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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
Free

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: charalampos.tzoulis@nevro.uib.no; e-mail: charalampos.tzoulis@helse-bergen.no

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INTRODUCTION

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

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ATAXIA

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].

FIGURE 1

FIGURE 1

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].

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DYSTONIA

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].

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PARKINSONISM

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].

FIGURE 2

FIGURE 2

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.

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NIGROSTRIATAL DEGENERATION SINE PARKINSONISM

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.

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CONCLUSION

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.

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Acknowledgements

None.

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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.

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Conflicts of interest

There are no conflicts of interest.

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REFERENCES AND RECOMMENDED READING

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

  • ▪ of special interest
  • ▪▪ of outstanding interest
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This work studies the involvement of the cerebellum in mitochondrial disease with movement disorders.

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Keywords:

cerebellar atrophy; neuropathology; nigrostriatal degeneration; parkinsonism

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