March 21, 2012
The first two pathogenic mutations in mtDNA were reported in 1988: 24 years later, over 200 point mutations and innumerable deletions have been associated with an extraordinary variety of human disorders, most of them multisystemic (“mitochondrial encephalomyopathies”) but some tissue-specific (for example, mitochondrial myopathies).
After a brief reminder of the unique rules of mitochondrial genetics, I will propose a genetic classification of the mitochondrial disorders and provide examples of different mtDNA-related diseases.
As a myologist by training, I feel obliged to stress the importance of the muscle biopsy in our diagnostic approach to mitochondrial diseases.
As mtDNA mutations are so common, it is
important to recognize which are pathogenic and which are neutral
polymorphisms. I will, therefore, review and provide examples of the
“canonical” criteria of mtDNA pathogenicity, including heteroplasmy,
single fiber PCR, and the cybrid technology.
I will proceed to show that we are far from scratching the bottom of the barrel.
We are still debating,
It has been aptly said that mtDNA is the slave of nuclear DNA (nDNA), in that, in the course of the millennia, mtDNA has lost most of its original autonomy and now depends heavily on nuclear DNA for its basic functions, including replication and maintenance.
Thus, besides disorders (reviewed above) due to “primary” mtDNA mutations, there are many disorders due to mutations in nuclear genes controlling mtDNA replication (mtDNA depletion syndromes), mtDNA maintenance (multiple mtDNA deletions syndromes) or mtDNA translation. These “indirect hits” (defects of intergenomic communication) are transmitted as mendelian traits but have genetic features that overlap with mitochondrial genetics.
Thanks to new generation mitoexome
sequencing, the neat subdivision between mtDNA depletion and
multiple mtDNA syndromes is crumbling, as mutations in the same
genes (usually involved with the homeostasis of the mitochondrial
nucleotide pool) can impair either mtDNA replication or maintenance
Although successful in primates and 2in
preliminary experiments with defective human
therapeutic modality requires careful ethical screening.