Secondary Logo

Movement disorders in mitochondrial disease

a clinicopathological correlation

Flønes, Irene H.a,b; Tzoulis, Charalamposa,b

doi: 10.1097/WCO.0000000000000583
MOVEMENT DISORDERS: Edited by Marie Vidailhet

Purpose of review The scope of this review is to give an updated account of movement disorders associated with mitochondrial disease, with a particular focus on recently discovered clinicopathological correlations.

Recent findings Movement disorders are common clinical manifestations of mitochondrial diseases, in part because of the high vulnerability of neurons controlling motor circuits to mitochondrial respiratory dysfunction and energy failure. Intriguingly, the clinicopathological correlations of movement disorders in mitochondrial disease do not always conform to established neurophysiological knowledge. In particular, nearly complete substantia nigra degeneration and nigrostriatal denervation can occur without being accompanied by any of the clinical signs traditionally associated with parkinsonism. This apparent paradox, may be because of compensation by concomitant impairment of other motor circuits involving the cerebellum and thalamus.

Summary Movement disorders commonly accompany mitochondrial disease and may show paradoxical clinical−anatomical correlations. Further research is warranted in order to elucidate the mechanisms underlying the phenotypic expression of movement disorders in mitochondrial disease. This knowledge will advance our understanding of the pathogenesis of movement disorders in a broader clinical and pathophysiological context.

aDepartment of Clinical Medicine, University of Bergen

bDepartment of Neurology, Haukeland University Hospital, Bergen, Norway

Correspondence to Charalampos Tzoulis, MD, PhD, Department of Neurology, Haukeland University Hospital, 5021 Bergen, Norway. Tel: +47 55975061; e-mails:; e-mail:

Back to Top | Article Outline


Mitochondrial diseases are a heterogeneous group of disorders caused by mutations in mitochondrial DNA (mtDNA) or nuclear genes controlling mitochondrial function. Although no single definition exists, mitochondrial disorders in a clinical context are commonly restricted to diseases associated with abnormalities of the mitochondrial respiratory chain (MRC) leading to impairment of the oxidative phosphorylation (OXPHOS). This definition is used throughout this review.

Mitochondrial diseases affect multiple organ systems, including the central and peripheral nervous system, skeletal muscle, heart, liver, kidney and the gastrointestinal tract, and cause a broad spectrum of clinical presentation. In the nervous system, mitochondrial dysfunction preferentially affects vulnerable, highly energy-dependent neuronal populations, including the Purkinje cells of the cerebellum, striatal neurons and the dopaminergic substantia nigra pars compacta (SNc). Degeneration of these neurons and their connections gives rise to a broad spectrum of hyperkinetic and hypokinetic movement disorders including ataxia, dystonia, myoclonus, parkinsonism, tremor and choreoathetosis.

The scope of this review is to give an updated account of movement disorders associated with mitochondrial disease, with a particular focus on clinicopathological correlations. We are concentrating mostly on the three most common complex types of movement disorder encountered in mitochondrial disease: ataxia, dystonia and parkinsonism. A comprehensive list of movement disorders associated with mitochondrial diseases is shown in Table 1.

Table 1

Table 1

Box 1

Box 1

Back to Top | Article Outline


Ataxia is among the most common and debilitating movement disorders in patients with mitochondrial disease, of either mtDNA or nuclear cause, because of the high prevalence of cerebellar degeneration [1].

Patients with POLG mutations have been extensively studied and exhibit the entire spectrum of cerebellar sensory and motor dysfunction encountered in mitochondrial disease (Fig. 1). They may, therefore, serve as a paradigm of mitochondrial ataxia. POLG encodes the catalytic subunit of the DNA-polymerase gamma, an enzyme that replicates and repairs the mtDNA [2]. POLG mutations impair mtDNA homeostasis causing mtDNA quantitative depletion and the accumulation of deletions and point mutations, which in turn lead to dysfunction of the mitochondrial respiratory chain and ATP deficiency [3–5]. Clinically, patients with POLG disease show a combination of cerebellar and sensory ataxia because of combined loss of the cerebellar input; dorsal root ganglion neurons and dorsal column of the spinal cord and output; Purkinje and dentate neurons [3,6,7]. Degeneration of the dentate nucleus correlates with hypertrophic olivary degeneration because of interruption of the dentate-rubro-olivary pathway within the Guillan−Morallet triangle and may be associated with rhythmic palatal tremor [8,9]. A mutation in the gene encoding the accessory POLG subunit (POLG2), which is essential for enzyme processivity [10], was recently shown in a Belgian pedigree with a late onset neurological disorder constituting cerebellar and sensory ataxia with tremor [11▪▪]. Other disorders of mtDNA replication, such as mutations of the mtDNA helicase Twinkle, cause a nearly identical ataxic syndrome affecting both afferent and efferent cerebellar pathways resulting in progressive sensory and cerebellar ataxia [1,12].



Ataxia of sensory and/or cerebellar type has been reported in numerous other nuclear mitochondrial diseases including disorders of mitochondrial nucleotide pool regulation (e.g. mutations in RRM2B, SUCLG2) [13,14], mitochondrial dynamics and quality control (e.g. mutations in OPA1) [15▪,16], mitochondrial tRNA synthetases and translation [17,18], nuclear-encoded MRC subunits [19,20] and coenzyme Q10 metabolism [21–23].

Ataxia commonly characterizes primary mtDNA mutations. Kearns−Sayre syndrome (KSS), caused by single mtDNA deletions, is a multisystem disorder characterized by the triad of onset before 20 years, pigmentary retinopathy and progressive external ophthalmoplegia. In addition, cerebellar ataxia is a common manifestation. Pathological features include loss of Purkinje cells with Bergmann's gliosis, astrocytic proliferation and spongiform degeneration of cerebellar white matter [24–27]. The dentate and inferior olivary nuclei may also be affected [24], although reports have been conflicting [25,27]. Ataxia in myoclonic epilepsy with ragged red fibers (MERRF) has been associated with neuronal loss and gliosis in the cerebellar cortex and spinocerebellar tracts as well as the dentate nucleus and olivary nuclei [27–30]. The syndrome of neuropathy, ataxia and retinitis pigmentosa (NARP), caused by mutations of MT-ATP6 encoding a subunit of the mitochondrial ATP-synthase, is characterized by early-onset ataxia of primarily sensory type, due to progressive sensory neuropathy. Cerebellar degeneration may also occur in some patients producing a combination of sensory and central ataxia, similar to that seen in POLG disease [31]. Ataxia occurs in approximately 33% of patients with the syndrome of mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS) [32] and correlates with degeneration of the cerebellar cortex. Typical for MELAS is the presence of focal Purkinje cell loss, caused by multiple microinfarcts, and relative preservation of the dentate and olivary nuclei [6,33,34].

Back to Top | Article Outline


Dystonia is the most common movement disorder in children with mitochondrial disease [35]. Although the population-based prevalence of dystonia in mitochondrial disease is not known, Leigh syndrome is probably the most common cause of dystonia among patients with mitochondrial disorders. Leigh syndrome, also known as subacute necrotizing encephalomyelopathy, is a genetically and phenotypically heterogeneous disorder of mostly infantile onset, which is commonly characterized by severe OXPHOS impairment. Leigh syndrome is caused by mutations in the mtDNA or a variety of nuclear genes encoding MRC subunits, complex assembly proteins, components of the Krebs cycle and other factors involved in mitochondrial bioenergetics [35].

In a multicenter study of 130 patients fulfilling the clinical criteria for Leigh syndrome, dystonia was present in ∼45% of the study population. Other clinical manifestations included delayed psychomotor development, progressive cognitive decline, hypotonia, dyskinesia, akinesia, ataxia and brainstem dysfunction [36]. Dystonia and dyskinesia in Leigh syndrome are commonly associated with degenerative and/or necrotic lesions of the basal ganglia showing a predilection for the putamen of the lentiform nucleus. A recent study assessing neuroimaging findings in 93 patients with clinically and genetically characterized Leigh syndrome showed that the basal ganglia (striatum) were affected in 88.2% of the cases, the thalamus in 29% and the brain-stem nuclei in 43% [37]. The mechanism underlying the particular vulnerability of the basal-ganglia in Leigh syndrome is not entirely understood. One possible explanation is severe neuronal ATP deficiency caused by the OXPHOS impairment commonly characterizing Leigh syndrome. It is known that striatal neurons are highly vulnerable to energy failure such as occurs with hypoxia [38], carbon monoxide [39] and cyanide poisoning [40]. This hypothesis does not entirely explain, however, the low prevalence of striatal involvement and dystonia/dyskinesia in other mitochondrial disorders with severe neuronal energy deficits such as POLG encephalopathy and MELAS.

In fact, focal dystonia has been reported in two cases with POLG disease [41,42], both of who had radiologically intact striatum, but lesions of the thalamus and cerebellum. It is possible that dystonia in these cases arises from functional neuronal impairment, rather than degeneration. Although striatal architecture is usually intact in POLG disease, MRC deficiency occurs in principal striatal neurons (unpublished data by the authors) and may lead to altered firing pattern because of altered neuronal metabolism. Alternatively, the thalamus and cerebellum may play a role. Recent research implicates the cerebellum in the pathogenesis of dystonia and in particular, its connections to the thalamus and olivary nuclei, all of which are commonly affected in POLG disease [43].

Dystonia occurs in some individuals with Leber's hereditary optic neuropathy (LHON), a maternally inherited disorder caused by mutations in complex-I-encoding mtDNA genes [44]. Cervical dystonia and parkinsonism has been reported in a patient with the common m.3460 G>A mutation in MT-ND1[45]. Moreover, generalized dystonia has been described in patients carrying less common mutations in MT-ND1[46], MT-ND3[47], MT-ND4[48] and MT-ND6[48–51]. Dystonic symptoms in LHON are commonly associated with lesions of the caudate nucleus and putamen. Interestingly, basal ganglia lesions without the clinical correlate of dystonia, have been described in patients with point mutations of the MT-ND6[44,51].

Deafness-Dystonia-Optic Neuropathy (DDON), previously called Mohr−Tranbjaerg syndrome, is an X-linked disorder caused by mutations in TIMM8A-encoding deafness dystonia protein 1 (DDP1), an inner mitochondrial membrane protein involved in mitochondrial transport. Patients develop slowly progressive generalized dystonia accompanied by progressive degeneration of the brain stem, corticospinal tract and the basal ganglia [52,53].

Infantile-onset or childhood-onset dystonia has been reported with disorders of mitochondrial lipid metabolism because of mutations of MECR or SERAC1. Both cause severe Leigh-like syndromes with progressive degeneration of the striatum and additional features. Additional characteristic features include optic atrophy in MECR mutations [54▪▪] and a severe syndrome including sensorineuronal deafness, spasticity and reversible neonatal liver dysfunction and hypoglycemia in SERAC1 mutations [55▪,56]. More recently, mutations in the ATAD3 gene cluster, involved in mtDNA maintenance and cholesterol metabolism, were reported to cause a severe infantile disorder characterized by pronounced brainstem and cerebellar hypoplasia with generalized dystonia, ataxia and severe encephalopathy [57].

Vocal cord dystonia has been reported as part of a syndrome including ataxia and myoclonus in an individual harbouring the common MERRF m.8344A>G mutation in the MT-TK gene [58]. Neuronal loss has been reported in the basal ganglia, substantia nigra and thalamus of MERRF patients [27–29]. Dystonia is only rarely seen, however, in these patients. Focal dystonia has been described as part of a KSS phenotype associated with MRI lesions in the inferior olivary nucleus, pontine and mesencephalic tegmentum, globus pallidus and thalamus [59].

Back to Top | Article Outline


Parkinsonism is defined as the combination of bradykinesia and either rigidity or tremor at rest. Syndromes with parkinsonism are etiologically and phenotypically heterogeneous, but the one feature they all share is dysfunction of the nigrostriatal pathway because of loss of the dopaminergic neurons SNc, and this is widely accepted as the cause of the cardinal clinical features.

The dopaminergic SNc is highly vulnerable to mitochondrial dysfunction. Substances that inhibit complex I of the MRC cause nigrostriatal degeneration and parkinsonism [60,61]. Furthermore, somatic mtDNA damage accumulates with age and in Parkinson's disease [62,63]. Mitochondrial dysfunction has been strongly associated with Parkinson's disease of both sporadic/idiopathic and familial cause. mtDNA maintenance is impaired in the SNc of individuals with Parkinson's disease, resulting in loss of the wild type mtDNA population [64]. Mitochondrial respiratory chain deficiency, preferentially affecting complex I, occurs throughout the Parkinson's disease brain [65–67]. Abnormal mitochondrial quality control has been linked to familial Parkinson's disease forms, including those caused by mutations in the genes encoding α-synuclein [68], LRRK2 [69], PINK1, parkin [70] and DJ-1 [71]. Moreover, variation in genes controlling mtDNA homeostasis such as POLG[72] and TFAM[73] has been associated with sporadic Parkinson's disease and the inherited mtDNA background also appears to play an important role [74,75]. Recently, mutations in COQ2 encoding an enzyme that functions in the biosynthesis of CoQ10 have been associated with an increased risk of familial and sporadic multiple-system atrophy (MSA) [76–78] and Parkinson's disease in East Asian populations [79].

In line with the profound mitochondrial vulnerability of the SNc, nigrostriatal degeneration is a common phenomenon in mitochondrial disease and shows a strong predilection for defects of mtDNA maintenance in which accumulation of somatic mtDNA damage occurs, including mutations of POLG, TWNK and OPA1[80,81]. Paradoxically, in spite of the high prevalence of SNc degeneration, considered to be the principal cause of the parkinsonistic syndrome, parkinsonism is a relatively uncommon manifestation of mitochondrial disease [35,82] (Fig. 2). Parkinsonism has been described with mutations in mtDNA [45,83–90] and nuclear-encoded mitochondrial genes [81,91–109,110▪▪]. Furthermore, parkinsonism has been described in a small number of cases with multiple mtDNA deletions, suggesting nuclear-encoded disorders of mtDNA maintenance, but with unknown genetic cause [108,111–115].



Parkinsonism in mitochondrial disease has a broad age of onset, with a mean of 51.5 ± 16 years. Clinical features vary from atypical hemiparkinsonism to a Parkinson's disease-like phenotype. Additional neurological features are present in all reported cases (Table 2). Response to dopaminergic treatment is variable. Positive symptomatic response is seen in some [45,83,86,88,89,91,92,94–98,100–103,105–107,111,113–116], whereas others develop early-onset dyskinesia or have poor response to treatment [45,86,94,97,98,103,105,112], or even a complete lack of dopaminergic response [90]. An overview of reported cases is shown in Table 2.

Table 2

Table 2

Table 2

Table 2

All examined individuals with mitochondrial parkinsonism had reduced tracer uptake on [123I]FP-CIT single photon emission computed tomography (CT; DaTscan) or [18F]-6-fluorodopa PET [91,96–98,101,103–105]. Furthermore, SNc degeneration was found on postmortem examination [86,91,95]. Lewy pathology has only been reported in a single patient who was compound heterozygous for the POLG mutations c.3311C>G and c.2542G>A. The patient developed parkinsonism at the age of 51 and had no family history of parkinsonism or other movement disorders [95]. It is, thus, uncertain whether the Lewy body pathology in this case is linked to the POLG mutations, or an incidental finding.

Back to Top | Article Outline


Although the SNc was affected in all reported cases of mitochondrial parkinsonism, severe SNc degeneration and nigrostriatal denervation can occur in patients with mitochondrial disease without any of the clinical correlates of parkinsonism. In fact, recent studies suggested that SNc degeneration is a common, possibly universal phenomenon in disease caused by POLG or TWNK mutations, yet clinical parkinsonism is an uncommon manifestation (Fig. 2) [80,117,118].

The discrepancy between nigrostriatal denervation and clinical parkinsonism cannot be explained based on differences in severity. Severe SNc degeneration resulting in nearly complete nigrostriatal denervation can occur in patients with POLG mutations without being accompanied by any of the clinical signs associated with parkinsonism [117]. Compensation by the developing brain, such as may occur with certain congenital or early acquired neuroanatomical defects also seems unlikely. A recent study of patients with POLG disease showed that nigrostriatal denervation becomes detectable by DaTscan after the age of 25 years and progresses with increasing age and disease duration, becoming nearly complete by the age of ∼ 50 (Fig. 2) [80].

One possible explanation is compensation by concurrent changes in other neuroanatomical pathways, in particular the cerebellum and thalamus, both of which are common in patients with POLG or TWNK-associated disease [80,117–119]. Interestingly, the phenomenon of nigrostriatal degeneration sine parkinsonism has been described in other neurological diseases with cerebellar involvement, such as inherited spinocerebellar ataxias (SCA) [120–123] and MSA-c [124]. Moreover, ipsilateral improvement of rigidity has been reported in an individual with parkinsonism after a cerebellar stroke [125], and surgical dentatectomy has been reported to produce similar results [126]. The common denominator of the above mentioned disorders is the cerebellar involvement. On the basis of this observation, we theorized that dysfunction of the cerebellum and its connections can modulate the dysfunction of the basal ganglia amelioration or preventing the manifestation of clinical parkinsonism [117].

As cerebellar ataxia and parkinsonism can co-exist, however, cerebellar degeneration alone is not sufficient to explain the complete lack of parkinsonism in patients with mitochondrial disease and severe nigrostriatal degeneration [86,91,98,99,101,111,120]. It is possible that additional compensatory action originates from concomitant degeneration of other structures modulating the activity of the basal ganglia, such as the thalamus and subthalamic nucleus.

Thalamic inhibition, either by deep brain stimulation or thalamotomy ameliorates tremor-dominant parkinsonism [127]. Thalamic involvement is common in POLG encephalopathy [117,128], and could counteract parkinsonism by modulating the cortico-striato-pallido-thalamo-cortical pathway.

Degeneration of the subthalamic nucleus, a well established target for stereotactic lesions or deep brain stimulation to ameliorate parkinsonism, has been shown in patients with SCA2 and SCA3 and proposed to explain the lack of parkinsonism in spite of severe nigrostriatal loss [120]. It is currently not known whether the STN is affected by neurodegeneration in POLG or other mitochondrial disorders. Therefore, its potential role in compensating parkinsonian symptoms in mitochondrial disease remains undetermined.

Back to Top | Article Outline


Movement disorders are common manifestations of mitochondrial disease because of a pathological predilection for energy-sensitive neurons controlling motor circuits. Although the clinicopathological correlations mostly conform to established neurophysiological knowledge, this is not always the case. Nearly complete nigrostriatal degeneration may occur in POLG-associated disease without being accompanied by any of the clinical signs traditionally associated with parkinsonism. Elucidating the mechanisms underlying this apparent lack of clinicopathological correlation in these cases will advance our understanding of the pathogenesis of movement disorders, not only with respect to mitochondrial disease but also in a broader clinical and pathophysiological context.

Back to Top | Article Outline



Back to Top | Article Outline

Financial support and sponsorship

This work was supported by grants from the Regional Health Authority of Western Norway (grant nos 911903 and 911988) and the Research Council of Norway (grant no 240369/F20) and the Bergen Research Foundation.

Back to Top | Article Outline

Conflicts of interest

There are no conflicts of interest.

Back to Top | Article Outline


Papers of particular interest, published within the annual period of review, have been highlighted as:

  • ▪ of special interest
  • ▪▪ of outstanding interest
Back to Top | Article Outline


1. Zeviani M, Simonati A, Bindoff LA. Ataxia in mitochondrial disorders. Handb Clin Neurol 2012; 103:359–372.
2. Ropp PA, Copeland WC. Cloning and characterization of the human mitochondrial DNA polymerase, DNA polymerase gamma. Genomics 1996; 36:449–458.
3. Tzoulis C, Tran GT, Coxhead J, et al. Molecular pathogenesis of polymerase gamma-related neurodegeneration. Ann Neurol 2014; 76:66–81.
4. Van Goethem G, Mercelis R, Lofgren A, et al. Patient homozygous for a recessive POLG mutation presents with features of MERRF. Neurology 2003; 61:1811–1813.
5. Ferrari G, Lamantea E, Donati A, et al. Infantile hepatocerebral syndromes associated with mutations in the mitochondrial DNA polymerase-gammaA. Brain 2005; 128 (Pt 4):723–731.
6. Lax NZ, Hepplewhite PD, Reeve AK, et al. Cerebellar ataxia in patients with mitochondrial DNA disease: a molecular clinicopathological study. J Neuropathol Exp Neurol 2012; 71:148–161.
7. Hakonen AH, Heiskanen S, Juvonen V, et al. Mitochondrial DNA polymerase W748S mutation: a common cause of autosomal recessive ataxia with ancient European origin. Am J Hum Genet 2005; 77:430–441.
8. Tzoulis C, Engelsen BA, Telstad W, et al. The spectrum of clinical disease caused by the A467T and W748S POLG mutations: a study of 26 cases. Brain 2006; 129 (Pt 7):1685–1692.
9. Konno T, Broderick DF, Tacik P, et al. Hypertrophic olivary degeneration: a clinico-radiologic study. Parkinsonism Relat Disord 2016; 28:36–40.
10. Yakubovskaya E, Chen Z, Carrodeguas JA, et al. Functional human mitochondrial DNA polymerase gamma forms a heterotrimer. J Biol Chem 2006; 281:374–382.
11▪▪. Van Maldergem L, Besse A, De Paepe B, et al. POLG2 deficiency causes adult-onset syndromic sensory neuropathy, ataxia and parkinsonism. Ann Clin Transl Neurol 2017; 4:4–14.

POLG2, previoulsy exclusively associated with myopathy, is linked to ataxia.

12. Hakonen AH, Goffart S, Marjavaara S, et al. Infantile-onset spinocerebellar ataxia and mitochondrial recessive ataxia syndrome are associated with neuronal complex I defect and mtDNA depletion. Hum Mol Genet 2008; 17:3822–3835.
13. Tyynismaa H, Ylikallio E, Patel M, et al. A heterozygous truncating mutation in RRM2B causes autosomal-dominant progressive external ophthalmoplegia with multiple mtDNA deletions. Am J Hum Genet 2009; 85:290–295.
14. Donti TR, Masand R, Scott DA, et al. Expanding the phenotypic spectrum of Succinyl-CoA ligase deficiency through functional validation of a new SUCLG1 variant. Mol Genet Metab 2016; 119:68–74.
15▪. Nasca A, Rizza T, Doimo M, et al. Not only dominant, not only optic atrophy: expanding the clinical spectrum associated with OPA1 mutations. Orphanet J Rare Dis 2017; 12:89.

This work expands the phenotypical spectrum of OPA1 mutations.

16. Amati-Bonneau P, Valentino ML, Reynier P, et al. OPA1 mutations induce mitochondrial DNA instability and optic atrophy ’plus’ phenotypes. Brain 2008; 131 (Pt 2):338–351.
17. Tzoulis C, Tran GT, Gjerde IO, et al. Leukoencephalopathy with brainstem and spinal cord involvement caused by a novel mutation in the DARS2 gene. J Neurol 2012; 259:292–296.
18. Fratter C, Raman P, Alston CL, et al. RRM2B mutations are frequent in familial PEO with multiple mtDNA deletions. Neurology 2011; 76:2032–2034.
19. Valanne L, Ketonen L, Majander A, et al. Neuroradiologic findings in children with mitochondrial disorders. AJNR Am J Neuroradiol 1998; 19:369–377.
20. Sweeney MG, Hammans SR, Duchen LW, et al. Mitochondrial DNA mutation underlying Leigh's syndrome: clinical, pathological, biochemical, and genetic studies of a patient presenting with progressive myoclonic epilepsy. J Neurol Sci 1994; 121:57–65.
21. Musumeci O, Naini A, Slonim AE, et al. Familial cerebellar ataxia with muscle coenzyme Q10 deficiency. Neurology 2001; 56:849–855.
22. Doimo M, Desbats MA, Cerqua C, et al. Genetics of coenzyme q10 deficiency. Mol Syndromol 2014; 5:156–162.
23. Hikmat O, Tzoulis C, Knappskog PM, et al. ADCK3 mutations with epilepsy, stroke-like episodes and ataxia: a POLG mimic? Eur J Neurol 2016; 23:1188–1194.
24. Tanji K, Vu TH, Schon EA, et al. Kearns-Sayre syndrome: unusual pattern of expression of subunits of the respiratory chain in the cerebellar system. Ann Neurol 1999; 45:377–383.
25. Oldfors A, Fyhr IM, Holme E, et al. Neuropathology in Kearns-Sayre syndrome. Acta Neuropathol 1990; 80:541–546.
26. Bresolin N, Moggio M, Bet L, et al. Progressive cytochrome c oxidase deficiency in a case of Kearns-Sayre syndrome: morphological, immunological, and biochemical studies in muscle biopsies and autopsy tissues. Ann Neurol 1987; 21:564–572.
27. McKelvie PA, Morley JB, Byrne E, Marzuki S. Mitochondrial encephalomyopathies: a correlation between neuropathological findings and defects in mitochondrial DNA. J Neurol Sci 1991; 102:51–60.
28. Oldfors A, Holme E, Tulinius M, Larsson NG. Tissue distribution and disease manifestations of the tRNA(Lys) A-->G(8344) mitochondrial DNA mutation in a case of myoclonus epilepsy and ragged red fibres. Acta Neuropathol 1995; 90:328–333.
29. Takeda S, Wakabayashi K, Ohama E, Ikuta F. Neuropathology of myoclonus epilepsy associated with ragged-red fibers (Fukuhara's disease). Acta Neuropathol 1988; 75:433–440.
30. Lombes A, Mendell JR, Nakase H, et al. Myoclonic epilepsy and ragged-red fibers with cytochrome oxidase deficiency: neuropathology, biochemistry, and molecular genetics. Ann Neurol 1989; 26:20–33.
31. Uziel G, Moroni I, Lamantea E, et al. Mitochondrial disease associated with the T8993G mutation of the mitochondrial ATPase 6 gene: a clinical, biochemical, and molecular study in six families. J Neurol Neurosurg Psychiatry 1997; 63:16–22.
32. DiMauro S, Hirano M. Melas. In GeneReviews®. Edited by Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A; 1993. Seattle (WA): University of Washington, Seattle; 1993-2018. 2001
33. Tsuchiya K, Miyazaki H, Akabane H, et al. MELAS with prominent white matter gliosis and atrophy of the cerebellar granular layer: a clinical, genetic, and pathological study. Acta Neuropathol 1999; 97:520–524.
34. Tanahashi C, Nakayama A, Yoshida M, et al. MELAS with the mitochondrial DNA 3243 point mutation: a neuropathological study. Acta Neuropathol 2000; 99:31–38.
35. Martikainen MH, Ng YS, Gorman GS, et al. Clinical, genetic, and radiological features of extrapyramidal movement disorders in mitochondrial disease. JAMA Neurol 2016; 73:668–674.
36. Sofou K, De Coo IF, Isohanni P, et al. A multicenter study on Leigh syndrome: disease course and predictors of survival. Orphanet J Rare Dis 2014; 9:52.
37. Sofou K, de Coo IFM, Ostergaard E, et al. Phenotype-genotype correlations in Leigh syndrome: new insights from a multicentre study of 96 patients. J Med Genet 2018; 55:21–27.
38. Calabresi P, Pisani A, Mercuri NB, Bernardi G. Hypoxia-induced electrical changes in striatal neurons. J Cereb Blood Flow Metab 1995; 15:1141–1145.
39. Prockop LD, Chichkova RI. Carbon monoxide intoxication: an updated review. J Neurol Sci 2007; 262:122–130.
40. Rachinger J, Fellner FA, Stieglbauer K, Trenkler J. MR changes after acute cyanide intoxication. AJNR Am J Neuroradiol 2002; 23:1398–1401.
41. Hinnell C, Haider S, Delamont S, et al. Dystonia in mitochondrial spinocerebellar ataxia and epilepsy syndrome associated with novel recessive POLG mutations. Mov Disord 2012; 27:162–163.
42. Synofzik M, Schule R, Schulte C, et al. Complex hyperkinetic movement disorders associated with POLG mutations. Mov Disord 2010; 25:2472–2475.
43. Prudente CN, Hess EJ, Jinnah HA. Dystonia as a network disorder: what is the role of the cerebellum? Neuroscience 2014; 260:23–35.
44. Mercuri MA, White H, Oliveira C. Vision loss and symmetric basal ganglia lesions in leber hereditary optic neuropathy. J Neuroophthalmol 2017; 37:411–413.
45. Nikoskelainen EK, Marttila RJ, Huoponen K, et al. Leber's ‘plus’: neurological abnormalities in patients with Leber's hereditary optic neuropathy. J Neurol Neurosurg Psychiatry 1995; 59:160–164.
46. Simon DK, Friedman J, Breakefield XO, et al. A heteroplasmic mitochondrial complex I gene mutation in adult-onset dystonia. Neurogenetics 2003; 4:199–205.
47. Wang K, Takahashi Y, Gao ZL, et al. Mitochondrial ND3 as the novel causative gene for Leber hereditary optic neuropathy and dystonia. Neurogenetics 2009; 10:337–345.
48. De Vries DD, Went LN, Bruyn GW, et al. Genetic and biochemical impairment of mitochondrial complex I activity in a family with Leber hereditary optic neuropathy and hereditary spastic dystonia. Am J Hum Genet 1996; 58:703–711.
49. Saracchi E, Difrancesco JC, Brighina L, et al. A case of Leber hereditary optic neuropathy plus dystonia caused by G14459A mitochondrial mutation. Neurol Sci 2013; 34:407–408.
50. Jun AS, Brown MD, Wallace DC. A mitochondrial DNA mutation at nucleotide pair 14459 of the NADH dehydrogenase subunit 6 gene associated with maternally inherited Leber hereditary optic neuropathy and dystonia. Proc Natl Acad Sci U S A 1994; 91:6206–6210.
51. Shoffner JM, Brown MD, Stugard C, et al. Leber's hereditary optic neuropathy plus dystonia is caused by a mitochondrial DNA point mutation. Ann Neurol 1995; 38:163–169.
52. Wallace DC, Murdock DG. Mitochondria and dystonia: the movement disorder connection? Proc Natl Acad Sci U S A 1999; 96:1817–1819.
53. Engl G, Florian S, Tranebjaerg L, Rapaport D. Alterations in expression levels of deafness dystonia protein 1 affect mitochondrial morphology. Hum Mol Genet 2012; 21:287–299.
54▪▪. Heimer G, Keratar JM, Riley LG, et al. MECR mutations cause childhood-onset dystonia and optic atrophy, a mitochondrial fatty acid synthesis disorder. Am J Hum Genet 2016; 99:1229–1244.

Original report of MECR mutations causing childhood-onset dystonia and optic atrophy syndrome.

55▪. Maas RR, Iwanicka-Pronicka K, Kalkan Ucar S, et al. Progressive deafness-dystonia due to SERAC1 mutations: a study of 67 cases. Ann Neurol 2017; 82:1004–1015.

Comprehensive study describing the SERAC1-associated syndrome.

56. Wortmann SB, Vaz FM, Gardeitchik T, et al. Mutations in the phospholipid remodeling gene SERAC1 impair mitochondrial function and intracellular cholesterol trafficking and cause dystonia and deafness. Nat Genet 2012; 44:797–802.
57. Desai R, Frazier AE, Durigon R, et al. ATAD3 gene cluster deletions cause cerebellar dysfunction associated with altered mitochondrial DNA and cholesterol metabolism. Brain 2017; 140:1595–1610.
58. Peng Y, Crumley R, Ringman JM. Spasmodic dysphonia in a patient with the A to G transition at nucleotide 8344 in mitochondrial DNA. Mov Disord 2003; 18:716–718.
59. Marie SK, Carvalho AA, Fonseca LF, et al. Kearns-Sayre syndrome ‘plus’. Classical clinical findings and dystonia. Arq Neuropsiquiatr 1999; 57:1017–1023.
60. Betarbet R, Sherer TB, MacKenzie G, et al. Chronic systemic pesticide exposure reproduces features of Parkinson's disease. Nat Neurosci 2000; 3:1301–1306.
61. Ramsay RR, Salach JI, Singer TP. Uptake of the neurotoxin 1-methyl-4-phenylpyridine (MPP+) by mitochondria and its relation to the inhibition of the mitochondrial oxidation of NAD+-linked substrates by MPP+. Biochem Biophys Res Commun 1986; 134:743–748.
62. Bender A, Krishnan KJ, Morris CM, et al. High levels of mitochondrial DNA deletions in substantia nigra neurons in aging and Parkinson disease. Nat Genet 2006; 38:515–517.
63. Kraytsberg Y, Kudryavtseva E, McKee AC, et al. Mitochondrial DNA deletions are abundant and cause functional impairment in aged human substantia nigra neurons. Nat Genet 2006; 38:518–520.
64. Dölle C, Flones I, Nido GS, et al. Defective mitochondrial DNA homeostasis in the substantia nigra in Parkinson disease. Nat Commun 2016; 7:13548.
65. Schapira AH, Cooper JM, Dexter D, et al. Mitochondrial complex I deficiency in Parkinson's disease. Lancet 1989; 1:1269.
66. Mizuno Y, Ohta S, Tanaka M, et al. Deficiencies in complex I subunits of the respiratory chain in Parkinson's disease. Biochem Biophys Res Commun 1989; 163:1450–1455.
67. Flones IH, Fernandez-Vizarra E, Lykouri M, et al. Neuronal complex I deficiency occurs throughout the Parkinson's disease brain, but is not associated with neurodegeneration or mitochondrial DNA damage. Acta Neuropathol 2018; 135:409–425.
68. Kamp F, Exner N, Lutz AK, et al. Inhibition of mitochondrial fusion by alpha-synuclein is rescued by PINK1, Parkin and DJ-1. EMBO J 2010; 29:3571–3589.
69. Wang X, Yan MH, Fujioka H, et al. LRRK2 regulates mitochondrial dynamics and function through direct interaction with DLP1. Hum Mol Genet 2012; 21:1931–1944.
70. Park J, Lee G, Chung J. The PINK1-Parkin pathway is involved in the regulation of mitochondrial remodeling process. Biochem Biophys Res Commun 2009; 378:518–523.
71. Thomas KJ, McCoy MK, Blackinton J, et al. DJ-1 acts in parallel to the PINK1/parkin pathway to control mitochondrial function and autophagy. Hum Mol Genet 2011; 20:40–50.
72. Balafkan N, Tzoulis C, Muller B, et al. Number of CAG repeats in POLG1 and its association with Parkinson disease in the Norwegian population. Mitochondrion 2012; 12:640–643.
73. Gaweda-Walerych K, Safranow K, Maruszak A, et al. Mitochondrial transcription factor A variants and the risk of Parkinson's disease. Neurosci Lett 2010; 469:24–29.
74. Pyle A, Foltynie T, Tiangyou W, et al. Mitochondrial DNA haplogroup cluster UKJT reduces the risk of PD. Ann Neurol 2005; 57:564–567.
75. van der Walt JM, Nicodemus KK, Martin ER, et al. Mitochondrial polymorphisms significantly reduce the risk of Parkinson disease. Am J Hum Genet 2003; 72:804–811.
76. Multiple-System Atrophy Research Collaboration. Mutations in COQ2 in familial and sporadic multiple-system atrophy. N Engl J Med 2013; 369:233–244.
77. Wen XD, Li HF, Wang HX, et al. Mutation analysis of COQ2 in Chinese patients with cerebellar subtype of multiple system atrophy. CNS Neurosci Ther 2015; 21:626–630.
78. Zhao Q, Yang X, Tian S, et al. Association of the COQ2 V393A variant with risk of multiple system atrophy in East Asians: a case-control study and meta-analysis of the literature. Neurol Sci 2016; 37:423–430.
79. Yang X, Xi J, Zhao Q, et al. Association of the COQ2 V393A variant with parkinson's disease: a case-control study and meta-analysis. PLoS One 2015; 10:e0130970.
80. Tzoulis C, Schwarzlmuller T, Biermann M, et al. Mitochondrial DNA homeostasis is essential for nigrostriatal integrity. Mitochondrion 2016; 28:33–37.
81. Carelli V, Musumeci O, Caporali L, et al. Syndromic parkinsonism and dementia associated with OPA1 missense mutations. Ann Neurol 2015; 78:21–38.
82. Finsterer J. Parkinson syndrome as a manifestation of mitochondriopathy. Acta Neurol Scand 2002; 105:384–389.
83. Thyagarajan D, Bressman S, Bruno C, et al. A novel mitochondrial 12SrRNA point mutation in parkinsonism, deafness, and neuropathy. Ann Neurol 2000; 48:730–736.
84. De Coo IF, Renier WO, Ruitenbeek W, et al. A 4-base pair deletion in the mitochondrial cytochrome b gene associated with parkinsonism/MELAS overlap syndrome. Ann Neurol 1999; 45:130–133.
85. Rana M, de Coo I, Diaz F, et al. An out-of-frame cytochrome b gene deletion from a patient with parkinsonism is associated with impaired complex III assembly and an increase in free radical production. Ann Neurol 2000; 48:774–781.
86. Simon DK, Pulst SM, Sutton JP, et al. Familial multisystem degeneration with parkinsonism associated with the 11778 mitochondrial DNA mutation. Neurology 1999; 53:1787–1793.
87. Larsson NG, Andersen O, Holme E, et al. Leber's hereditary optic neuropathy and complex I deficiency in muscle. Ann Neurol 1991; 30:701–708.
88. Horvath R, Kley RA, Lochmuller H, Vorgerd M. Parkinson syndrome, neuropathy, and myopathy caused by the mutation A8344G (MERRF) in tRNALys. Neurology 2007; 68:56–58.
89. Martikainen MH, Kytovuori L, Majamaa K. Juvenile parkinsonism, hypogonadism and Leigh-like MRI changes in a patient with m.4296G>A mutation in mitochondrial DNA. Mitochondrion 2013; 13:83–86.
90. Vital C, Julien J, Martin-Negrier ML, et al. Parkinsonism in a patient with Leber hereditary optic neuropathy (LHON). Rev Neurol (Paris) 2015; 171:679–680.
91. Luoma P, Melberg A, Rinne JO, et al. Parkinsonism, premature menopause, and mitochondrial DNA polymerase gamma mutations: clinical and molecular genetic study. Lancet 2004; 364:875–882.
92. Van Goethem G, Lofgren A, Dermaut B, et al. Digenic progressive external ophthalmoplegia in a sporadic patient: recessive mutations in POLG and C10orf2/Twinkle. Hum Mutat 2003; 22:175–176.
93. Mancuso M, Filosto M, Oh SJ, DiMauro S. A novel polymerase gamma mutation in a family with ophthalmoplegia, neuropathy, and Parkinsonism. Arch Neurol 2004; 61:1777–1779.
94. Davidzon G, Greene P, Mancuso M, et al. Early-onset familial parkinsonism due to POLG mutations. Ann Neurol 2006; 59:859–862.
95. Betts-Henderson J, Jaros E, Krishnan KJ, et al. Alpha-synuclein pathology and Parkinsonism associated with POLG1 mutations and multiple mitochondrial DNA deletions. Neuropathol Appl Neurobiol 2009; 35:120–124.
96. Synofzik M, Asmus F, Reimold M, et al. Sustained dopaminergic response of parkinsonism and depression in POLG-associated parkinsonism. Mov Disord 2010; 25:243–245.
97. Invernizzi F, Varanese S, Thomas A, et al. Two novel POLG1 mutations in a patient with progressive external ophthalmoplegia, levodopa-responsive pseudo-orthostatic tremor and parkinsonism. Neuromuscul Disord 2008; 18:460–464.
98. Remes AM, Hinttala R, Karppa M, et al. Parkinsonism associated with the homozygous W748S mutation in the POLG1 gene. Parkinsonism Relat Disord 2008; 14:652–654.
99. Galassi G, Lamantea E, Invernizzi F, et al. Additive effects of POLG1 and ANT1 mutations in a complex encephalomyopathy. Neuromuscul Disord 2008; 18:465–470.
100. Pagnamenta AT, Taanman JW, Wilson CJ, et al. Dominant inheritance of premature ovarian failure associated with mutant mitochondrial DNA polymerase gamma. Hum Reprod 2006; 21:2467–2473.
101. Hudson G, Schaefer AM, Taylor RW, et al. Mutation of the linker region of the polymerase gamma-1 (POLG1) gene associated with progressive external ophthalmoplegia and Parkinsonism. Arch Neurol 2007; 64:553–557.
102. Baloh RH, Salavaggione E, Milbrandt J, Pestronk A. Familial parkinsonism and ophthalmoplegia from a mutation in the mitochondrial DNA helicase twinkle. Arch Neurol 2007; 64:998–1000.
103. Kiferle L, Orsucci D, Mancuso M, et al. Twinkle mutation in an Italian family with external progressive ophthalmoplegia and parkinsonism: a case report and an update on the state of art. Neurosci Lett 2013; 556:1–4.
104. Vandenberghe W, Van Laere K, Debruyne F, et al. Neurodegenerative Parkinsonism and progressive external ophthalmoplegia with a Twinkle mutation. Mov Disord 2009; 24:308–309.
105. Brandon BR, Diederich NJ, Soni M, et al. Autosomal dominant mutations in POLG and C10orf2: association with late onset chronic progressive external ophthalmoplegia and Parkinsonism in two patients. J Neurol 2013; 260:1931–1933.
106. Gurgel-Giannetti J, Camargos ST, Cardoso F, et al. POLG1 Arg953Cys mutation: expanded phenotype and recessive inheritance in a Brazilian family. Muscle Nerve 2012; 45:453–454.
107. Milone M, Wang J, Liewluck T, et al. Novel POLG splice site mutation and optic atrophy. Arch Neurol 2011; 68:806–811.
108. Sato K, Yabe I, Yaguchi H, et al. Genetic analysis of two Japanese families with progressive external ophthalmoplegia and parkinsonism. J Neurol 2011; 258:1327–1332.
109. Garone C, Rubio JC, Calvo SE, et al. MPV17 mutations causing adult-onset multisystemic disorder with multiple mitochondrial DNA deletions. Arch Neurol 2012; 69:1648–1651.
110▪▪. Schreglmann SR, Riederer F, Galovic M, et al. Movement disorders in genetically confirmed mitochondrial disease and the putative role of the cerebellum. Mov Disord 2018; 33:146–155.

This work studies the involvement of the cerebellum in mitochondrial disease with movement disorders.

111. Wilcox RA, Churchyard A, Dahl HH, et al. Levodopa response in Parkinsonism with multiple mitochondrial DNA deletions. Mov Disord 2007; 22:1020–1023.
112. Checcarelli N, Prelle A, Moggio M, et al. Multiple deletions of mitochondrial DNA in sporadic and atypical cases of encephalomyopathy. J Neurol Sci 1994; 123:74–79.
113. Chalmers RM, Brockington M, Howard RS, et al. Mitochondrial encephalopathy with multiple mitochondrial DNA deletions: a report of two families and two sporadic cases with unusual clinical and neuropathological features. J Neurol Sci 1996; 143:41–45.
114. Siciliano G, Mancuso M, Ceravolo R, et al. Mitochondrial DNA rearrangements in young onset parkinsonism: two case reports. J Neurol Neurosurg Psychiatry 2001; 71:685–687.
115. Casali C, Bonifati V, Santorelli FM, et al. Mitochondrial myopathy, parkinsonism, and multiple mtDNA deletions in a Sephardic Jewish family. Neurology 2001; 56:802–805.
116. Imamine R, Arima H, Kusakabe M, et al. Genetic analysis of two Japanese patients with nonclassical 21-hydroxylase deficiency. Intern Med 2009; 48:705–709.
117. Tzoulis C, Tran GT, Schwarzlmuller T, et al. Severe nigrostriatal degeneration without clinical parkinsonism in patients with polymerase gamma mutations. Brain 2013; 136 (Pt 1):2393–2404.
118. Palin EJ, Paetau A, Suomalainen A. Mesencephalic complex I deficiency does not correlate with parkinsonism in mitochondrial DNA maintenance disorders. Brain 2013; 136:2379–2392.
119. Lax NZ, Whittaker RG, Hepplewhite PD, et al. Sensory neuronopathy in patients harbouring recessive polymerase gamma mutations. Brain 2012; 135 (Pt 1):62–71.
120. Schols L, Reimold M, Seidel K, et al. No parkinsonism in SCA2 and SCA3 despite severe neurodegeneration of the dopaminergic substantia nigra. Brain 2015; 138 (Pt 11):3316–3326.
121. Varrone A, Salvatore E, De Michele G, et al. Reduced striatal [123I]FP-CIT binding in SCA2 patients without parkinsonism. Ann Neurol 2004; 55:426–430.
122. Kozlov G, Denisov AY, Girard M, et al. Structural basis of defects in the sacsin HEPN domain responsible for autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS). J Biol Chem 2011; 286:20407–20412.
123. Bouchard RW, Bouchard JP, Bouchard R, Barbeau A. Electroencephalographic findings in Friedreich's ataxia and autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS). Can J Neurol Sci 1979; 6:191–194.
124. Purcell S, Neale B, Todd-Brown K, et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 2007; 81:559–575.
125. Erichsen AK, Koht J, Stray-Pedersen A, et al. Prevalence of hereditary ataxia and spastic paraplegia in southeast Norway: a population-based study. Brain 2009; 132 (Pt 6):1577–1588.
126. Toth S. Effect of removal of the nucleus dentatus on Parkinson's syndrome [Hungarian]. Ideggyogy Sz 1961; 14:148–158.
127. Machado A, Rezai AR, Kopell BH, et al. Deep brain stimulation for Parkinson's disease: surgical technique and perioperative management. Mov Disord 2006; 21 (Suppl 14):S247–S258.
128. Tzoulis C, Neckelmann G, Mork SJ, et al. Localized cerebral energy failure in DNA polymerase gamma-associated encephalopathy syndromes. Brain 2010; 133 (Pt 5):1428–1437.

cerebellar atrophy; neuropathology; nigrostriatal degeneration; parkinsonism

Copyright © 2018 Wolters Kluwer Health, Inc. All rights resereved.