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Table 4. Parkinsonism associated with mtDNA mutations
Gene Mutation Clinical features of parkinsonism Other clinical features Ref.
MtDNA Large single deletions Asymmetrical or symmetrical parkinsonism PEO Schreglmann et al. [14] , 2018
MT-ND4 m.11778G > A Asymmetrical akinesia, rigidity LHON Vital et al. [58] , 2015
Bilateral akinesia, rigidity LHON Simon et al. [57] , 1999
MT-TI m.4296G > A Bilateral akinesia, rigidity LS, hypogonadism Martikainen et al. [54] , 2013
MT-TK m.8344A > G Asymmetrical akinesia, rigidity, tremor MERRF Horvath et al. [53] , 2007
MT-RNR1 m.1095T > C Hemiparkinsonism with akinesia, rigidity, tremor Hypoacusia, neuropathy Thyagarajan et al. [52] , 2000
MT-CYB 4 bp deletion Symmetrical akinesia, rigidity, tremor Stroke-like episodes De Coo et al. [55] , 1999

PEO: progressive external ophthalmoplegia; LHON: Leber hereditary optic neuropathy; MERRF: mitochondrial encephalomyopathy with
ragged red fibers

The majority of reports describing a Parkinson-like phenotype in the context of a mitochondrial syndrome
are associated with mutation in nDNA genes but more rarely extrapyramidal features have been described in
few cases of mtDNA-related syndromes, such as MERRF, MELAS, and LHON [52-54] . De Coo et al. reported
[55]
on a patient with a MELAS-like syndrome with parkinsonism due to a 4-bp deletion in the mitochondrial
cytochrome B gene (MTCYB) [55,56] . Similarly, bradykinesia and rigidity were reported in LHON cases with
mutation in ND4 gene [57,58] . The main reports on mtDNA mutations associated with parkinsonism are
summarized in Table 4.

Recent studies have demonstrated that the nigrostriatal system is very vulnerable to mitochondrial
[59]
dysfunction , and conditions characterized by an impairment of mtDNA maintenance and consequently
accumulation of somatic mtDNA damage are frequently associated with a nigrostriatal degeneration with
[14]
or without clinical signs of parkinsonism . In the last two decades, several reports have described MD
cases with a complicated phenotype, including parkinsonian features such as akinesia, resting tremor, and
rigidity due to mutations in nuclear genes involved in mtDNA maintenance such as POLG, TWNK [60,61] ,
and, more rarely, OPA1, MPV17, and POLG2 [62-64] . POLG1-related syndromes are the most common forms,
either dominant or recessive, associated with levodopa responsive parkinsonism with a variable onset of
the parkinsonism from early to advanced age [65-73] . Nevertheless, parkinsonism has been reported in few
pathogenic TWNK mutations. TWNK (named also C10orf2) is a gene encoding the Twinkle protein, an
adenine nucleotide-dependent DNA helicase that is involved in the maintenance of mtDNA integrity.

Patients showed an asymmetrical parkinsonism with progressive external ophtalmoplegia (PEO) and
myopathy and a wide range of disease onset from juvenile to adult forms [74-77] .

In recent years, it has been demonstrated that genes involved in mitochondrial dynamics have impaired
mtDNA maintenance; among them, mutations in OPA1, but also in AFG3L2 and SPG7, have been related
to nigrostriatal dysfunction. Some years ago, we described two unrelated families harboring a heterozygous
dominant OPA1 mutation with a clinical picture characterized by PEO, parkinsonism, cognitive impairment,
and nigrostriatal dysfunction at DAT-SCAN. Functional studies revealed an imbalance of autophagy and
mitophagy .
[62]

Recently, among 35 SPG7 patients, parkinsonism was observed in 21% of cases. mtDNA copy number
[78]
quantification in blood revealed significantly lower mtDNA levels in either patients or carriers than controls .

An overview of clinical, genetic, and neuroradiological findings in MD cases with parkinsonism due to
mitochondrial-related nDNA genes reported in the literature is summarized in Table 5 [79-84] .

Clinical presentation of mitochondrial parkinsonism (MP) seems not different from idiopathic Parkinson
disease and for this reason MP can be overlooked. For instance, parkinsonism related to POLG mutations