Clinical Characteristics of Charcot-Marie-Tooth Disease Type 4J

Area of Science:

• Neurology
• Genetics
• Rare Diseases

Background:

• Charcot-Marie-Tooth disease type 4J (CMT4J) is an autosomal recessive genetic disorder caused by variants in the *Factor-Induced Gene 4* (*FIG4*) gene.
• Preclinical studies suggest adeno-associated virus serotype 9-FIG4 gene therapy is a potential treatment for CMT4J.

Purpose of the Study:

• To further characterize the clinical phenotype of CMT4J across pediatric and adult populations.
• To evaluate the feasibility of validated outcome measures for future clinical trials in CMT4J.
• To assess the utility of exploratory biomarkers, including muscle MRI fat fraction and neurofilament light chain levels.

Main Methods:

• A cross-sectional study enrolled 19 genetically confirmed CMT4J patients (14 pediatric, 5 adult) through the Inherited Neuropathy Consortium.
• Disease severity was assessed using standardized CMT-specific outcome measures (e.g., CMTPedS, PedsQL, Vineland) and biomarkers (muscle MRI fat fraction, electrophysiology, neurofilament light chain).
• Descriptive statistics and correlation analyses were performed to explore relationships between clinical variables and biomarkers.

Main Results:

• The most frequent symptoms included gross motor delay and distal muscle weakness (14/19 patients), alongside cognitive and respiratory deficits (8/19 patients).
• Asymmetric weakness was noted in 2 patients, and nonuniform slowing of nerve conduction velocities in 6 patients.
• A significant positive correlation was observed between neurofilament light chain levels and the Charcot-Marie-Tooth Disease Pediatric Scale (CMTPedS) in pediatric patients.

Conclusions:

• This study provides crucial baseline clinical and biomarker data for a diverse CMT4J cohort, highlighting motor, cognitive, and respiratory symptoms.
• The feasibility of using clinical outcomes like CMTPedS for assessing pediatric CMT4J severity was demonstrated.
• Neurofilament light chain levels show promise as a biomarker correlating with disease severity in pediatric CMT4J, warranting further investigation.