MDDS is caused by mutations that may be inherited from the parents or may form spontaneously during development of the fetus. MDDS is associated with mutations in the genes TK2, SUCLA2, RRM2B, DGUOK, POLG, TYMP, SUCLG1, and TWNK. Myopathic<unk>  is strongly correlated to a variety of mutations in the gene TK2, seeing a reduction of TK2 activity to less than 32% in people with<unk>  found with the mutation. Because TK2 plays a key role in the mitochondrial salvage pathways of several deoxyribonucleoside triphosphates (dNTPs), a lowered activity would lead to less cycling of nucleotides. This lack of nucleotide recycling is detrimental since the mitochondria cannot synthesize entirely new deoxynucleotides, and the inner membrane of the mitochondria prevents the negatively charged nucleotides of the cytosol from entering. The SUCLA2 gene codes for the beta-subunit of SCS-A. This enzyme catalyzes the synthesis of succinate and coenzyme A into succinyl-CoA, but is also associated with the complex formed by nucleoside diphosphate kinase (NDPK) in the last step of the dNTP salvage pathway. The RRM2B gene, which is expressed in the cell nucleus, codes for one of two versions of the R2 subunit of ribonucleotide reductase, which generates nucleotide precursors required for<unk>  replication by reducing ribonucleoside diphosphates to deoxyribonucleoside diphosphates. The version of R2 encoded by RRM2B is induced by TP53, and is required for normal<unk>  repair and mtDNA synthesis in non-proliferating cells. The other form of R2 is expressed only in dividing cells. The DGUOK gene encodes for mitochondrial deoxyguanosine kinase (dGK), which catalyzes the phosphorylation of deoxyribonucleosides into nucleotides. POLG encodes for the catalytic subunit pol γA, which is part of mitochondrial<unk>  polymerase. Other causes are mutations of thymidine phosphorylase (TyMP), succinate-CoA ligase, alpha sub unit (SUCLG1) and TWNK (also known as PEO1 and C10orf2).
Mitochondrial DNA depletion syndrome
Mitochondrial disease
Glutaminase deficiency
Pyruvate kinase deficiency
Pyruvate dehydrogenase deficiency
3-Methylcrotonyl-CoA carboxylase deficiency
Succinyl-CoA:3-oxoacid CoA transferase deficiency
Contiguous gene syndrome