The clinical spectrum of nuclear DNA-related mitochondrial disorders

We review the clinical presentations of nuclear DNA-related mitochondrial diseases, including those due to mutations in genes encoding subunits of the respiratory chain (RC) (direct hits), those involving ancillary factors needed for the assembly or stability of the RC (indirect hits), those affecting the intergenomic cross-talk, and those due to alterations in the protein milieu of the RC. This field is already vast and is getting rapidly larger with the application of homozygosity mapping and MitoExome sequencing. The clinical spectrum is also predictably vast, but more homogeneous than that of mitochondrial DNA Mitochondrial DNA (mtDNA)-related disorders. In general, nuclear DNA (nDNA)-related diseases have infantile or early childhood onset, rapidly downhill course with rare survival into adolescence, and are dominated by encephalopathy (most commonly Leigh syndrome), hypertrophic cardiomyopathy, hepatocerebral syndrome, and nephropathy (often nephrotic syndrome). Exceptions to these generalizations are seen especially in disorders due to mtDNA multiple deletions and mtDNA depletion, where the rules of Mendelian genetics and mitochondrial genetics overlap.