Genetic Mechanisms and Early Diagnosis of Hereditary Polyneuropathy in Children
Abstract
Background: Hereditary polyneuropathies in children comprise a genetically heterogeneous group of disorders affecting peripheral nerve function, leading to progressive motor and sensory impairment. Early diagnosis remains challenging due to phenotypic variability, delayed clinical recognition, and overlap with acquired neuropathies. Although advances in molecular genetics have improved disease characterization, their integration into routine pediatric diagnostic pathways remains inconsistent. Methods: A systematic review with exploratory synthesis was conducted following a PICOS-based framework. Literature was searched across PubMed/MEDLINE, Embase, Scopus, and Web of Science up to March 2026. Studies focusing on pediatric hereditary polyneuropathy with genetic or diagnostic outcomes were included. Data were synthesized narratively, with exploratory analysis of genetic mechanisms, diagnostic yield, and clinical outcomes. Results: A total of 41 studies were included. Genetic mechanisms were broadly categorized into myelin-related (48%), axonal transport (27%), mitochondrial dysfunction (15%), and ion channel/metabolic pathways (10%). Autosomal dominant inheritance was most common (55%), followed by autosomal recessive (30%) and X-linked patterns (15%). Diagnostic yield varied by method, with nerve conduction studies demonstrating limited etiological confirmation (25–30%), while targeted gene panels (40–55%), next-generation sequencing (50–65%), and whole exome sequencing (60–72%) showed progressively higher detection rates. Early implementation of genetic testing reduced diagnostic delay by approximately 2–5 years and was associated with improved clinical management, including earlier therapeutic interventions and enhanced genetic counseling. Exploratory analysis indicated higher diagnostic yield in early-onset cases and greater disease severity in axonal and mitochondrial subtypes. Conclusion: Genetic mechanisms play a central role in the pathogenesis and clinical variability of hereditary polyneuropathy in children. Early integration of molecular diagnostics significantly improves diagnostic accuracy and patient management. Establishing standardized, early diagnostic pathways incorporating genomic testing is essential to optimize outcomes and support precision-based pediatric care.