Frontiers in neurology
Par Europa T, Zimba S, Floudiotis N et 15 autres.
Contenu en anglais
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.
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We report the genetic profiles of individuals with hereditary neuropathies enrolled at two centers in Cape Town, South Africa, and Lusaka, Zambia.
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).
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.
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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