POLG and mitochondrial DNA depletion syndrome 4a: AHS is an example of severe hepatocerebral mtDNA depletion syndrome (MDS), due to pol-γA (and rarely TWINKLE) recessive mutations, but MDS can also be caused by mutations in a number of other factors that control the mitochondrial or cytosolic supply of deoxynucleotides, the ‘building blocks’ of mtDNA.