Screening for PRX mutations in a large Chinese Charcot-Marie-Tooth disease cohort and literature review

Front Neurol. 2023 Jul 4:14:1148044. doi: 10.3389/fneur.2023.1148044. eCollection 2023.

Abstract

Background: Periaxins (encoded by PRX) play an important role in the stabilization of peripheral nerve myelin. Mutations in PRX can lead to Charcot-Marie-Tooth disease type 4F (CMT4F).

Methods: In this study, we screened for PRX mutations using next-generation sequencing and whole-exome sequencing in a large Chinese CMT cohort consisting of 465 unrelated index patients and 650 healthy controls. Sanger sequencing was used for the validation of all identified variants. We also reviewed all previously reported PRX-related CMT cases and summarized the clinical manifestations and genetic features of PRX-related CMTs.

Results: The hit rate for biallelic PRX variants in our cohort of Chinese CMT patients was 0.43% (2/465). One patient carried a previously unreported splice-site mutation (c.25_27 + 9del) compound heterozygous with a known nonsense variant. Compiling data on CMT4F cases and PRX variants from the medical literature confirmed that early-onset (95.2%), distal amyotrophy or weakness (94.0%), feet deformity (75.0%), sensory impairment or sensory ataxia (65.5%), delayed motor milestones (60.7%), and spinal deformity (59.5%) are typical features for CMT4F. Less frequent features were auditory impairments, respiratory symptoms, late onset, dysarthria or hoarseness, ophthalmic problems, and central nervous system involvement. The two cases with biallelic missense mutations have later onset age than those with nonsense or frameshift mutations. We did not note clear correlations between the type and site of mutations and clinical severity or distinct constellations of symptoms.

Conclusion: Consistent with observations in other countries and ethnic groups, PRX-related CMT is rare in China. The clinical spectrum is wider than previously anticipated.

Keywords: Charcot-Marie-Tooth disease; mutation; next-generation sequencing; periaxin; whole-exome sequencing.

Grants and funding

This study was funded by the National Natural Science Foundation of China (81873784 and 82071426), Clinical Cohort Construction Program of Peking University Third Hospital, Grant/Award Number: BYSYDL2019002 and BYSYDL2021007, and Clinical Medicine Plus X-Youth Scholars Project, Peking University, the Fundamental Research Funds for the Central Universities (PKU2021LCXQ019).