Clinical and genetic features of a cohort of patients with MFN2-related neuropathy

Abstract

Charcot-Marie-Tooth disease type 2A (CMT2A) is a rare inherited axonal neuropathy caused by mutations in MFN2 gene, which encodes Mitofusin 2, a transmembrane protein of the outer mitochondrial membrane. We performed a cross-sectional analysis on thirteen patients carrying mutations in MFN2, from ten families, describing their clinical and genetic characteristics. Evaluated patients presented a variable age of onset and a wide phenotypic spectrum, with most patients presenting a severe phenotype. A novel heterozygous missense variant was detected, p.K357E. It is located at a highly conserved position and predicted as pathogenic by in silico tools. At a clinical level, the p.K357E carrier shows a severe sensorimotor axonal neuropathy. In conclusion, our work expands the genetic spectrum of CMT2A, disclosing a novel mutation and its related clinical effect, and provides a detailed description of the clinical features of a cohort of patients with MFN2 mutations. Obtaining a precise genetic diagnosis in affected families is crucial both for family planning and prenatal diagnosis, and in a therapeutic perspective, as we are entering the era of personalized therapy for genetic diseases.

Figure 1

Genetic and bioinformatic analysis. (A) Schematic representation of MFN2 protein structure, showing the localization of all the mutations detected in the current cohort (B) Conservation among orthologous genes of the K357 amino acid (mutation site), with the colours used by the Clustal Omega multiple sequence alignment program (red = hydrophobic, light blue = positively charged, pink = negatively charged, light green = polar, aquamarine = aromatic, dark green = glycine, orange = proline) (C) Pedigree of the patient carrying the p.K357E MFN2 variant. Circles correspond to females, squares to males. The black symbol indicates the proband affected by CMT2A, whereas the white ones are used for healthy relatives.

Figure 2

Nerve biopsy of patient carrying the p.K357E variant. (A) Sural nerve, semithin section, toluidine blue (400× magnification): several onion bulbs (arrows). (B) Electron micrograph; transverse section. One myelinated axon is surrounded by concentric proliferation of Schwann cells. Bar = 1 µm.