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

Among 1,300 screened patients with persistent toe walking, 72 were identified as heterozygous PYGM variant carriers.

• This represents a cross-sectional, retrospective study design.
• Patients were evaluated using a standardized clinical protocol and a validated 49-gene next-generation sequencing neuromuscular panel.
• Variants were classified as pathogenic, likely pathogenic, or of uncertain significance (VUS) according to ACMG/AMP guidelines.
• All 72 children met criteria for idiopathic toe walking prior to genetic evaluation.

Toe walking was bilateral in all 72 cases identified as PYGM variant carriers.

• Bilateral toe walking occurred in 100% of the PYGM variant carrier cohort.
• This finding was consistent across all variant classification subgroups (pathogenic, likely pathogenic, and VUS).
• The bilateral nature was part of the standardized clinical assessment protocol.

Severe dorsiflexion restriction of 5 degrees or less was present in 80.5% of PYGM variant carriers.

• Dorsiflexion restriction was defined as ≤5° for the purposes of this study.
• This finding affected the large majority of the 72-patient cohort.
• Dorsiflexion restriction was assessed as part of the standardized clinical protocol.

Pes cavus was observed in 93% of children carrying heterozygous PYGM variants.

• Pes cavus was detected in 93% of the 72-patient cohort.
• This high prevalence of pes cavus may reflect an underlying neuromuscular contribution to foot deformity.
• Pes cavus was assessed as part of the standardized clinical evaluation.

Muscle symptoms including pain, fatigue, or cramps occurred in approximately one-third of PYGM variant carriers.

• Approximately one-third of the 72 children reported muscle-related symptoms.
• Symptoms included muscle pain, fatigue, and/or cramps.
• VUS carriers displayed comparable but slightly milder muscle symptom frequencies than pathogenic/likely pathogenic (P/LP) carriers.
• These symptoms are consistent with features seen in glycogen storage disease type V (McArdle disease), caused by biallelic PYGM mutations.

Only 12.5% of children with heterozygous PYGM variants were able to perform heel walking.

• 12.5% of the 72-patient cohort could perform heel walking.
• This indicates that the vast majority (87.5%) were unable to heel walk.
• Inability to heel walk reflects the severity of functional limitation in this cohort.

Speech difficulties were reported in 56.9% of children carrying heterozygous PYGM variants.

• Speech difficulties were present in 56.9% of the 72 PYGM variant carriers.
• This relatively high prevalence of speech difficulties suggests possible broader neurodevelopmental involvement.
• The association between PYGM variants and speech difficulties was an observational finding; causality was not established.

Heterozygous PYGM variants may contribute to subtle neuromuscular phenotypes in children with persistent idiopathic toe walking, though causality cannot be inferred.

• The study design was cross-sectional and retrospective, precluding causal inference.
• Analyses were descriptive in nature.
• The authors suggest genetic testing can be considered in persistent toe walking when clinical findings raise suspicion for an underlying neuromuscular or metabolic condition.
• PYGM encodes myophosphorylase, and biallelic loss-of-function variants cause McArdle disease; the role of heterozygous variants in producing subclinical phenotypes is not well established.