We present the current knowledge on the genetic and phenotypic aspects of
mitochondrial DNA depletion syndromes. The human
mitochondrial DNA encodes 13 of the 82 structural
proteins of the mitochondrial electron transport chain. The replication and maintenance of the
mtDNA require a large number of nuclear encoded
enzymes and balanced
nucleotide pools. Mitochondrial
nucleotide synthesis is of major importance because of the constant need for
nucleotides for
mtDNA maintenance even in quiescent cells. As de novo
enzymes are not present in the mitochondria, synthesis is accomplished via the salvage pathway. Defective
mtDNA synthesis and maintenance manifest by multiple deletions or by depletion of the mitochondrial genome. Patients with multiple deletions typically present with
progressive external ophthalmoplegia, ptosis and, exercise intolerance after the first decade of life.
mtDNA depletion is usually an infantile disease characterized by severe
muscle weakness,
hepatic failure, or renal tubulopathy with fatal outcome. Linkage analysis in families with multiple
mtDNA deletions reveal mutations in
proteins that participate in
mtDNA replication, the
mitochondrial DNA polymerase gene, and the Twinkle gene, a putative mitochondrial helicase and in factors which play a role in mitochondrial
nucleotide metabolism, the
adenine nucleotide translocator, and the
thymidine phosphorylase gene. We have recently identified mutations in an additional two essential
proteins in the
nucleotide salvage pathway, the mitochondrial
deoxyribonucleoside kinases. The phenotype was distinctive for each gene, with
hepatic failure and
encephalopathy associated with mutations in the
deoxyguanosine kinase gene and isolated devastating
myopathy as the sole manifestation of
thymidine kinase 2 deficiency. The tissue selectivity of these disorders and especially the exclusive muscle involvement in
thymidine kinase 2 mutations is puzzling. The normal sequence of the remaining
mtDNA copies in spite of a serious mitochondrial
nucleotide imbalance is also unexpected. We propose several tissue-specific protective mechanisms and a time window, likely encompassing fetal life and even early infancy, during which nuclear
nucleotide synthesis provides mitochondrial needs in all organs. We also speculate on future genes to be discovered in other phenotypes of
mtDNA depletion.