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chromosome X and encodes for a protein (deafness dystonia protein 1) located in the inner mitochondrial
membrane and implicated in the mitochondrial protein transport system [34,35] . Dystonia is the second major
feature of MTS and is usually generalized, affecting more cranio-cervical muscles, and slowly progressive.
Age of onset is significantly variable, ranging from the first to the fourth decade. Interestingly, adult-onset
focal dystonia (torticollis and writer’s cramp) with no evidence of hearing impairment has been reported in
[35]
female carriers . Brain MRI in this condition do not show the basal ganglia lesions that are usually evident
in the majority of MD patients with dystonia.

Dystonia in MD adults
Dystonia is a MoD reported also in adult MD cases. The association of Leber hereditary optic neuropathy
(LHON) with variable combination of progressive generalized dystonia and visual loss is well known, and
[36]
is occasionally accompanied by pyramidal tract signs and intellectual impairment . Dystonia can precede
ocular abnormalities by several years. LHON is due to homoplasmic mtDNA mutations in MT-ND1, MT-
ND4, and MT-ND6; the three primary mutations are m.3460G > A, m.11778G > A, and m.14484T > C,
which are all described in combination with generalized dystonia [37,38] . Less common mutations in different
mtDNA ND genes are described in patients with generalized dystonia [39,40] . In the presence of dystonia,
brain MRI shows frequently bilateral putamen and caudate nuclei lesions that have rarely been described in
[41]
patients carrying MT-ND6 mutations without dystonia .

Dystonia has sporadically been reported in some classical mtDNA-related syndromes such as Kearns-Sayre
Syndrome (KSS), a sporadic condition due to large single deletions and characterized by progressive external
ophthalmoplegia, cardiac conduction block, and pigmentary retinal degeneration in combination with
[42]
other symptoms, e.g., ataxia, dystonia, and extraneurological signs . Focal dystonia has been described in
single case reports of MELAS (mitochondrial encephalomyopathy with stroke-like episodes) and MERRF
(myoclonus epilepsy with ragged-red fibers) [43,44] .

Dystonia is also rarely reported in MD patients harboring mutations in POLG (mitochondrial DNA
polymerase γ), which is considered one of the most mutated nuclear genes in MD and is associated with a
very heterogeneous phenotype characterized by progressive external ophthalmoplegia, myoclonic epilepsy,
parkinsonism, and ataxia. In some POLG cases, the phenotype also includes cervical dystonia, focal eyelid
[45]
dystonia, and limb dystonia but not as a prominent feature .

CHOREA/CHOREOATETOSIS
[8]
Choreic or choreathetotic movements have been described in children with LS. In the study by Martikainen et al. ,
6/42 MD patients with movement disorders (14%) presented with chorea or complex hyperkinetic movement
disorders.

Choreic movements are rarely reported in adult-onset MD. Among mtDNA mutations, chorea has been
described in a single case associated with the G11778A mutation. The patient presented at age 24 with
involuntary movements that initially involved both hands and further became generalized; by the age of
[46]
37, she also developed severe dementia . Few MELAS cases are described with acute-onset chorea often
triggered by hyperglycemia [47-49] .

PARKINSONISM
Parkinsonism is the most frequent hypokinetic disorder in adult MD patients. It has been associated with
[50]
mtDNA and nDNA gene variants . In a study focused on the evaluation of cardinal features of parkinsonism
[51]
such as bradykinesia, tremor, and rigidity, the prevalence of parkinsonism was calculated at 12% ; although
a possible incidental association was supposed, the complexity of the phenotype does not support this
concern.