Two Novel GDAP1 Mutations with Intermediate Type Autosomal Recessive Charcot-Marie-Tooth Neuropathy (P05.145)

Abstract

Objective: We report two different types of intermediate AR CMT patients with GDAP1 mutations: a His256Arg homozygous mutation, and two heterozygous Pro111His and Val219Gly mutations. Background Various phenotypes have been reported in Charcot-Marie-Tooth disease (CMT) patients carrying mutations in the GDAP1 gene, e.g. autosomal recessive (AR) axonal, AR demyelinating, AR intermediate, and autosomal dominant (AD) axonal neuropathies. Design/Methods: This study included two Korean autosomal recessive CMT families (FC316 and FC426) with GDAP1 mutations (totally 8 individuals: 2 patients, 4 carriers and 2 normals). Disease severities were measured by CMT neuropathy score (CMTNS) and functional disability scale (FDS). MNCVs were carried out on 6 individuals (2 patients, 3 carriers and 1normal). Leg MRI and sural nerve biopsy were performed on 2 patients. The mutation in the GDAP1 gene was screened by PCR amplification and subsequent sequencing of all exons. Results: Two patients showed an early-onset of severe neuropathy with prominent distal lower limb weakness within the first decade of life. The present patients are similar to those with other AR CMT.By neuropathological criteria, two patients showed well documented neuropathological findings consisting of mixed demyelinating and axonal neuropathies and the presence of abnormal mitochondria in nerve biopsy materials was suggestive of the regulatory role of GDAP1 in mitochondrial network dynamics. In addition, nerve conduction velocities of both patients fall in the intermediate range. The leg MRI features were predominantly involved anterolateral compartment muscles of the calf. But, deep and superficial posterior compartments of the low leg were nearly normal. Those findings were different from reported axonal CMT neuropathies with GDAP1 mutations, and similar to the demyelinating CMT1A neuropathies. Conclusions: The fatty replacements of leg muscles were different within the same GDAP1 gene mutations, and the leg MRI provides a valuable non-invasive method for phenotypic evaluation of muscular involvement in CMT neuropathies harboring GDAP1 mutations. Disclosure: Dr. Chung has nothing to disclose.