Mitochondrial DNA depletion syndrome (MDS) refers to a group of autosomal recessive disorders which cause the affected tissues to suffer from a significant drop in mitochondrial DNA. Symptoms may manifest as myopathic, hepatopathic, and/or encephalomyopathic. These syndromes affect tissue found in the muscle, liver, or both the muscle and brain, respectively. The condition is typically fatal in infancy and early childhood, though some have survived to their teenage years with the myopathic variant and some have survived into adulthood with the SUCLA2 encephalimyopathic variant There is currently no curative treatment for any form of MDSs, though some preliminary treatments have shown a reduction in symptoms.
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Causes
The myopathic form of MDS manifests symptoms within the first year of life, and is diagnosed by higher levels of serum creatine kinase, which is atypical in other mitochondrial myopathies. Myopathic MDSs is strongly correlated to a variety of mutations in the gene TK2, seeing a reduction of TK2 activity to less than 32% in MDS patients 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 encephalomyopathic form of MDS is commonly characterized by psychomotor retardation, muscle hypotonia, hearing impairment, and generalized seizures. A common mutation in this form of MDSs involves a mutation in the SUCLA2 gene, which 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. Other encephalomyopathic forms of MDS have been associated with mutations in the RRM2B gene.
The hepatopathic form of MDS involves the onset of symptoms including hypotonia, hypoglycemia, persistent vomiting, and failure to thrive within the first year of life. Mutations in three genes have been linked to hepatopathic MDS: DGUOK, POLG, and MPV17. DGUOK 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.
Myopathic form (TK2 related)
Typically, 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 patients have survived to late childhood and adolescence.
Encephalomyopathic form (SUCLA2 and RRM2B related)
A 2007 study based on 12 cases from the Faroe Island (where there is a relatively high incidence due to a founder effect) suggested that the outcome is often poor with early lethality. More recent studies (2015) with 50 SUCLA2-mtDNA DS patients with range of 16 different mutations show a high variability in outcomes with a number of patients surviving into adulthood (median survival was 20 years. There is significant evidence (p = 0.020) that SUCLA2 patients with missense mutations have longer survival rates. This could support the hypothesis that some missense mutations are associated with some residual enzyme activity - this should be interpreted cautiously given the small number of patients and the lack of direct experimental evidence of residual activity.
RRM2B mutations have been reported in about 15 infants with severe encephalomyopathic MDS that is associated with early-onset (neonatal or infantile), multi-organ presentation, and mortality during infancy.
Hepatopathic form (DGUOK, POLG, and MPV17 related)
Liver dysfunction is progressive in the majority of individuals with both forms of DGUOK-related MDS and is the most common cause of death. For children with the multi-organ form, liver transplantation provides no survival benefit.
Liver disease typically progresses to liver failure in affected children with MPV17-related MDS and liver transplantation remains the only treatment option for liver failure. Approximately half of affected children reported did not undergo liver transplantation and died because of progressive liver failure—the majority during infancy or early childhood. A few children were reported to survive without liver transplantation.