Mitochondrial DNA depletion syndromes: review and updates of genetic basis, manifestations, and therapeutic options

Abstract

Mitochondrial DNA (mtDNA) depletion syndromes (MDS) are a genetically and clinically heterogeneous group of autosomal recessive disorders that are characterized by a severe reduction in mtDNA content leading to impaired energy production in affected tissues and organs. MDS are due to defects in mtDNA maintenance caused by mutations in nuclear genes that function in either mitochondrial nucleotide synthesis (TK2, SUCLA2, SUCLG1, RRM2B, DGUOK, and TYMP) or mtDNA replication (POLG and C10orf2). MDS are phenotypically heterogeneous and usually classified as myopathic, encephalomyopathic, hepatocerebral or neurogastrointestinal. Myopathic MDS, caused by mutations in TK2, usually present before the age of 2 years with hypotonia and muscle weakness. Encephalomyopathic MDS, caused by mutations in SUCLA2, SUCLG1, or RRM2B, typically present during infancy with hypotonia and pronounced neurological features. Hepatocerebral MDS, caused by mutations in DGUOK, MPV17, POLG, or C10orf2, commonly have an early-onset liver dysfunction and neurological involvement. Finally, TYMP mutations have been associated with mitochondrial neurogastrointestinal encephalopathy (MNGIE) disease that typically presents before the age of 20 years with progressive gastrointestinal dysmotility and peripheral neuropathy. Overall, MDS are severe disorders with poor prognosis in the majority of affected individuals. No efficacious therapy is available for any of these disorders. Affected individuals should have a comprehensive evaluation to assess the degree of involvement of different systems. Treatment is directed mainly toward providing symptomatic management. Nutritional modulation and cofactor supplementation may be beneficial. Liver transplantation remains controversial. Finally, stem cell transplantation in MNGIE disease shows promising results.

Figures

Fig. 1

Schematic presentation of protein involved in mitochondrial nucleotide pools maintenance and mitochondrial DNA replication. TK2 = mitochondrial thymidine kinase 2 (encoded by TK2 gene); dGK = mitochondrial deoxyguanosine kinase (encoded by the DGUOK gene); SUCL = succinyl CoA ligase (SUCL is composed of an alpha subunit, encoded by SUCLG1 and a beta subunit, encoded by either SUCLA2 or SUCLG2); NDPK = nucleoside diphosphate kinase; POLG = DNA polymerase gamma (POLG is a heterotrimer enzyme composed of one catalytic subunit encoded by POLG and two accessory subunits encoded by POLG2); TP = thymidine phosphorylase (encoded by TYMP gene); RNR = ribonucleotide reductase (RRM2B encodes the p53-inducible small subunit (p53R2) of the RNR); dNMP = deoxynucleoside monophosphate; dNDP = deoxynucleoside diphosphate; dNTP = deoxynucleoside triphosphate; NDP = nucleoside diphosphate; dTMP = deoxythymidine monophosphate; TK1 = cytosolic thymidine kinase 1; TYMS = thymidylate synthase. The twinkle protein is encoded by C10orf2 and the MPV17 by the MPV17 gene