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The role of mitochondria in idiopathic and familiar Parkinson has been studied for several years and
discussing this issue is beyond the scope of the present review. PD was for a long time considered a non-
genetic disorder, but, in the last twenty years, several genes have been associated with familial PD. Many
genes associated to familial PD are strictly related to mitochondrial function, and different studies have
demonstrated that mitochondrial dysfunction has a major role in the pathogenesis of both sporadic and
familial PD [85,86] . For instance, two PD-related proteins, PTEN-induced serine/threonine kinase 1 encoded by
PINK1 and E3 ubiquitin ligase Parkin encoded by PRKN, regulate mitochondrial quality control, modulating
mitochondrial biogenesis via PGC1alfa. However, it has been shown that LRRK2 interacts with several key
[87]
regulators of mitochondrial fission/fusion . Progress on the pathogenesis of PD led to the development
of therapeutic strategies targeting mitochondrial dysfunction in PD. Some agents were evaluated in clinical
trials to act on neurodegeneration and disease progression but most of them failed to show any efficacy on
[88]
PD .

MYOCLONUS
Myoclonus is a well-known symptom of MD and its presence is traditionally considered in association with
MERRF. Myoclonus in MD is due to a cortical involvement, mainly affects face and distal upper extremities,
[89]
and is classified as focal, multifocal, or generalized .

In a study on a large group of mitochondrial patients listed in the database of the “Nation-wide Italian
Collaborative Network of Mitochondrial Diseases”, we evaluated the relevance of myoclonus. Data analysis
revealed that myoclonus is rather infrequent in MD; in fact, it was reported in only 3.6% of patients (39 of
[90]
1,086) . In 7 of 24 MERRF patients (29%), myoclonus was the presenting clinical sign at onset.

Myoclonus has also been described in other classical mitochondrial encephalopathies due to mtDNA
[94]
mutations, such as MELAS and LHON [91-93] . More rarely, it has been reported in patients with LS . Among
MD defects due to nDNA mutations, myoclonus is part of the complex phenotype of Alpers syndrome
(hepatocerebral syndrome and mtDNA depletion) and MEMSA (myoclonus epilepsy, myopathy, and sensory
ataxia), both associated with mutations in POLG [95,96] .

Subcortical myoclonus has also rarely been described in CoQ10 deficiency due ADCK3 mutations in
[97]
association with dystonia (see in Section Ataxia) .

ATAXIA
Although ataxia is not considered, strictu sensu, a movement disorder, it seems worth considering this
clinical feature in the present review because it is one of the main and debilitating symptoms among MD.
Pure cerebellar ataxia or spinocerebellar forms but also sensitive ataxia due to a sensory system involvement
[98]
are reported, sometimes in combination, in MD patients .

The genetic spectrum of mitochondrial ataxias is quite heterogeneous: it is encountered in several mtDNA
mutations, such as large rearrangements or point mutations, but is included in many variants of different
nDNA genes as well.

In the last few years, the development of exome-based technologies increased consistently the number of
mitochondrial-related genes recognized as responsible for complex encephalopathies with ataxia, making
it difficult to deal with this issue. Moreover, variants in the same gene can be associated with a clinical
continuum of heterogeneous syndromes, ranging from infantile to late- onset forms (e.g., POLG-related
disorders).