Severe mitochondrial DNA depletion in infancy.

Mitochondrial DNA (mtDNA) copy number reduction, known as the mitochondrial DNA depletion syndrome (MDS), is a common cause of severe mitochondrial disorders of infancy and early childhood. MDS results from defects in nuclear encoded factors involved in mtDNA maintenance and within the past years mutations in the POLG1, DGUOK, MPV17, PEO1, SUCLG1, TK2, SUCLA2 and TYMP genes have proven to be implicated in the pathogenesis of this disorder. The clinical phenotypes associated with the different gene alterations vary considerately but present either as a hepatocerebral or a myopathic syndrome. We have identified a homozygous p.E85 deletion in exon 3 of the RRM2B gene in a neonate. The patient, born to first-cousin Caucasian parents, presented with lactic acidosis, severe hypotonia, deafness, blindness and hyperammonemia. Muscle biopsy showed RRF, a combined respiratory chain defects and massive subcomplexes of ATP synthase both with traditional spectrophotometry and BN-PAGE. Western blotting using antibodies against selective OXPHOS subunits indicated the preservation of nuclear encoded complex II. She died at 2 months of age. Mutations of the RRM2B gene, encoding the cytosolic R2 subunit of a p53 controlled ribonucleotide reductase (p53R2), have been reported to cause severe depletion of muscle mtDNA by Bourdon et al. 2007. Indeed, <5% residual amount of mtDNA was measured in muscle tissue of our patient. Aberrations in these 9 genes count only for a minority of all MDS cases. It is expected that other genes involved will be identified soon.