Persistent toe walking as a prominent feature in pediatric PMP22- Related neuropathies: A retrospective cohort study

Abstract

Purpose Persistent toe walking in children is often considered idiopathic; however, increasing evidence suggests that alterations in the PMP22 gene—implicated in Charcot-Marie-Tooth disease type 1 A (CMT1A) and Hereditary Neuropathy with Liability to Pressure Palsies (HNPP)—may contribute to its pathogenesis. This study investigates the association between PMP22 variants (duplications, deletions, and point mutations) and toe walking in children, aiming to delineate their clinical and genetic characteristics.

Methods A retrospective analysis was performed on 22 pediatric patients (mean age: 7.7 years) with persistent toe walking and confirmed PMP22 variants identified through a 49-gene next-generation sequencing (NGS) panel. In selected cases, Multiplex Ligation-dependent Probe Amplification (MLPA) was applied to confirm copy number variations. Comprehensive clinical evaluations included musculoskeletal, neurological, and developmental assessments.

Results All identified variants demonstrated dominant inheritance. Pathogenic variants were present in 54.5 % of patients, likely pathogenic in 31.8 %, and variants of uncertain significance (VUS) in 13.6 %. Among pathogenic cases, most carried PMP22 duplications, one had a deletion, and the remainder harbored the missense variant p.(Thr118Met). The three VUS carriers exhibited comparatively milder phenotypes, such as muscle cramps, lumbar hyperlordosis, mild dorsiflexion restriction, hyporeflexia, pes cavus, and clinodactyly/brachydactyly; only one presented with tremor. Lumbar hyperlordosis (90.9 %) and pes cavus (90.9 %) were the most consistent findings.

Conclusions Persistent toe walking may represent an early sign of PMP22-related neuropathies rather than a benign idiopathic gait pattern. The predominance of PMP22 duplications and characteristic neuromuscular features highlight the clinical utility of integrating NGS and MLPA testing for accurate diagnosis, targeted management, and genetic counseling.

Authors’ Contributions

David Pomarino: Conceptualized the study, designed the methodology, and performed primary data acquisition and analysis. Drafted the initial manuscript and coordinated revisions.

Kevin M. Rostásy: Provided critical intellectual input on neurological interpretations, validated clinical correlations, and revised the manuscript for scientific rigor.

Bastian Fregien: Contributed to orthopedic phenotyping, reviewed genetic-clinical associations, and approved the final version for publication.

All authors reviewed and approved the final manuscript, ensuring accountability for their respective contributions.

Ethical statement

This study was conducted in accordance with the ethical principles of the World Medical Association Declaration of Helsinki. All procedures were performed in compliance with relevant laws and institutional guidelines and were approved by the ethical board of the

Deutschen Verbandes für Physiotherapie an der Physio-Akademie in Wremen, Germany (project number 2025-02).

Prior to participation, written informed consent was obtained from all subjects. The consent process included explanations of the study's purpose, procedures, and any potential implications of the results. All data collected were formally anonymized to protect participant confidentiality.

This manuscript was prepared in accordance with the International Committee of Medical Journal Editors (ICMJE) recommendations.

Study Registration: The study is registered in the German Clinical Trials Register at https://www.drks.de/DRKS00031141. Number: DRKS00031141

Funding

This research did not receive any specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Declaration of Competing Interest

The Authors declare that there is no conflict of interest.

Declaration of Generative AI and AI-assisted technologies in the writing process

Generative AI Deepseek was used in the writing phase of this manuscript exclusively for linguistic polishing and enhancing clarity. All scientific reasoning, data analysis, and intellectual substance remain the sole contribution of the authors. The AI was not employed in the research process itself.

Acknowledgments

We are deeply grateful to the children and families who participated in this study, whose cooperation was essential to this research. We sincerely thank the medical teams for their expert clinical evaluations, project review, and the valuable feedback throughout this study.

Special appreciation goes to the dedicated administrative, technical and support staff at Pomarino Praxis für Ganganomalien in Hamburg for their meticulous work in data collection and study coordination. We acknowledge Labor Dr. Heidrich & Colleagues for their expert genetic testing and analysis.

Appendix A. Supplementary material

Supplementary data associated with this article can be found in the online version at doi:10.1016/j.gmg.2025.100082.

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