The patients with a severe infanthood encephalomyopathy and death as a child carry mutations in C12orf65 interrupting the RF-1 domain (p.L84X).17 Conversely, mutations sparing the RF-1 domain seem to cause a milder phenotype as reported in the cases presented here as well as in the SPG55 cases. Here, MTRFR is linked to mitochondrial DNA depletion syndrome, encephalomyopathic form with methylmalonic aciduria.