MDDS is associated with mutations in the genes TK2, SUCLA2, RRM2B, DGUOK, POLG, TYMP, SUCLG1,  and TWNK.Myopathic MDS 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 MDS 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 DNA replication by reducing ribonucleoside diphosphates to deoxyribonucleoside diphosphates. The version of R2 encoded by RRM2B is induced by TP53, and is required for normal DNA 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 DNA polymerase.Other causes are mutations of thymidine phosphorylase (TyMP), succinate-CoA ligase, alpha sub unit (SUCLG1) and TWNK (also known as PEO1 and C10orf2). Diagnosis
MDDS is diagnosed based on systemic symptoms presenting in infants, followed by a clinical examination and laboratory tests (for example, high lactate levels are common) medical imaging, and usually is finally confirmed and formally identified by genetic testing. Classification
MDDS are a group of genetic disorders that share a common pathology — a lack of functioning DNA in mitochondria. There are generally four classes of MDDS:
a form that primarily affects muscle associated with mutations in the TK2 gene;
a form that primarily affects the brain and muscle associated with mutations in the genes SUCLA2, SUCLG1, or RRM2B;
a form that primarily affects the brain and the liver associated with mutations in DGUOK, MPV17, POLG, or TWNK (also called PEO1); and
a form that primarily affects the brain and the gastrointestinal tract associated with mutations in ECGF1 (also called TYMP). Treatment
There are no treatments for MDDS, but some of the symptoms can be managed. For survivors living with MDDS, there are drugs to control epilepsy, and physical therapy can help with muscle control. Liver transplants may benefit people with liver involvement. Prognosis
Myopathic form
The TK2 related myopathic form results in muscle weakness, rapidly progresses, leading to respiratory failure and death within a few years of onset. The most common cause of death is pulmonary infection. Only a few people have survived to late childhood and adolescence.