A severe recessive and a mild dominant form of Charcot-Marie-Tooth disease associated with a newly identified Glu222Lys GDAP1 gene mutation.

Abstract

Charcot-Marie-Tooth (CMT) disease caused by mutations in the GDAP1 gene has been shown to be inherited via traits that may be either autosomal recessive (in the majority of cases) [CMT4A] or autosomal dominant [CMT2K]. CMT4A disease is characterized by an early onset, and a severe clinical course often leading to a loss of ambulation, whereas CMT2K is characterized by a mild clinical course of benign axonal neuropathy beginning even in the 6th decade of life. Clinical data from a GDAP1 mutated patient suggests that the presence of a particular mutation is associated with a certain trait of inheritance. The association of a particular GDAP1 gene mutation and a dominant or recessive trait of inheritance is of special importance for genetic counseling and the prenatal diagnostics as regards severe forms of CMT. In the present study we report on two CMT families in which a newly identified Glu222Lys mutation within the GDAP1 gene segregates both in autosomal dominant and recessive traits. Our study shows that at least some GDAP1 gene mutations may segregate with the CMT phenotype as both dominant and recessive traits. Thus, genetic counseling for CMT4A/CMT2K families requires more extensive data on GDAP1 phenotype-genotype correlations.

Targeted exomes reveal simultaneous MFN2 and GDAP1 mutations in a severe Charcot‐Marie‐Tooth disease type 2 phenotype

“…Sanger sequencing showed that the three family members are heterozygous ( Fig. 1b) for this previously described pathogenic mutation [1]. These MFN2 and GDAP1 variants are absent from the dbSNP and ExAC databases.…”

In vivo time-lapse imaging of mitochondria in healthy and diseased peripheral myelin sheath

“…Intriguingly GDAP1 has been involved both in axon-related disease CMT2K (Cassereau et al, 2011) and myelinrelated disease CMT4A (Kabzińska et al, 2014), suggesting that mitochondria of both glia and axons are involved. Moreover mutations in OPA1 (optic atrophy 1), a gene essential for mitochondria fusion, were recently shown to give rise to systemic neurodegeneration including a peripheral neuropathy with features of axonal degeneration and demyelination (Bonneau et al, 2014;Yu-Wai-Man et al, 2010).…”

A Network Pharmacology Approach for the Identification of Common Mechanisms of Drug‐Induced Peripheral Neuropathy

“…It acts as a regulator of mitochondrial fission and there is abundant evidence associating alterations of this gene to the hereditary Charcot‐Marie‐Tooth neuropathy (CMT). Different mutations of this gene have been observed and linked to different clinical manifestations of CMT . Some mechanisms involving changes in mitochondrial movement, abnormal distribution, and perturbations in mitochondrial fission in CMT have been associated with mutations of GDAP1 .…”

“…Different mutations of this gene have been observed and linked to different clinical manifestations of CMT. 31,32 Some mechanisms involving changes in mitochondrial movement, abnormal distribution, 33 and perturbations in mitochondrial fission 34 in CMT have been associated with mutations of GDAP1. Our results may provide a starting point for further exploration of therapies targeting mitochondrial processes, 35 which might have beneficial effects in the treatment of DIPN.…”