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Persistent toe walking as a prominent feature in pediatric PMP22- Related neuropathies: A retrospective cohort study
David Pomarino1, Kevin M Rostásy2, Bastian Fregien3
1Pomarino. Praxis für Ganganomalien, Hamburg, Germany.
Insights
Persistent toe walking in children may signal PMP22 gene-related neuropathies, not just idiopathic causes. Genetic testing like next-generation sequencing (NGS) is crucial for diagnosis and management.
Area of Science:
- Genetics
- Neurology
- Pediatrics
Background:
- Persistent toe walking is often idiopathic, but PMP22 gene alterations are increasingly implicated.
- PMP22 gene variants are linked to Charcot-Marie-Tooth disease type 1A (CMT1A) and Hereditary Neuropathy with Liability to Pressure Palsies (HNPP).
Purpose of the Study:
- Investigate the association between PMP22 variants (duplications, deletions, point mutations) and pediatric toe walking.
- Characterize the clinical and genetic features of children with PMP22 variants and toe walking.
Main Methods:
- Retrospective analysis of 22 pediatric patients with persistent toe walking and confirmed PMP22 variants.
- Utilized a 49-gene next-generation sequencing (NGS) panel and Multiplex Ligation-dependent Probe Amplification (MLPA) for variant confirmation.
- Conducted comprehensive musculoskeletal, neurological, and developmental assessments.
Main Results:
- Pathogenic PMP22 variants were identified in 54.5% of patients, with duplications being most common.
- Lumbar hyperlordosis (90.9%) and pes cavus (90.9%) were the most consistent clinical findings.
- Variants of uncertain significance (VUS) were associated with milder phenotypes.
Conclusions:
- Persistent toe walking can be an early indicator of PMP22-related neuropathies.
- Integrating NGS and MLPA testing is vital for accurate diagnosis and management of PMP22-related disorders.
- Genetic testing aids in targeted management and genetic counseling for affected families.
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.
