C12orf65 participates in the process of mitochondrial translation and has been 
shown to be associated with a spectrum of phenotypes, including early onset 
optic atrophy, progressive encephalomyopathy, peripheral neuropathy, and spastic 
paraparesis.We used whole-genome homozygosity mapping as well as exome 
sequencing and targeted gene sequencing to identify novel C12orf65 
disease-causing mutations in seven affected individuals originating from two 
consanguineous families. In four family members affected with childhood-onset 
optic atrophy accompanied by slowly progressive peripheral neuropathy and 
spastic paraparesis, we identified a homozygous frame shift mutation c.413_417 
delAACAA, which predicts a truncated protein lacking the C-terminal portion. In 
the second family, we studied three affected individuals who presented with 
early onset optic atrophy, peripheral neuropathy, and spastic gait in addition 
to moderate intellectual disability. Muscle biopsy in two of the patients 
revealed decreased activities of the mitochondrial respiratory chain complexes I 
and IV. In these patients, we identified a homozygous splice mutation, 
g.21043 T>A (c.282+2 T>A) which leads to skipping of exon 2. Our study broadens 
the phenotypic spectrum of C12orf65 defects and highlights the triad of optic 
atrophy, axonal neuropathy and spastic paraparesis as its key clinical features. 
In addition, a clear genotype-phenotype correlation is anticipated in which 
deleterious mutations which disrupt the GGQ-containing domain in the first 
coding exon are expected to result in a more severe phenotype, whereas 
down-stream C-terminal mutations may result in a more favorable phenotype, 
typically lacking cognitive impairment.