A genetic profile of hereditary neuropathies in two Southern African cohorts
11 affiliations
- 1UCT Neuroscience Institute, University of Cape Town
- 2Neurology Research Group, Department of Medicine, University of Cape Town
- 3Department of Internal Medicine, University of Zambia School of Medicine
- 4Department of Paediatrics and Child Health, School of Medicine and Health Sciences, University of Lusaka
- 5Department of Neurology, University of Rochester Medical Center
- 6Department of Physiotherapy, University of Zambia School of Health Sciences
- 7Department of Clinical Neurosciences, University of Cambridge
- 8Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, University College London
- 9Department of Genomic Medicine, University of Cambridge
- 10Clinical Omics and Informatics (COIN) Unit, UCT Neuroscience Institute, University of Cape Town
- 11African Bioinformatics Institute
Abstract
Introduction: Data on hereditary neuropathies in African populations are sparse. In sub-Saharan Africa, genetic testing for Charcot–Marie–Tooth (CMT)-related neuropathies has been largely limited to PMP22 screening for demyelinating CMT.
Aim: We report the genetic profiles of individuals with hereditary neuropathies enrolled at two centers in Cape Town, South Africa, and Lusaka, Zambia.
Methods: Between 2019 and 2024, consecutive patients with suspected CMT were enrolled in the International Centre for Genomic Medicine in Neuromuscular Diseases (ICGNMD) consortium. The Cape Town center also enrolled patients locally between 2017 and 2019. Electrophysiological testing categorized participants into demyelinating CMT (CMT1; median motor nerve conduction velocity (CV) ≤ 25 m/s), axonal CMT (CMT2; >45 m/s), or intermediate CMT (CMTi; >25; ≤45 m/s). PMP22 assays were performed in probands with CMT1/CMTi, while RFC1 assays were performed in adults with sensory ataxic neuropathy (SAN). All other participants underwent whole exome sequencing (WES) or whole genome sequencing (WGS).
Results: The 68 probands had a median age at symptom onset of 13 years (interquartile range 6;26). In total, 32 (47%) had CMT2, seven (10%) had CMT1, seven (10%) had CMTi, and the remaining (32%) had sensory, sensory ataxic, motor, or complex neuropathies. Genetic diagnoses were determined in 54% of probands. All five individuals with CMT1 and PMP22 duplications had European ancestry, except for one individual with admixed ancestry. CMT2 was most frequently caused by heterozygous pathogenic or likely pathogenic variants in MFN2 (22%). Compound heterozygous MPV17 variants (p.Gln36Ter; p.Arg125Trp) were found in four probands of African ancestry with CMT2 or CMTi. Single cases categorized as CMT2 had single variants in 13 different genes. Furthermore, one individual with late-onset CMTi had an MPZ variant. In total, four “complex” neuropathies had variants in PEX11B, SERAC1, TDP1, and ATM . Homozygous TDP1 p.His493Arg variants were shared between two unrelated probands of African ancestry with complex sensory ataxic neuropathy. One family of European ancestry had pseudodominant homozygous RFC1 expansions.
Conclusion: The genetic profile of CMT in Southern Africa differs from that reported elsewhere. MFN2- assocaited CMT2 was the most common subtype. CMT1 was absent in individuals of African ancestry. MPV17 -associated neuropathy was found in CMT2/CMTi cases from South Africa.
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BibTeX
@article{europa2026genetic,
title = {{A genetic profile of hereditary neuropathies in two Southern African cohorts}},
author = {Tarin Europa and Stanley Zimba and Niki Floudiotis and Somwe Wa Somwe and David Bearden and Musambo Kapapa and Rita Horvath and Lindsay Wilson and Natalia Dominik and Michael Hanna and Mary M. Reilly and Christopher J. Record and Katherine Schon and Saifeldeen M. Elshahawy and Nabeelah Peerbhai and Jeannine M. Heckmann and Michelle Kvalsund and Melissa Nel},
journal = {Frontiers in Neurology},
year = {2026},
month = oct,
doi = {10.3389/fneur.2026.1918540},
url = {https://www.frontiersin.org/articles/10.3389/fneur.2026.1918540/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - A genetic profile of hereditary neuropathies in two Southern African cohorts
AU - Tarin Europa
AU - Stanley Zimba
AU - Niki Floudiotis
AU - Somwe Wa Somwe
AU - David Bearden
AU - Musambo Kapapa
AU - Rita Horvath
AU - Lindsay Wilson
AU - Natalia Dominik
AU - Michael Hanna
AU - Mary M. Reilly
AU - Christopher J. Record
AU - Katherine Schon
AU - Saifeldeen M. Elshahawy
AU - Nabeelah Peerbhai
AU - Jeannine M. Heckmann
AU - Michelle Kvalsund
AU - Melissa Nel
PY - 2026
DA - 2026/10/07
JO - Frontiers in Neurology
DO - 10.3389/fneur.2026.1918540
UR - https://www.frontiersin.org/articles/10.3389/fneur.2026.1918540/full
AB - Introduction: Data on hereditary neuropathies in African populations are sparse. In sub-Saharan Africa, genetic testing for Charcot–Marie–Tooth (CMT)-related neuropathies has been largely limited to PMP22 screening for demyelinating CMT. Aim: We report the genetic profiles of individuals with hereditary neuropathies enrolled at two centers in Cape Town, South Africa, and Lusaka, Zambia. Methods: Between 2019 and 2024, consecutive patients with suspected CMT were enrolled in the International Centre for Genomic Medicine in Neuromuscular Diseases (ICGNMD) consortium. The Cape Town center also enrolled patients locally between 2017 and 2019. Electrophysiological testing categorized participants into demyelinating CMT (CMT1; median motor nerve conduction velocity (CV) ≤ 25 m/s), axonal CMT (CMT2; >45 m/s), or intermediate CMT (CMTi; >25; ≤45 m/s). PMP22 assays were performed in probands with CMT1/CMTi, while RFC1 assays were performed in adults with sensory ataxic neuropathy (SAN). All other participants underwent whole exome sequencing (WES) or whole genome sequencing (WGS). Results: The 68 probands had a median age at symptom onset of 13 years (interquartile range 6;26). In total, 32 (47%) had CMT2, seven (10%) had CMT1, seven (10%) had CMTi, and the remaining (32%) had sensory, sensory ataxic, motor, or complex neuropathies. Genetic diagnoses were determined in 54% of probands. All five individuals with CMT1 and PMP22 duplications had European ancestry, except for one individual with admixed ancestry. CMT2 was most frequently caused by heterozygous pathogenic or likely pathogenic variants in MFN2 (22%). Compound heterozygous MPV17 variants (p.Gln36Ter; p.Arg125Trp) were found in four probands of African ancestry with CMT2 or CMTi. Single cases categorized as CMT2 had single variants in 13 different genes. Furthermore, one individual with late-onset CMTi had an MPZ variant. In total, four “complex” neuropathies had variants in PEX11B, SERAC1, TDP1, and ATM . Homozygous TDP1 p.His493Arg variants were shared between two unrelated probands of African ancestry with complex sensory ataxic neuropathy. One family of European ancestry had pseudodominant homozygous RFC1 expansions. Conclusion: The genetic profile of CMT in Southern Africa differs from that reported elsewhere. MFN2- assocaited CMT2 was the most common subtype. CMT1 was absent in individuals of African ancestry. MPV17 -associated neuropathy was found in CMT2/CMTi cases from South Africa.
SN - 1664-2295
ER -