Mitochondrial DNA depletion syndrome.

The mitochondrial genome (mt) is a small (16.5kb) DNA molecule that is normally present in multiple copies in individual mitochondria. MtDNA depletion syndrome (MDDS) is a recently recognized disorder involving a quantitative defect of mtDNA, that is inherited in an autosomal-recessive mode. The patients are born after an uneventful pregnancy and often normal at birth, but deteriorate in the neonatal period or early childhood. There are two main clinical presentations : myopathic and hepatocerebral. In the first group children usually present with devasting myopathy and neurological abnormalities. In the second condition patients suffer from early progressive hepatic failure with hypotonia, hypoglycaemia, lactic acidosis and progressive neurodegeneration as described in Alpers syndrome. We used real-time PCR techniques to quantify the level of mtDNA in fibroblast, blood, and muscle or liver tissue of patients suspected clinically and on the basis of the biochemical data. Of all patients clinical presentation of MDDS, mtDNA depletion was documented in ten. Molecular analysis of known nuclear mutant genes was undertaken and the exons of the TK2, DGUOK and polG genes were sequenced. In two patients DGUOK gene mutations were revealed, while in four other patients recessive polG mutations were seen. It is known that mutations in these genes count only for a fraction of MDDS cases. Recently mutations in two other nuclear genes, SUCLA and MPV17, segregating with mtDNA depletion were identified in patients with MDDS.