OBJECTIVE: Charcot-Marie Tooth disease (CMT) forms a clinically and genetically 
heterogeneous group of disorders. Although a number of disease genes have been 
identified for CMT, the gene discovery for some complex form of CMT has lagged 
behind. The association of neuropathy and optic atrophy (also known as CMT type 
6) has been described with autosomaldominant, recessive and X-linked modes of 
inheritance. Mutations in Mitofusin 2 have been found to cause dominant forms of 
CMT6. Phosphoribosylpyrophosphate synthetase-I mutations cause X-linked CMT6, 
but until now, mutations in the recessive forms of disease have never been 
identified.
METHODS: We here describe a family with three affected individuals who inherited 
in an autosomal recessive fashion a childhood onset neuropathy and optic 
atrophy. Using homozygosity mapping in the family and exome sequencing in two 
affected individuals we identified a novel protein-truncating mutation in the 
C12orf65 gene, which encodes for a protein involved in mitochondrial 
translation. Using a variety of methods we investigated the possibility of 
mitochondrial impairment in the patients cell lines.
RESULTS: We described a large consanguineous family with neuropathy and optic 
atrophy carrying a loss of function mutation in the C12orf65 gene. We report 
mitochondrial impairment in the patients cell lines, followed by multiple lines 
of evidence which include decrease of complex V activity and stability (blue 
native gel assay), decrease in mitochondrial respiration rate and reduction of 
mitochondrial membrane potential.
CONCLUSIONS: This work describes a mutation in the C12orf65 gene that causes 
recessive form of CMT6 and confirms the role of mitochondrial dysfunction in 
this complex axonal neuropathy.