Spine deformities in Charcot-Marie-Tooth 4C caused by SH3TC2 gene mutations

Area of Science:

• Genetics
• Neurology
• Molecular Biology

Background:

• Charcot-Marie-Tooth (CMT) disease encompasses inherited peripheral neuropathies with diverse inheritance patterns.
• Autosomal recessive (AR) CMT includes a demyelinating form linked to the 5q23-q33 region (CMT4C).
• Previous studies identified 11 mutations in the SH3TC2 gene in ARCMT patients of various European origins.

Purpose of the Study:

• To identify mutations within the SH3TC2 gene in consanguineous CMT families.
• To investigate the genetic basis of demyelinating autosomal recessive Charcot-Marie-Tooth disease linked to the CMT4C locus.

Main Methods:

• Haplotype segregation and linkage analysis were performed on 10 consanguineous CMT families.
• The SH3TC2 gene was screened for mutations in families linked to the CMT4C locus.

Main Results:

• Mutations in the SH3TC2 gene were identified in all 10 families studied, with eight novel mutations and one recurrent mutation (R954X).
• Six of the ten mutations were located in exon 11 of the SH3TC2 gene.
• Clinical findings included early onset (ages 2-10), significant scoliosis/kyphoscoliosis, foot deformities, and preserved ambulation, with giant axons observed in some biopsies.

Conclusions:

• Charcot-Marie-Tooth type 4C (CMT4C) presents with significant intrafamilial variability, complicating genotype-phenotype correlations.
• Spine deformities are a characteristic hallmark of CMT4C, warranting neurological examination in cases of scoliosis.
• The R954X mutation should be considered a priority in genetic analysis for CMT4C before extensive exon 11 sequencing.