Two mtDNA-associated clinical syndromes have been described that result from a primary molecular defect involving the nuclear genome. Both conditions are inherited as Mendelian autosomal traits. The first condition is the dominantly-inherited mitochondrial myopathy with multiple deletions of mtDNA. These patients become symptomatic in the third decade of life with progressive external ophthalmoplegia, progressive limb weakness, bilateral cataracts and precocious death. The condition is inherited as an autosomal dominant trait. These patients have exercise intolerance with lactic acidosis, and ragged red fibers are seen in the biopsied muscle tissue. This condition also has been described with optic atrophy and ptosis with limb weakness and peripheral neuropathy developing later in life. Of note, patients have normal appearance to the retinal pigmentary epithelium.

Other clinical syndromes associated with multiple mtDNA deletions include recurrent myoglobinuria, inclusion body myositis, ocular myopathy with depression, and MNGIE.

The second example of an intergenomic signaling defect is the mtDNA depletion syndrome with variable tissue expression. This condition was first described as an autosomal recessive trait. The nuclear gene defect is associated with a quantitative reduction of mtDNA copy number. Two phenotypes have emerged. The first represents a fatal congenital condition with limb weakness, hypotonia, and nephropathy. Other signs include cardiomyopathy and seizures. Lactic acidosis and RRF may be present and the family history may be consistent with an autosomal recessive trait.