
[11] B. Rohkamm, M. M. Reilly, H. Lochmüller, B. Schlotter-Weigel, N. Barisic, L. Schols L, et al., “Further Evidence for Genetic Heterogeneity of Distal HMN Type V, CMT2 with Predominant Hand Involvement and Silver Syndrome,” Neurological Sciences, Vol. 263, No. 1-2, 2007, pp. 100-106. doi:10.1016/j.jns.2007.06.047

Copyright © 2023 by authors and Scientific Research Publishing Inc.

Creative Commons License

This work and the related PDF file are licensed under a Creative Commons Attribution 4.0 International License.