Global medical genetics · 2025
A comparative phenotypic analysis of a heterogeneous PMP22 cohort presenting with persistent toe-walking versus classic PMP22-related Neuropathies.
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Pomarino David, Rostásy Kevin M, Fregien Bastian, Schönfeldt Jan Oliver, Nazarkin Alexander
Аннотация
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.
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.