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Saneto. J Transl Genet Genom 2020;4:384-428 I http://dx.doi.org/10.20517/jtgg.2020.40 Page 397

disease is associated with mtDNA depletion and childhood onset. The milder disorders have onset in early-
to-late adulthood and associated with multiple mtDNA deletions. Variant changes within the POLG gene
can determine mode of inheritance. Variants found in certain sites within the polymerase region produce
autosomal dominant or recessive disease, but variants in the linker and exonuclease regions produce
autosomal recessive disorders. Furthermore, the phenotype and genotype remain blurred as both autosomal
dominant and recessive variants induce CPEO. However, in a large cohort of CPEO patients, all had either
a single large mtDNA deletion or multiple small mtDNA deletions [113] . However, not all patients with
variants in genes responsible for multiple mtDNA deletions have CPEO [117] . The reasons for this remain
unknown. However, unlike single large mtDNA deletion-induced CPEO, those nuclear-encoded genes
giving rise to CPEO and multiple mtDNA deletion express sensory neuropathy [124] . Medically refractory
seizures early in life is associated with mtDNA depletion, autosomal recessive inheritance, and mostly
associated with Alpers-Huttenlocher syndrome [125] . The mechanism of valporic acid-induced hepatopathy
[34]
in Alpers-Huttenlocher syndrome is not understood .
Some genes give rise to both mtDNA multiple deletions and mtDNA depletion, while others do not. The
exact mechanism of why this happens is not clear. Mutations in the 5’-3’ DNA helicase TWNK induces
both autosomal recessive and dominant disease. The protein product of TWNK, twinkle, acts as the
DNA and RNA helicase. The dominant form of the disease causes an adult onset CPEO with myopathy
and multiple mtDNA deletions [126] . The autosomal recessive disease is expressed as an mtDNA depletion
syndrome presenting with severe epileptic encephalopathy [127] . Other variants in TWNK induce a recessive
syndrome found in the Finnish ethnic group that produces infantile onset spinocerebellar ataxia, with
mtDNA depletion found in the liver and brain [128] . SSBP1 is required to stabilize single-stranded mtDNA
and stimulates DNA synthesis by POLG. As described above, dominant pathological variants in SSBP1 have
recently been shown to induce optic atrophy, hearing loss, and foveopathy with mtDNA depletion, and
recessive variants express features of Pearson, Kearns-Sayre, and Leigh syndrome [105,116,129] .

Several of the replisome gene products are involved in the maturation of newly synthesized mtDNA
strands and have been implicated in mtDNA repair. MGME1 produces a single-stranded DNA flappase
involved in processing of 5’ mtDNA ends generated during replication. Compromise in this processing
protein produces multiple mtDNA deletions with disease onset from childhood to adulthood. Disease
is expressed by CPEO, muscle weakness and wasting, and respiratory muscle weakness [130] . DNA2 and
RNASEH1 products are found both in the nucleus and mitochondrion, and both products are involved in
mtDNA repair in long-patch base-excision repair. Variants in these genes produce CPEO and proximal
muscle weakness [130,131] . Onset of disease is distinct, variants in DNA2 present in childhood while RNASEH1
presents during adulthood [131] .

Defects in the control of mitochondrial deoxyribonucleoside pools
The requirement for constant mtDNA replication requires an adequate and balanced pool of
deoxyribonucleoside triphosphates (dNTPs) and deoxyribonucleoside 5’triphosphate precursors. Multiple
mtDNA deletions and/or depletion have been associated with pathological variants in nine nuclear
encoded genes involved in the balance of dNTP pools [12,117,132] . Synthesis of dNTPs occurs by the de novo
pathway that is cell cycle dependent or by the cell cycle independent salvage pathway. The salvage pathway
is uniquely important for dNTPs in post-mitotic cells such as neurons and muscle cells. Alterations in the
balance of nucleotide pools lead to increased mutagenesis or mtDNA deletions. There are six genes that
control intramitochondrial dNTP giving rise to disease: SUCLA1, SUCLG1, TK2, SAMHD1, ABAT, and
DGUOK. The three other genes that control dNTP pools also induce disease: TYMP, RRM2B, and GUK1.

mtDNA diseases arising from dysregulation of dNTP pools mostly induce mtDNA multiple deletions,
however some also induce mtDNA depletion. Depletion-induced diseases are more severe and earlier in