Clinical Features in Children with Persistent Toe Walking Who Carry Heterozygous PYGM Variants: A Cross-Sectional...

Area of Science:

• Neuromuscular Disorders
• Pediatric Neurology
• Clinical Genetics

Background:

• Persistent toe walking (TW) in children can indicate underlying neuromuscular or metabolic conditions.
• Investigating genetic factors like PYGM variants is crucial for understanding idiopathic TW.
• Heterozygous carriers of PYGM variants may present with subclinical phenotypes.

Purpose of the Study:

• To investigate the clinical and genetic characteristics of children with persistent toe walking carrying PYGM variants.
• To explore potential subclinical neuromuscular phenotypes in heterozygous PYGM variant carriers.

Main Methods:

• Cross-sectional, retrospective study of 72 children with idiopathic TW.
• Utilized a standardized clinical protocol and a 49-gene next-generation sequencing neuromuscular panel.
• Classified variants according to ACMG/AMP guidelines.

Main Results:

• 72 PYGM variant carriers identified among 1,300 screened patients.
• All carriers exhibited bilateral toe walking; 80.5% had severe dorsiflexion restriction.
• Pes cavus (93%), muscle symptoms (approx. 1/3), and speech difficulties (56.9%) were common.
• 12.5% could perform heel walking; VUS carriers showed milder muscle symptoms than P/LP carriers.

Conclusions:

• Heterozygous PYGM variants may contribute to subtle neuromuscular phenotypes in children with persistent toe walking.
• Genetic testing for PYGM variants can be considered in persistent TW cases with suspected underlying neuromuscular/metabolic conditions.