The mitochondrial protein SLC25A46 has been recently identified as a novel 
pathogenic cause in a wide spectrum of neurological diseases, including 
inherited optic atrophy, Charcot-Marie-Tooth type 2, Leigh syndrome, progressive 
myoclonic ataxia and lethal congenital pontocerebellar hypoplasia. SLC25A46 is 
an outer membrane protein, member of the Solute Carrier 25 (SLC25) family of 
nuclear genes encoding mitochondrial carriers, with a role in mitochondrial 
dynamics and cristae maintenance. Here we identified a loss-of-function mutation 
in the Slc25a46 gene that causes lethal neuropathology in mice. Mutant mice 
manifest the main clinical features identified in patients, including ataxia, 
optic atrophy and cerebellar hypoplasia, which were completely rescued by 
expression of the human ortholog. Histopathological analysis revealed previously 
unseen lesions, most notably disrupted cytoarchitecture in the cerebellum and 
retina and prominent abnormalities in the neuromuscular junction. A distinct 
lymphoid phenotype was also evident. Our mutant mice provide a valid model for 
understanding the mechanistic basis of the complex SLC25A46-mediated 
pathologies, as well as for screening potential therapeutic interventions.