A recurrent MORC2 mutation causes Charcot-Marie-Tooth disease type 2Z

Area of Science:

• Genetics
• Neurology
• Molecular Biology

Background:

• Charcot-Marie-Tooth disease (CMT) encompasses a group of inherited neuropathies.
• MORC2 gene mutations have been implicated in CMT, but specific pathogenic variants require further elucidation.
• Understanding genotype-phenotype correlations is crucial for diagnosing and managing CMT.

Purpose of the Study:

• To confirm the pathogenicity of the p.Ala406Val mutation in the MORC2 gene.
• To characterize the clinical presentation of neuropathy associated with this specific MORC2 mutation.
• To investigate potential drug-induced neurotoxicity in patients with MORC2-related neuropathy.

Main Methods:

• Genetic sequencing to identify mutations in affected individuals.
• Clinical evaluation of neurological symptoms and progression.
• Electrophysiological studies to assess nerve function.
• Review of patient history for potential environmental or drug exposures.

Main Results:

• Identified a p.Ala406Val (c.1217C>T) mutation in the MORC2 gene in three individuals from two families.
• The neuropathy presented with progressive distal to proximal weakness, starting in childhood or early adulthood.
• One patient experienced acute worsening of weakness following vinblastine treatment for Hodgkin lymphoma.

Conclusions:

• The p.Ala406Val mutation in MORC2 is a confirmed cause of severe neuropathy.
• This study reports the first case of vinblastine-induced neurotoxicity in Charcot-Marie-Tooth disease type 2Z.
• The findings highlight the importance of genetic testing and careful consideration of treatment side effects in patients with CMT.