Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an autosomal recessive disease with
mitochondrial DNA (
mtDNA) alterations and is caused by mutations in the nuclear gene encoding
thymidine phosphorylase (TP). The cardinal clinical manifestations are ptosis,
ophthalmoparesis, gastrointestinal dysmotility,
cachexia,
peripheral neuropathy, and
leukoencephalopathy. Skeletal muscle shows mitochondrial abnormalities, including ragged-red fibers and
cytochrome c oxidase deficiency, together with
mtDNA depletion, multiple deletions or both. In MNGIE patients, TP mutations cause a loss-of-function of the cytosolic
enzyme, TP. As a direct consequence of the TP defect,
thymidine metabolism is altered. High blood levels of this
nucleoside are likely to lead to
mtDNA defects even in cells that do not express TP, such as skeletal muscle. We hypothesize that high concentrations of
thymidine affect dNTP (deoxyribonucleoside
triphosphate) metabolism in mitochondria more than in cytosol or nuclei, because mitochondrial dNTPs depend mainly on the
thymidine salvage pathway, whereas nuclear dNTPs depend mostly on de novo pathway. The imbalance in the mitochondrial dNTP homeostasis affects
mtDNA replication, leading to
mitochondrial dysfunction.