MFN2 mutation distribution and genotype/phenotype correlation in Charcot-Marie-Tooth type 2

Area of Science:

• Genetics
• Neurology
• Molecular Biology

Background:

• Charcot-Marie-Tooth type 2 (CMT2) is a group of inherited peripheral neuropathies.
• Mutations in the mitofusin 2 (MFN2) gene are known to cause CMT2.
• Understanding the spectrum and impact of MFN2 mutations is crucial for diagnosis and treatment.

Purpose of the Study:

• To investigate the frequency and spectrum of mitofusin 2 (MFN2) mutations in a cohort of patients with Charcot-Marie-Tooth type 2 (CMT2).
• To characterize the clinical and electrophysiological phenotypes associated with MFN2 mutations in CMT2.
• To identify novel MFN2 mutations and determine their contribution to CMT2.

Main Methods:

• Screening of 323 families and isolated patients with CMT phenotypes for mutations in the MFN2 gene.
• Identification and characterization of MFN2 mutations in probands.
• Clinical assessment of patients, including phenotype severity, onset, and additional features.
• Electrophysiological studies to evaluate nerve conduction parameters.
• Histopathological examination of sural nerve biopsies.

Main Results:

• Identified 22 distinct MFN2 mutations in 29 probands, with 14 being novel.
• Mutations were exclusively located in the cytoplasmic domains of the MFN2 protein.
• Patients exhibited severe CMT phenotypes, with 28% requiring wheelchair dependence.
• Common features included early onset, severe disease, optic atrophy, and reduced nerve action potential amplitudes.
• Sural nerve biopsies revealed loss of large myelinated fibers and mitochondrial abnormalities.
• MFN2 mutations accounted for 33% of CMT2 cases with a family history.

Conclusions:

• MFN2 mutations are a major genetic cause of Charcot-Marie-Tooth type 2, particularly in patients with a family history.
• MFN2 mutations lead to a severe, often early-onset, axonal neuropathy with characteristic electrophysiological and pathological findings.
• The identification of novel mutations expands the known mutation spectrum for MFN2-related CMT2.