Liver transplantation for mitochondrial DNA depletion syndrome caused by MPV17 deficiency: a case report and literature review

The maintenance of mitochondrial DNA (mtDNA) depends on a number of nuclear gene-encoded proteins including a battery of enzymes forming the replisome needed to synthesize mtDNA. These enzymes need to be in balanced quantities to function properly that is in part achieved by exchanging intramitochondrial contents through mitochondrial fusion. In addition, mtDNA synthesis requires a balanced supply of nucleotides that is achieved by nucleotide recycling inside the mitochondria and import from the cytosol. Mitochondrial DNA maintenance defects (MDMDs) are a group of diseases caused by pathogenic variants in the nuclear genes involved in mtDNA maintenance resulting in impaired mtDNA synthesis leading to quantitative (mtDNA depletion) and qualitative (multiple mtDNA deletions) defects in mtDNA. Defective mtDNA leads to organ dysfunction due to insufficient mtDNA-encoded protein synthesis, resulting in an inadequate energy production to meet the needs of affected organs. MDMDs are inherited as autosomal recessive or dominant traits, and are associated with a broad phenotypic spectrum ranging from mild adult-onset ophthalmoplegia to severe infantile fatal hepatic failure. To date, pathogenic variants in 20 nuclear genes known to be crucial for mtDNA maintenance have been linked to MDMDs, including genes encoding enzymes of mtDNA replication machinery (POLG, POLG2, TWNK, TFAM, RNASEH1, MGME1, and DNA2), genes encoding proteins that function in maintaining a balanced mitochondrial nucleotide pool (TK2, DGUOK, SUCLG1, SUCLA2, ABAT, RRM2B, TYMP, SLC25A4, AGK, and MPV17), and genes encoding proteins involved in mitochondrial fusion (OPA1, MFN2, and FBXL4).

Mitochondrial DNA depletion syndromes (MDSs) form a group of autosomal recessive disorders characterized by profoundly decreased mitochondrial DNA copy numbers in affected tissues. Three main clinical presentations are known: myopathic, encephalomyopathic and hepatocerebral. The first is associated with mutations in thymidine kinase 2 (TK2) and p53-induced ribonucleotide reductase B subunit (RRM2B); the second with mutations in succinate synthase A (SUCLA2) and B (SUCLG1); the third with mutations in Twinkle (PEO1), pol-gammaA (POLG1), deoxyguanosine kinase (DGUOK) and MPV17 (MPV17). In this work, we review the MDS-associated phenotypes and present our own experience of 32 MDS patients, with the aim of defining the mutation frequency of the known genes, the clinical spectrum of the diseases, and the genotype-phenotype correlations. Five of our patients carried previously unreported mutations in one of the eight MDS genes.

Impairment of mitochondrial energy metabolism has been associated with a wide range of human disorders. Large-scale partial deletions of mitochondrial DNA (mtDNA) cause sporadic Kearns-Sayre syndrome, a fatal multisystem disorder, in which the majority of mtDNAs in affected tissues have deletions (Delta-mtDNAs). Since most mtDNA-related diseases, including Kearns-Sayre syndrome, are recessive, only a few wild-type mtDNAs can compensate for the deleterious effects of many Delta-mtDNAs. We have developed a pharmacological approach to reduce the proportion of Delta-mtDNAs in vitro, in which we grow cells in medium containing ketone bodies, replacing glucose as the carbon source. Cells containing 100% Delta-mtDNA died after 5 days of treatment, whereas those containing 100% wild-type mtDNA survived. Furthermore, in a cloned heteroplasmic cell line, the proportion of wild-type mtDNA increased from 13% initially to approximately 22% after 5 days in ketogenic medium and was accompanied by a dramatic improvement in mitochondrial protein synthesis. We also present evidence that treatment with ketone bodies caused "heteroplasmic shifting" not only among cells (ie, intercellular selection) but also within cells (ie, intracellular selection). The demonstration that ketone bodies can distinguish between normal and respiratorily compromised cells points to the potential use of a ketogenic diet to treat patients with heteroplasmic mtDNA disorders.