Genetic and clinical spectrum of early growth response 2-related Charcot-Marie-Tooth disease in a Brazilian cohort

Abstract

Background Charcot-Marie-Tooth (CMT) disease is a genetically diverse group of hereditary neuropathies. Most studies on the frequency of CMT subtypes report that the early growth response 2 (EGR2) gene accounts for less than 1% of cases. However, data regarding the epidemiology and clinical characteristics of EGR2-related CMT in Central and South America remain limited.

Objective To characterize the clinical and genetic features of EGR2-related CMT in a Brazilian cohort.

Methods We retrospectively analyzed clinical and ancillary data from four individuals with confirmed molecular diagnosis of EGR2-related CMT. Patients were categorized based on age of onset, motor nerve conduction velocity of the ulnar nerve, and nerve biopsy findings when available. Next-generation sequencing was utilized for genetic analysis.

Results Pathogenic and likely pathogenic variants were identified exclusively in the three zinc-finger domains of EGR2, including a novel variant, c.1234G > C (p.Glu412Gln). Patients exhibited significant variation in clinical severity and phenotypes. Dysphagia, respiratory complications, and scoliosis were prominent features.

Conclusion Our findings corroborate the complex and varied clinical presentations of EGR2-related CMT, highlighting respiratory issues and dysphagia as significant features. Comprehensive clinical assessment and early genetic diagnosis are essential for managing this condition's diverse phenotypic spectrum.

Keywords

Hereditary Sensory and Motor Neuropathy - Charcot-Marie-Tooth Disease - Early Growth Response Protein 2

Authors' Contributions

EBUC: conceptualization, data curation, formal analysis, investigation, methodology, project administration, and writing – original draft; SCLS: conceptualization, data curation, investigation, and writing – review & editing; OJMN: conceptualization, formal analysis, investigation, methodology, and writing – original draft; CMC and GVR: data curation; and MCDNBF: data curation, investigation, and writing – review & editing.

Data Availability Statement

The data supporting the present study's findings are available upon reasonable request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.

Editor-in-Chief: Hélio A. G. Teive.

Associate Editor: Francisco de Assis Aquino Gondim.

Publication History

Received: 04 October 2024

Accepted: 05 January 2025

Article published online:
22 April 2025

• References

• 1 Foley C, Schofield I, Eglon G, Bailey G, Chinnery PF, Horvath R. Charcot-Marie-Tooth disease in Northern England. J Neurol Neurosurg Psychiatry 2012; 83 (05) 572-573
• 2 Kurihara S, Adachi Y, Wada K, Awaki E, Harada H, Nakashima K. An epidemiological genetic study of Charcot-Marie-Tooth disease in Western Japan. Neuroepidemiology 2002; 21 (05) 246-250
• 3 Morocutti C, Colazza GB, Soldati G. et al. Charcot-Marie-Tooth disease in Molise, a central-southern region of Italy: an epidemiological study. Neuroepidemiology 2002; 21 (05) 241-245
• 4 Braathen GJ, Sand JC, Lobato A, Høyer H, Russell MB. Genetic epidemiology of Charcot-Marie-Tooth in the general population. Eur J Neurol 2011; 18 (01) 39-48
• 5 Nicolaou P, Zamba-Papanicolaou E, Koutsou P. et al. Charcot-Marie-Tooth disease in Cyprus: epidemiological, clinical and genetic characteristics. Neuroepidemiology 2010; 35 (03) 171-177
• 6 Saporta MA. Charcot-Marie-Tooth disease and other inherited neuropathies. Continuum (Minneap Minn) 2014; 20 (5 Peripheral Nervous System Disorders): 1208-1225
• 7 Echaniz-Laguna A, Cauquil C, Chanson JB. et al. EGR2 gene-linked hereditary neuropathies present with a bimodal age distribution at symptoms onset. J Peripher Nerv Syst 2023; 28 (03) 359-367
• 8 Cortese A, Wilcox JE, Polke JM. et al. Targeted next-generation sequencing panels in the diagnosis of Charcot-Marie-Tooth disease. Neurology 2020; 94 (01) e51-e61
• 9 Rossor AM, Carr AS, Devine H. et al. Peripheral neuropathy in complex inherited diseases: an approach to diagnosis. J Neurol Neurosurg Psychiatry 2017; 88 (10) 846-863
• 10 Montecchiani C, Pedace L, Lo Giudice T. et al. ALS5/SPG11/KIAA1840 mutations cause autosomal recessive axonal Charcot-Marie-Tooth disease. Brain 2016; 139 (Pt 1): 73-85
• 11 Warner LE, Mancias P, Butler IJ. et al. Mutations in the early growth response 2 (EGR2) gene are associated with hereditary myelinopathies. Nat Genet 1998; 18 (04) 382-384
• 12 Warner LE, Svaren J, Milbrandt J, Lupski JR. Functional consequences of mutations in the early growth response 2 gene (EGR2) correlate with severity of human myelinopathies. Hum Mol Genet 1999; 8 (07) 1245-1251
• 13 Nagarajan R, Svaren J, Le N, Araki T, Watson M, Milbrandt J. EGR2 mutations in inherited neuropathies dominant-negatively inhibit myelin gene expression. Neuron 2001; 30 (02) 355-368
• 14 Lupo V, Won S, Frasquet M. et al. Bi-allelic mutations in EGR2 cause autosomal recessive demyelinating neuropathy by disrupting the EGR2-NAB complex. Eur J Neurol 2020; 27 (12) 2662-2667
• 15 Boerkoel CF, Takashima H, Bacino CA, Daentl D, Lupski JR. EGR2 mutation R359W causes a spectrum of Dejerine-Sottas neuropathy. Neurogenetics 2001; 3 (03) 153-157
• 16 Leonardi L, Garibaldi M, Fionda L. et al. Widening the phenotypical spectrum of EGR2-related CMT: Unusual phenotype for R409W mutation. Clin Neurophysiol 2019; 130 (01) 93-94
• 17 Sevilla T, Sivera R, Martínez-Rubio D. et al. The EGR2 gene is involved in axonal Charcot-Marie-Tooth disease. Eur J Neurol 2015; 22 (12) 1548-1555
• 18 Szigeti K, Wiszniewski W, Saifi GM. et al. Functional, histopathologic and natural history study of neuropathy associated with EGR2 mutations. Neurogenetics 2007; 8 (04) 257-262
• 19 Mikesová E, Hühne K, Rautenstrauss B. et al. Novel EGR2 mutation R359Q is associated with CMT type 1 and progressive scoliosis. Neuromuscul Disord 2005; 15 (11) 764-767
• 20 Vandenberghe N, Upadhyaya M, Gatignol A. et al. Frequency of mutations in the early growth response 2 gene associated with peripheral demyelinating neuropathies. J Med Genet 2002; 39 (12) e81
• 21 Uchôa Cavalcanti EB, Santos SCL, Martins CES. et al. Charcot-Marie-Tooth disease: Genetic profile of patients from a large Brazilian neuromuscular reference center. J Peripher Nerv Syst 2021; 26 (03) 290-297
• 22 Murphy SM, Laura M, Fawcett K. et al. Charcot-Marie-Tooth disease: frequency of genetic subtypes and guidelines for genetic testing. J Neurol Neurosurg Psychiatry 2012; 83 (07) 706-710
• 23 Wang R, He J, Li JJ. et al. Clinical and genetic spectra in a series of Chinese patients with Charcot-Marie-Tooth disease. Clin Chim Acta 2015; 451 (Pt B): 263-270
• 24 Yoshimura A, Yuan JH, Hashiguchi A. et al. Genetic profile and onset features of 1005 patients with Charcot-Marie-Tooth disease in Japan. J Neurol Neurosurg Psychiatry 2019; 90 (02) 195-202
• 25 Pareyson D, Taroni F, Botti S. et al. Cranial nerve involvement in CMT disease type 1 due to early growth response 2 gene mutation. Neurology 2000; 54 (08) 1696-1698
• 26 Padilha JPD, Brasil CS, Hoefel AML. et al. Diagnostic yield of targeted sequential and massive panel approaches for inherited neuropathies. Clin Genet 2020; 98 (02) 185-190
• 27 Murphy SM, Herrmann DN, McDermott MP. et al. Reliability of the CMT neuropathy score (second version) in Charcot-Marie-Tooth disease. J Peripher Nerv Syst 2011; 16 (03) 191-198
• 28 Cervato MC. Varstation: a Complete and Efficient Tool to Support NGS Data Analysis. Bioinformatics & Proteomics Open Access Journal. 2021; 5 (01)
• 29 Musso M, Balestra P, Taroni F, Bellone E, Mandich P. Different consequences of EGR2 mutants on the transactivation of human Cx32 promoter. Neurobiol Dis 2003; 12 (01) 89-95
• 30 Fusco C, Spagnoli C, Salerno GG. et al. Charcot-Marie-Tooth disease with pyramidal features due to a new mutation of EGR2 gene. Acta Biomed 2019; 90 (01) 104-107
• 31 Yoshihara T, Kanda F, Yamamoto M. et al. A novel missense mutation in the early growth response 2 gene associated with late-onset Charcot–Marie–Tooth disease type 1. J Neurol Sci 2001; 184 (02) 149-153
• 32 Hsu YH, Lin KP, Guo YC, Tsai YS, Liao YC, Lee YC. Mutation spectrum of Charcot-Marie-Tooth disease among the Han Chinese in Taiwan. Ann Clin Transl Neurol 2019; 6 (06) 1090-1101
• 33 Damm F, Mylonas E, Cosson A. et al. Acquired initiating mutations in early hematopoietic cells of CLL patients. Cancer Discov 2014; 4 (09) 1088-1101
• 34 Chu XJ, Du K, Meng LC. et al. EGR2-related mixed demyelinating and axonal Charcot-Marie-Tooth disease: An electrodiagnostic, nerve imaging, and histological study. Clin Neuropathol 2022; 41 (06) 245-252
• 35 Tozza S, Magri S, Pennisi EM. et al. A novel family with axonal Charcot-Marie-Tooth disease caused by a mutation in the EGR2 gene. J Peripher Nerv Syst 2019; 24 (02) 219-223
• 36 Spiesshoefer J, Henke C, Kabitz HJ. et al. Phrenic nerve involvement and respiratory muscle weakness in patients with Charcot-Marie-Tooth disease 1A. J Peripher Nerv Syst 2019; 24 (03) 283-293
• 37 Benson B, Sulica L, Guss J, Blitzer A. Laryngeal neuropathy of Charcot-Marie-Tooth disease: further observations and novel mutations associated with vocal fold paresis. Laryngoscope 2010; 120 (02) 291-296
• 38 Grosz BR, Golovchenko NB, Ellis M. et al. A de novo EGR2 variant, c.1232A > G p.Asp411Gly, causes severe early-onset Charcot-Marie-Tooth Neuropathy Type 3 (Dejerine-Sottas Neuropathy). Sci Rep 2019; 9 (01) 19336