A comparative phenotypic analysis of a heterogeneous PMP22 cohort presenting with persistent toe-walking versus classic PMP22-related Neuropathies

Abstract

Background The Peripheral Myelin Protein 22 (PMP22) gene plays a central role in peripheral nerve myelination, and dosage alterations (deletion, duplication, or point mutation) are established causes of hereditary neuropathies such as Charcot-Marie-Tooth disease type 1 A (CMT1A), CMT1E, and Hereditary Neuropathy with Liability to Pressure Palsies (HNPP). However, its potential contribution to atypical developmental motor phenotypes such as persistent toe-walking (PTW) has not been systematically explored.

Objective To characterize the phenotypic spectrum of pediatric PMP22 variant carriers presenting with PTW and to compare their clinical features with those of established PMP22-related neuropathies.

Methods This retrospective study analyzed 22 children with PMP22 variants (pathogenic, likely pathogenic, or of uncertain significance) identified through a targeted 49-gene next-generation sequencing panel. Detailed phenotypic data were collected across five clinical domains—genetic, developmental, gait and musculoskeletal, neurological, and associated comorbidities—and compared to standardized phenotype frequencies for CMT1A, CMT1E, and HNPP derived from Orphanet and the Human Phenotype Ontology (HPO) databases.

Results Persistent tip-toe gait was universal, accompanied by pes cavus, lumbar hyperlordosis, tremor, and hyporeflexia. Speech and language difficulties were reported in 45 % of cases, and a family history of toe-walking in 40 %. Additional muscle symptoms and neurological findings were reported, developmental disorders were also reported.

Conclusions Children carrying PMP22 variants with PTW exhibit a distinct phenotype differing from classic demyelinating neuropathies. The findings suggest that a subset of idiopathic toe-walking cases may represent a developmental manifestation within the PMP22-related disease spectrum, highlighting the value of genetic testing in reevaluating gait disorders of uncertain etiology.

Keywords

PMP22 variants / Persistent toe-walking / Hereditary neuropathies / Phenotypic analysis

Ethical statement

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 and available if requested.

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

Authors’ contributions

David Pomarino conceptualized and designed the study, developed the methodology, collected and analyzed the primary data, and prepared the first draft of the manuscript. Kevin M. Rostásy provided critical revisions for intellectual content. Bastian Fregien participated in the orthopedic evaluation, contributed to the integration of genetic and clinical data, and reviewed the manuscript for accuracy. Jan Oliver Schönfeldt supported data curation, assisted in visualization and figure preparation, and contributed to the review and editing of the final manuscript. Alexander Nazarkin assisted with formal analysis, provided technical support for data processing, and contributed to the final review and editing of the paper. All authors read and approved the final version of the manuscript and agree to be accountable for the integrity of the work.

Funding

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

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.

Acknowledgment

We extend our heartfelt gratitude to the children and families who took part in this study; their willingness and cooperation made this research possible. We are equally thankful to the medical teams for their thorough clinical assessments, thoughtful project review, and invaluable feedback throughout the course of this work.

Our special thanks go to the dedicated administrative, technical, and support staff at Pomarino Praxis für Ganganomalien in Hamburg for their careful data collection and coordination efforts. We also acknowledge Labor Dr. Heidrich & Colleagues for their expert contribution to the genetic analyses.

Appendix A. Supplementary material

Supplementary data associated with this article can be found in the online version at doi:10.1016/j.gmg.2025.100081.

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