Related Experiment Video
Updated: Jul 15, 2025
Modeling Charcot-Marie-Tooth Disease In Vitro by Transfecting Mouse Primary Motoneurons
Published on: January 7, 2019
Mutational screening of Greek patients with axonal Charcot-Marie-Tooth disease using targeted next-generation
Zoi Kontogeorgiou1, Chrisoula Kartanou1, Michail Rentzos2
1Neurogenetics Unit, 1st Department of Neurology, Eginition Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece.
Background And Aims:
Axonal forms of Charcot-Marie-Tooth disease (CMT) are classified as CMT2, distal hereditary motor neuropathy (dHMN) or hereditary sensory neuropathy (HSN) and can be caused by mutations in over 100 genes. We presently aimed to investigate for the first time the genetic landscape of axonal CMT in the Greek population.
Methods:
Sixty index patients with CMT2, dHMN or HSN were screened by a combination of Sanger sequencing (GJB1) and next-generation sequencing custom-made gene panel covering 24 commonly mutated genes in axonal CMT.
Results:
Overall, 20 variants classified as pathogenic or likely pathogenic were identified in heterozygous state in 20 index cases, representing 33.3% of the cohort. Of these, 14 were known pathogenic/likely pathogenic and six were designated as such according to ACMG classification, after in silico evaluation, testing for familial segregation and further literature review. The most frequently involved genes were GJB1 (11.7%), MPZ (5%) and MFN2 (5%), followed by DNM2 (3.3%) and LRSAM1 (3.3%). Single cases were identified with mutations in BSCL2, HSPB1 and GDAP1.
Interpretation:
A wide phenotypic variability in terms of severity and age of onset was noted. Given the limited number of genes tested, the diagnostic yield of the present panel compares favourably with studies in other European populations. Our study delineates the genetic and phenotypic variability of inherited axonal neuropathies in the Greek population and contributes to the pathogenicity characterization of further variants linked to axonal neuropathies.
Insights
Genetic analysis of Greek patients revealed mutations in 33.3% of cases with axonal Charcot-Marie-Tooth disease (CMT). GJB1, MPZ, and MFN2 were the most frequently implicated genes in this inherited neuropathy study.
Area of Science:
- Genetics
- Neurology
- Molecular Biology
Background:
- Axonal Charcot-Marie-Tooth disease (CMT), including CMT2, distal hereditary motor neuropathy (dHMN), and hereditary sensory neuropathy (HSN), is genetically heterogeneous, with over 100 implicated genes.
- Understanding the genetic basis of these inherited neuropathies is crucial for diagnosis and potential therapeutic strategies.
Observation:
- A cohort of sixty Greek index patients with axonal CMT (CMT2, dHMN, HSN) underwent genetic screening using Sanger sequencing and a next-generation sequencing gene panel.
- This comprehensive approach targeted 24 commonly mutated genes associated with axonal CMT.
Findings:
- Pathogenic or likely pathogenic variants were identified in 33.3% of the index cases (20 out of 60).
- The most frequently mutated genes were GJB1 (11.7%), MPZ (5%), and MFN2 (5%), with additional mutations found in DNM2, LRSAM1, BSCL2, HSPB1, and GDAP1.
- Six novel variants were characterized according to ACMG classification, contributing to the understanding of genotype-phenotype correlations.
Implications:
- This study provides the first comprehensive genetic landscape of axonal CMT in the Greek population.
- The findings highlight significant genetic and phenotypic variability, aiding in the diagnosis and characterization of inherited axonal neuropathies.
- The diagnostic yield of the employed gene panel is comparable to other European studies, suggesting its utility in clinical settings.
