GDAP1 mutations in Italian axonal Charcot-Marie-Tooth patients: Phenotypic features and clinical course

Area of Science:

• Genetics
• Neurology

Background:

• Mutations in the ganglioside-induced differentiation associated-protein 1 (GDAP1) gene are linked to Charcot-Marie-Tooth (CMT) axonal neuropathy, presenting in both autosomal recessive (AR) and dominant (AD) forms.
• The prevalence of heterozygous, dominant GDAP1 mutations in the Italian CMT population remains uncharacterized.

Purpose of the Study:

• To determine the frequency of dominant GDAP1 mutations in Italian patients with axonal CMT.
• To explore the correlation between these mutations and clinical manifestations.

Main Methods:

• Genomic DNA sequencing and copy number variation analysis were performed on 109 Italian axonal CMT patients.
• All patients had previously been tested for common axonal AD genes.

Main Results:

• Heterozygous mutations in GDAP1 were identified in eight patients (7.3%), harboring five previously reported mutations.
• The relative frequency of GDAP1 mutations (7.3%) exceeded that of MFN2 (6.3%) and MPZ (5.0%) in this cohort.
• Observed mutations exhibited variable penetrance, with symptom onset in the first decade and a slower progression compared to AR-CMT.

Conclusions:

• Dominant GDAP1 mutations are a significant cause of axonal CMT in Italy, with a frequency higher than MFN2 and MPZ.
• The milder clinical features and indolent course associated with these mutations are important for prognostic assessments.
• GDAP1 should be considered the primary gene for analysis in Italian patients diagnosed with CMT2.