While early-onset (neonatal, infancy, or childhood) POLG-SDs such as MCHS or AHS are often associated with mtDNA depletion, the mtDNA defects in adolescent or young adult-onset disorders such as ANS, MIRAS, or PEO are mostly associated with (accumulating) mtDNA deletions [9]. This evidence concerns the gene POLG and mitochondrial DNA depletion syndrome 4a.