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A recent meta-analysis including five studies with 385 Leigh syndrome patients showed that 32% of the
[18]
patients carried mtDNA mutations, whereas 38% had nDNA mutations .

In a retrospective study on 34 patients with LS, dystonia was found in 59% and was present usually as
[19]
generalized or multifocal form . In other studies, the recurrence was variable usually because of the
retrospective nature of the studies and also the small number of patients included [20-23] .

Different mtDNA mutations are reported in patients with dystonia and LS or LLS including mainly mtDNA
encoded complex subunits such as ATP6, ND3, or ND6 [8,24,25] .

Interestingly, the 10197G > A in ND3 shows a quite variable phenotype ranging from LS to LHON. Recently,
a review of published data on patients harboring the m.10197G > A mutation showed that 38% of patients
had a stable dystonia associated with ataxia, seizures, and dysarthria. The same mutation was also described
[26]
in a single large family with LHON and dystonia . Neuroimaging findings were consistent with LS.
[24]
Dystonic postures appeared early and sometimes had a remitting-relapsing course .

The m.14459G > A mutation in ND6 has been described in pediatric patients with generalized dystonia (also
named as DYT-mt-ND6) with heterogeneous clinical manifestations, ranging from isolated dystonia with
no cognitive involvement to encephalopathy with dystonia, dysphagia, pyramidal tracts dysfunction, and
[27]
cognitive impairment .

[28]
Variants in several nDNA genes are reported in patients with LS . We can distinguish nuclear genes encoding
OXPHOS enzymes and their assembly factors, defects of mitochondrial DNA maintenance and translation,
mitochondrial membrane lipid remodeling, and pyruvate dehydrogenase.

Among LS patients due to nDNA genes, SURF1 gene is one of the most frequently involved genes. SURF1
is a cytochrome c assembly factor and related mutations cause an isolated complex IV deficiency. Clinical
symptoms begin in late infancy with gastro-intestinal symptoms, developmental delay, ophthalmoplegia,
[29]
ataxia, seizures, dystonia, and respiratory failure .
Recently, a mutation in NDUFAF6, a complex I assembly factor, has been described in three siblings with
childhood onset dystonia associated with bilateral striatal necrosis, neurological regression, and long
[30]
survival .

Among mtDNA depletion syndromes, mutations in SUCLA2 gene, leading to succinyl-CoA synthase
deficiency, have been reported in patients with neonatal onset encephalomyopathy, deafness, dystonia, and
MRI abnormalities of putamen and caudate nuclei. As another nuclear gene causing mtDNA depletion,
ATAD3 gene has been associated with a severe encephalopathy with generalized dystonia, ataxia, and
[31]
brainstem and cerebellar hypoplasia .
Mutations of MECR or SERAC1, genes involved in the mitochondrial lipid metabolism and transport, are
associated with severe Leigh-like syndromes with early onset dystonia [32,33] .

Dystonia with childhood onset has been reported in complex phenotypes causing by combined oxidative
phosphorylation deficiencies due to different mitochondrial genes, such as MTFMT and FARS2 involved in
[8]
mtDNA translation .

Of interest is a well-defined syndrome characterized by deafness, dystonia, and optic neuropathy previously
called Mohr-Tranebjaerg syndrome (MTS) due to mutations in TIMM8A. The gene is located on