Genetics of Mitochondrial Disease with Focus on Movement Disorders




© Springer International Publishing Switzerland 2015
Susanne A. Schneider and José M. Tomás Brás (eds.)Movement Disorder Genetics10.1007/978-3-319-17223-1_18


18. Genetics of Mitochondrial Disease with Focus on Movement Disorders



Josef Finsterer  and Salma Majid Wakil2


(1)
Krankenanstalt Rudolfstiftung (KAR), Vienna, 1180, Austria

(2)
Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, 11211, Saudi Arabia

 



 

Josef Finsterer



Abstract

There is increasing awareness that mitochondrial disorders with involvement of the central nervous system may also manifest with movement disorders. Movement disorders most frequently manifesting in mitochondrial disorders are ataxia, parkinsonism, dystonia, choreoathetosis, cerebral palsy, and non-Parkinson’s tremor. More rarely, myoclonus, restless leg syndrome, tic disorders, or stereotypy disorders were described in mitochondrial disorders. Syndromic as well as nonsyndromic mitochondrial disorders may present with movement disorders. Frequently, the movement disorder is not the only clinical manifestation but one among others. It may be the dominant phenotypic feature or an ancillary manifestation. Clinical manifestations other than movement disorders may result from additional affection of the central nervous system, the eyes, the ears, the endocrine organs, the heart, the guts, the kidneys, the skin, or the bone marrow. Genes most frequently mutated in mitochondrial movement disorders are POLG1, twinkle, tRNAs, and respiratory chain complex I subunit genes. Treatment of movement disorders in mitochondrial disorders is not at variance from treatment of movement disorders in other patients, but therapy may be less beneficial than in non-mitochondrial patients.


Keywords
Mitochondrial disorderCentral nervous systemMovement disordersParkinsonAtaxiaAthetosisChoreaDystoniaTremorCerebral palsy


Abbreviations


ACO2

Aconitase-2 gene

ADCK3

AarF domain containing kinase-3

ANT1

ADP/ATP translokase-1

ARSAL

Autosomal recessive spastic ataxia with leukoencephalopathy

CABC1

Chaperone activity of bc1 complex gene (synonymous with ADCK3)

CNS

Central nervous system

CoQ

Coenzyme Q

COX

Cytochrome c oxidase

CPEO

Chronic progressive external ophthalmoplegia

CSF

Cerebrospinal fluid

DDS

Deafness diabetes syndrome

DNA

Desoxynucleic acid

DYTCA

Dystonia cerebellar ataxia syndrome

HSD10

Hydroxysteroid dehydrogenase 10

IMMP2L

Inner mitochondrial membrane peptidase-2-like

IOSCA

Infantile-onset spinocerebellar ataxia

LHON

Leber’s hereditary optic neuropathy

MELAS

Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes

MERRF

Myoclonic epilepsy with ragged-red fibers syndrome

MHBD

2-Methyl-3-hydroxybutyryl-CoA dehydrogenase

MID

Mitochondrial disorder

MILS

Maternally inherited Leigh syndrome

MPV17

Mitochondrial inner membrane protein

MR1

Myofibrillogenesis regulator 1 gene

MRI

Magnetic resonance imaging

mtDNA

Mitochondrial DNA

MTS

Mitochondria-targeted sequence

NARP

Neuropathy, ataxia, retinitis pigmentosa syndrome

nDNA

Nuclear DNA

PCH

Pontocerebellar hypoplasia

POLG1

Polymerase gamma-1

RARS2

Mitochondrial arginyl-transfer RNA synthetase gene

RCC

Respiratory chain complex

SANDO

Sensory ataxia neuropathy dysarthria and ophthalmoplegia

TACO1

Translational activator of cytochrome-c-oxidase gene

tRNA

Transfer ribonucleic acid

UPDRS

Unified Parkinson’s Disease Rating Scale



Introduction


Mitochondrial disorders (MIDs) are usually multisystem disorders either already at onset of the clinical manifestations or sooner or later during the disease course [1]. One of the organs frequently affected in MIDs is the central nervous system (CNS) [2]. Among the various CNS manifestations, movement disorders are the ones less well appreciated. This chapter wants to highlight the genetic background of those MIDs which go along with clinical manifestations of a movement disorder and, if reported, the management of these patients.


Methods


Data for this chapter were collected by searches of MEDLINE, Current Contents, and PubMed and of references from relevant articles using the search terms “mitochondrial DNA,” “nuclear DNA,” “deletion,” “multiple deletions,” “POLG1,” and “twinkle” in combination with “mitochondrial disorder,” “respiratory chain,” “mitochondrial cytopathy,” “MELAS,” “MERRF,” “CPEO,” “NARP,” “MILS,” “LHON,” “IOSCA,” “SANDO,” and “Leigh syndrome.” Considered were articles about humans, animals, and cell cultures published in English between 1966 and 2014 and investigated in randomized (blinded or open label) clinical trials, longitudinal studies, case series, or case reports. All age groups and both sexes were included. Excluded were abstracts or reports about meetings. Papers matching these criteria were studied and discussed for their suitability to be included in this chapter.


Definition of Movement Disorders


Movement disorders comprise a huge spectrum of diseases, which go along with abnormal movements [3]. Movement disorders include akathisia (inability to sit still), akinesia (lack of movement), associated movements (mirror movements or homolateral synkinesias), athetosis (contorted torsion or twisting), ataxia (lack of coordination of movements), ballism (violent involuntary rapid and irregular movements), bradykinesia (slow movement), cerebral palsy (static encephalopathy), chorea (rapid involuntary movement), dyskinesia (abnormal, involuntary movement), dystonia (sustained torsion), blepharospasm, writer’s cramps, spasmodic torticollis (twisting of head and neck), dopamine-responsive dystonia (hereditary progressive dystonia with diurnal fluctuation or Segawa’s disease), essential tremor, geniospasm (episodic involuntary up and down movements of the chin or lower lips), myoclonus (brief, involuntary twitching of a muscle or a group of muscles), mirror movements (involuntary movements on one side of the body mirroring voluntary movements of the other side), Parkinson’s disease, paroxysmal kinesigenic dyskinesia, restless leg syndrome, spasms, stereotypic movement disorder, stereotype (repetition), Tic disorders (involuntary, compulsive repetitive, stereotyped movements), and tremor (oscillations) [3].


Parkinson’s Syndrome (Parkinsonism)



POLG1 Mutations


Since recent years, it is well established that polymerase γ-1 (POLG1) mutations are occasionally associated with levodopa-responsive parkinsonism [4]. Even polymorphisms within the POLG1 gene seem to predispose for Parkinson’s syndrome, at least in the Chinese population [4]. The fact that POLG1 mutations are more frequently associated with parkinsonism than mutations in other MID causing genes was confirmed by a number of cases with parkinsonism carrying a POLG1 mutation [5].

In a 48-year-old female carrying a POLG1 mutation manifesting as multisystem MID, parkinsonism was a dominant phenotypic feature [6]. In a Brazilian family carrying a POLG1 mutation, three family members were clinically affected. One patient presented with chronic progressive external ophthalmoplegia (CPEO), polyneuropathy, cardiomyopathy, and parkinsonism with onset at the age of 20 [7]. The oldest brother of the index case had a similar phenotype. An older sister presented with CPEO and depression [7]. Parkinsonism in the index patient improved under pramipexole 3 mg/day [7]. In a compound heterozygote for a POLG1 mutation, orthostatic tremor evolved into levodopa-responsive parkinsonism [8]. In addition to parkinsonism, the patient presented with autosomal recessive CPEO [8]. In a 71-year-old male with CPEO, ptosis, hypoacusis, dysarthria, dysphagia, polyneuropathy, migraine, myopathy, cardiomyopathy, symmetric rigidity, and tremor, manifestations of parkinsonism were assessed as 26 on the Unified Parkinson’s Disease Rating Scale (UPDRS) part III [9]. Carbidopa/levodopa in a dosage of 75/300 mg/day reduced the UPDRS score to 14 [9]. Since the patient did not tolerate this medication over a longer period, it was switched to clonazepam with success [9]. A male patient with CPEO developed bradykinesia, rigidity, and camptocormia in the third decade [10]. Parkinsonism in this patient was only partially responsive to dopaminergic replacement [10]. His father and brother presented with a similar phenotype, which was attributed to a POLG1 mutation in all of them [10]. Mutations in the POLG1 gene, which manifest as Alpers syndrome in children, may cause parkinsonism in addition to ataxia, CPEO, polyneuropathy, and hypoacusis in elderly patients (see also section “Ataxia”) [11]. In a large family with parkinsonism and CPEO, multiple mitochondrial DNA (mtDNA) deletions due to a POLG1 mutation were found to be causative [12]. A patient carrying an ADP/ATP translocase 1 (ANT1) and POLG1 mutation presented with parkinsonism in addition to CPEO, sensory and cerebellar ataxia, polyneuropathy, and depression (see also section “Ataxia”) [13]. The mutations were associated with multiple mtDNA deletions [13]. Parkinsonism due to POLG1 mutations may not only occur together with CPEO [9] but also with other movement disorders. Early-onset parkinsonism and polyneuropathy may be another phenotypic expression of a POLG1 mutation [14]. Parkinsonism due to POLG1 mutations may be additionally associated with premature ovarian failure [15].

Occasionally, POLG1 mutations may cause only marked nigrostriatal degeneration without overt clinical parkinsonism [16]. In these patients, structural abnormalities may be found in the thalamus and the cerebellum [16]. On the cellular level, dopaminergic nigral neurons of patients with POLG1 encephalopathy show increased mtDNA depletion compared to patients with idiopathic Parkinson’s disease [16]. There are some indications that a CAG-repeat number of 6–9 or 12–14 predisposes for the development of Parkinson’s disease at least in some populations [17, 18]. The normal poly-Q tract in exon 2 of the POLG1 gene has 10–11 CAG repeats. POLG1 mutation-related parkinsonism may be differentiated from idiopathic Parkinson’s disease by means of the neuromelatonin MRI [5].


Other Genes


Not only POLG1 mutations may go along with parkinsonism but also mutations in other genes encoding mitochondrial proteins, tRNAs, or rRNAs, such as C10orf2 (twinkle, encodes for the twinkle helicase, a functional partner of the polymerase γ [19]), MPV17, MT-TI (tRNA(Ile)), 12S-rRNA, MT-TL (tRNA(Leu)), and tRNA(Ile). In an Italian family carrying a twinkle gene mutation, the index patient developed parkinsonism at the age of 82 in addition to ptosis, ophthalmoplegia, and hypoacusis since childhood [20]. Parkinsonism responded only moderately to levodopa. The 79-year-old sister of the index patient had developed resting and postural tremor and rigor (plastic hypertonia) since the age of 76 [20]. In a 74-year-old male with ptosis, CPEO, progressive left-sided weakness, mild proximal myopathy, exercise intolerance, predominantly left-sided parkinsonism with hypomimia, mild resting tremor, and moderate bradykinesia were found [9]. He scored 10 on the UPDRS part III [9]. The phenotype was attributed to a mutation in the twinkle gene [9]. In a 65-year-old male with polyneuropathy, ptosis, CPEO, diabetes, exercise intolerance, steatohepatopathy, depression, and gastrointestinal dysmotility, parkinsonism was a further phenotypic feature of the underlying mutation in the MPV17 gene [21]. The MPV17 mutation caused multiple mtDNA deletions without indication for mtDNA depletion [21]. In a single Italian family carrying a mutation in the mitochondrial 12S-rRNA gene, the phenotype was characterized by deafness, polyneuropathy, and parkinsonism [22]. The mutation resulted in depletion of mitochondrial glutathione and combined respiratory chain complex (RCC) II/III deficiency [22]. Administration of gentamicin dramatically increased the number of apoptotic cells in this family [22]. In a 55-year-old Japanese female with dementia, tetraspasticity, CPEO, myopathy, deafness, and diabetes, carrying an MT-TL (tRNA(Leu)) mutation, parkinsonism was diagnosed at the age of 55 [23]. Her 48-year-old brother had similar manifestations of the mutation, but instead of parkinsonism, he presented with ataxia (see also section “Ataxia”) [23]. Cerebral MRI showed supra- and infratentorial atrophy and periventricular hyperintensities [23]. Pyruvate and lactate were elevated in the serum. Parkinsonism may also occur in patients carrying MT-TI (tRNA(Ile)) gene mutations [24]. Parkinsonism in these patients may go along with developmental retardation and hypogonadism [24]. In a neonate with episodes of truncal hypertonia and apnea progressing to a hypokinetic-rigid syndrome characterized by hypokinesia, tremor, head lag, absent suck and gag reflexes, hyperreflexia, ankle and jaw clonus, and autonomic dysfunction, mtDNA depletion was detected in the muscle homogenate [25]. Respiratory chain enzymology demonstrated decreased RCCIV activity [25]. Treatment with pyridoxal phosphate, tetrahydrobiopterin, and levodopa was ineffective [25]. The underlying genetic defect could not be detected. In a study of 32 patients with idiopathic Parkinson’s disease, the mtDNA deletion mt.4977del was found in 15 patients and thus much more frequent than in the control group [26].


Ataxia


Cerebellar or sensory ataxia is a frequent phenotypic manifestation of MIDs with cerebral or peripheral nerve involvement [27, 28]. Ataxia may develop in syndromic as well as nonsyndromic MIDs. Among the syndromic MIDs, ataxia is a dominant phenotypic feature in infantile-onset spinocerebellar ataxia (IOSCA), pontocerebellar hypoplasia (PCH), Alpers syndrome, sensory ataxia neuropathy dysarthria and ophthalmoplegia (SANDO), autosomal recessive spastic ataxia with leukoencephalopathy (ARSAL) syndrome, dystonia and cerebellar ataxia (DYTCA) syndrome, Ekbom syndrome, and Leigh syndrome.


Syndromic MIDs


In two Korean patients with IOSCA due to a compound heterozygote mutation in the twinkle gene, the phenotype additionally included polyneuropathy and myopathy [29]. The nDNA mutation secondarily caused multiple mtDNA deletions [29]. Since the age of 15 months, the two children additionally developed athetosis, hypoacusis, and intellectual decline (see also section “Athetosis”) [29]. In another family, two members presented with IOSCA due to another twinkle mutation [30]. In addition to ataxia, the two patients developed polyneuropathy, athetosis, seizures, hypoacusis, and ophthalmoplegia (see also section “Athetosis”) [30]. Twinkle mutations may not only cause IOSCA but also Alpers syndrome. In two infants with early-onset encephalopathy, muscle hypotonia, athetosis, sensory neuropathy, ataxia, hypoacusis, CPEO, intractable epilepsy, and hepatopathy, reminiscent to Alpers syndrome, the phenotype was caused by mutations in the twinkle gene (see also section “Athetosis”) [19]. The mutations secondarily caused mtDNA depletion in the liver [19]. In Alpers syndrome due to POLG1 mutations, ataxia may be found in addition to parkinsonism, CPEO, polyneuropathy, and hypoacusis (see also section “Parkinson’s syndrome (parkinsonism)”) [11]. In a female child carrying a MT-TK (tRNA(Lys)) mutation, the phenotype was classified as Leigh syndrome with progressive ataxia, myoclonus, seizures, and cognitive decline (see also section “Myoclonus”) [31]. Cerebral MRI showed T2 hyperintensities in the putamen and the posterior medulla. Cerebrospinal fluid (CSF) lactate was elevated and muscle biopsy showed COX-negative fibers [31]. Ataxia and polyneuropathy were the dominant phenotypic features in another patient with Leigh syndrome due to a mutation in the mitochondrial ATP6 gene [32]. Adult-onset ataxia, polyneuropathy, and pyramidal dysfunction were the clinical manifestations in two families carrying other ATP6 mutations [33]. Mutations in the ATP6 gene were responsible for Leigh syndrome, initially manifesting with ataxia and dysarthria [34]. In Leigh syndrome due to a ND6 mutation, the patient presented with dystonia, ataxia, optic atrophy, and epilepsy (see also section “Dystonia”) [35]. Sensory ataxia is a typical feature of the clinical presentation in SANDO syndrome due to twinkle mutations [36]. However, SANDO with sensory neuropathy, dysarthria, and CPEO may be also due to POLG1 mutations [37]. In a patient with SANDO, manifesting as polyneuropathy with sensory ataxia, gait disturbance with falls, blurred vision, CPEO, tremor, and dementia, the causative mutation was located in the POLG1 gene (see also section “Non-Parkinson’s tremor”) [38]. In two siblings with DYTCA syndrome and neuropathy, the phenotype could be attributed to a homozygous missense mutation in exon2 of the COX20 gene (see also section “Dystonia”) [39]. Ataxia is also a dominant clinical feature of PCH. In a patient with PCH type 6, the phenotype included cerebellar and cerebral atrophy, microcephaly, epilepsy, dystonia, optic atrophy, thinning of the corpus callosum, and lactic acidosis (see also section “Dystonia”) [40]. The phenotype was attributed to a mutation in the RARS2 gene, which encodes the mitochondrial arginyl-tRNA synthetase, a protein essential for translation of mitochondrially synthesized proteins [40]. Mutations in the mitochondrial methionyl-tRNA synthetase 2 (MARS2) gene have been recently shown to cause autosomal recessive spastic ataxia with leukoencephalopathy (ARSAL) in humans [41]. Affected patients not only presented with reduced MARS2 activity but also reduced RCCI activity [41]. Cerebellar ataxia is a key feature of Ekbom syndrome additionally manifesting with photomyoclonus, skeletal deformities and lipoma (see also section “Restless leg syndrome”) [42]. Ekbom syndrome is due to mutations in the mitochondrial tRNA(Lys) gene [42].


Nonsyndromic MIDs


Cerebellar or sensory ataxia is not only a typical feature of the clinical presentation in syndromic but also in nonsyndromic MIDs. Nonsyndromic MIDs with ataxia may be due to mtDNA mutations or nDNA mutations.


mtDNA Mutations


In a family in which two members were affected by a nonsyndromic, multisystem MID, a 48-year-old male presented with dementia, quadruspasticity, CPEO, myopathy, deafness, diabetes, and additionally ataxia [23]. The MID was due to a mutation in the mitochondrial MT-TL (tRNA(Leu)) gene [23]. In an adult male carrying an MT-TE (tRNA(Glu)) mutation, the phenotype was characterized by early-onset cataract, progressive paraparesis, and ataxia [43]. Muscle biopsy showed COX-deficient fibers, and biochemical investigations revealed a RCCI defect [43]. Rarely, ataxia may be found in patients carrying the MERRF mutation m.8344A > G [44]. The dominant feature of the phenotype, however, may be CNS demyelination and demyelinating polyneuropathy, associated with palpitations, tinnitus, bilateral 6th nerve palsy, and flaccid quadruparesis [44]. Ataxia has been also reported in a patient carrying a mutation in the tRNA(Pro) gene [45]. He additionally presented with retinitis pigmentosa, dysarthria, hypoacusis, and leukoencephalopathy [45]. In two patients carrying a tRNA(Ser) mutation, cerebellar ataxia was part of the phenotype in addition to myoclonus, epilepsy, and progressive hypoacusis (see also section “Myoclonus”) [46]. Cerebellar ataxia, in addition to hypogonadism, and chorioretinal dystrophy were the dominant clinical manifestations of a mtDNA deletion resulting in deficiency of RCCI [47]. In patients with cerebellar ataxia due to mtDNA mutations, the cell density was decreased in the cerebellum, suggesting that the olivary-cerebellum is particularly vulnerable to mtDNA mutations [27].


nDNA Mutations


Sensory and cerebellar ataxia was part of the multisystem phenotype in a patient with parkinsonism, CPEO, polyneuropathy, and depression (see also section “Parkinson’s syndrome (parkinsonism)”) [13]. The phenotype was due to mutations in the ANT1 and POLG1 genes [13]. Ataxia in nonsyndromic, multisystem MIDs may be also caused by mutations in the OPA1 gene [48]. Additionally, these patients present with color vision deficit, muscle hypotonia, gastrointestinal dysmotility, dysphagia, and severe, early-onset optic atrophy [48]. Ataxia together with late-onset, progressive optic atrophy and myopathy may be the clinical manifestations of mutations in the gene encoding the flavoprotein subunit of RCCII [49]. Ataxia was part of the phenotype in six patients carrying mutations in the CABC1/ADCK3 gene [50]. In addition to ataxia, all patients presented with cerebellar ataxia, epilepsy, and myopathy and some of them with dystonia, spasticity, tremor, migraine, and cognitive impairment (see also section “Dystonia”) [50]. Ataxia was one among several other features in a consanguineous Israeli Bedouin family carrying a mutation in the UQCRQ gene (see also section “Dystonia”) [51]. Furthermore, ataxia can be a phenotypic feature in primary coenzyme-Q deficiency [52]. In a study of 4 patients carrying mutations in the ADCK3/CABC1 gene, the phenotype was characterized by progressive cerebellar ataxia and epilepsy [52]. In two siblings from a consanguineous Pakistani family, cerebellar ataxia and severe myoclonus could be attributed to a mutation in the ADCK3/CABC1 gene, encoding a mitochondrial protein involved in the CoQ metabolism (see also section “Myoclonus”) [53]. The mutation resulted in primary coenzyme-Q deficiency, and supplementation of CoQ was followed by marked clinical improvement [53]. Ataxia was also the dominant manifestation in a patient with CPEO who carried a twinkle mutation [36]. Even polymorphisms in one of the RCCI genes may be associated spinocerebellar ataxia [54].


Dystonia


Dystonia is characterized by sustained muscle contractions causing twisting or repetitive movements or abnormal postures [3]. It may manifest focally, segmentally, regionally, or in a generalized distribution. Focal dystonia includes blepharospasm, oromandibular dystonia, hemifacial spasm, cervical dystonia, spasmodic dysphonia, writer’s cramps, or pelvic floor dystonia. Dystonia as a manifestation of MID has been described in syndromic and nonsyndromic MIDs.


Syndromic MIDs


Among the syndromic MIDs, dystonia may be particularly found in Leber’s hereditary optic neuropathy (LHON) for which the acronym LDYT has been coined [55]. LDYT may be due to mutations in the ND3, ND4, or ND6 genes, respectively [55]. In a large Dutch family with LHON, the phenotype additionally included spastic dystonia [56]. Causative mutations were found in the mitochondrial ND4 and ND6 genes, respectively [56]. In a five-generation Belgian family with 12 affected subjects, a mutation in the ND6 gene manifested with a broad phenotypic heterogeneity, ranging from progressive myoclonic epilepsy, dystonia, and hypokinetic-rigid syndrome to migraine, LHON, optic atrophy, hypoacusis, and diabetes [57]. Activity of RCCI was mildly reduced on muscle biopsy [57]. In a 17-year-old female, LHON was accompanied by spasticity, dystonia, and dysarthria [58]. Biochemical investigations revealed an RCCI defect [58]. Rarely, dystonia may be part of the phenotype in Leigh syndrome caused by a mutation in the ND6 gene [35]. The patient additionally presented with ataxia, optic atrophy, and epilepsy (see also section “Ataxia”) [35]. In a patient with Leigh syndrome due to a mutation in the ND3 gene, dystonia was an additional phenotypic characteristic [59]. Dystonia in addition to slowly progressive cognitive decline and visual impairment was also the clinical manifestation of a homozygous mutation in the TACO1 gene in five individuals from a consanguineous family [60]. The disorder was classified as Leigh syndrome after cerebral MRI had shown bilaterally symmetric lesions of the basal ganglia [60]. Dystonia is also a typical phenotypic feature of deafness-dystonia syndrome (DDS), also known as Mohr-Tranebjaerg syndrome [61]. DDS is characterized by early-onset deafness, dystonia, cortical blindness, spasticity, and dementia [62]. DDS is due to mutations in the TIMM8a gene on chromosome X, which encodes a protein responsible for the transport and sorting of proteins to the inner mitochondrial membrane [61]. In a Turkish family with DYTCA syndrome, two affected siblings additionally presented with sensory neuropathy (see also section “Ataxia”) [39]. Dystonia manifested as torticollis in the affected female and regional leg dystonia in the affected male [39]. Biochemical investigations revealed a RCCIV defect and CoQ deficiency [39]. The phenotype was due to a homozygous missense mutation in exon 2 of the COX20 gene [39]. A mutation in the COX20 gene was also the cause of ataxia and muscle hypotonia in another patient with a RCCIV defect [63]. In a patient with progressive cerebellar and cerebral atrophy, microcephaly, and epilepsy, PCH type 6 was diagnosed [40]. Additional manifestations usually described in types 2 and 4, such as dystonia, optic atrophy, thinning of the corpus callosum, and lactic acidosis, were also present [40]. The phenotype was attributed to a mutation in the RARS2 gene, which encodes the mitochondrial arginyl-tRNA synthetase, a protein essential for translation of mitochondrially synthesized proteins [40]. Dystonia is a typical phenotypic manifestation of paroxysmal non-kinesigenic dyskinesia (PNKD), which is due to mutations in the myofibrillogenesis regulator 1 (MR1) gene (see also sections “Athetosis” and “Chorea”) [64].


Nonsyndromic MIDs


Slowly progressive dystonia with cognitive impairment and striatal lesions may be the dominant clinical feature in patients carrying mutations in the ND6 gene [65]. Muscle biopsy in these patients may show deficiency of RCCI [65]. Progressive generalized dystonia was the main clinical presentation of a patient carrying a mutation in the ND6 gene [66]. He also showed bilateral striatal necrosis on MRI [66]. Dystonia was part of the phenotype also in four patients and two of their siblings carrying mutations in the CABC1/ADCK3 gene [50]. In addition to dystonia all patients presented with cerebellar ataxia, epilepsy, and myopathy and some of them with spasticity, tremor, migraine, and cognitive impairment (see also section “Ataxia”) [50]. Muscle biopsy showed lipid accumulation, mitochondrial proliferation, and COX-negative fibers. RCC activities and CoQ were decreased [50]. In a consanguineous Israeli Bedouin family a mutation in the UQCRQ gene, encoding the ubiquinol-c-reductase complex III subunit 7, caused a nonlethal phenotype characterized by severe psychomotor retardation, dystonia, athetosis, ataxia, muscle hypotonia, and dementia (see also sections “Ataxia” and “Athetosis”) [51]. There was mild lactic acidosis, hyperintense putamen and hypointense caudate and lentiform nuclei on MRI and RCCIII deficiency on muscle biopsy in affected individuals [51]. In three Korean children, a mutation in the ND3 gene manifested with childhood-onset, progressive generalized dystonia and in one of them with stroke-like episodes [67]. In a single patient, a mutation in the NDUFV1 gene manifested clinically with CPEO, cerebellar ataxia, spasticity, and dystonia [68]. Muscle biopsy revealed a RCCI defect. Ketogenic diet had a beneficial effect on CPEO but not on the other manifestations [68]. In a patient with adult-onset dystonia, spasticity, and myopathy, a heteroplasmic missense mutation in the ND1 gene was causative [69]. Dystonia due to fumarase deficiency was part of the phenotype in two siblings of consanguineous parents [70]. They additionally presented with progressive encephalopathy, leukopenia, and neutropenia [70]. A causative missense mutation was found in the fumarase gene [70].


Athetosis


Athetosis is a clinical characteristic of MIDs with CNS involvement but less frequently appreciated than ataxia, parkinsonism, or dystonia. Usually, athetosis is associated with chorea. In a Korean family carrying a twinkle mutation, two family members (infants) manifested as infantile-onset spinocerebellar ataxia (IOSCA) (see also section “Ataxia”) [29]. They developed normally until the age of 18 months and then developed athetosis, ataxia, hypoacusis, axonal polyneuropathy, and intellectual decline afterwards [29]. Muscle biopsy showed multiple mtDNA mutations [29]. In another family with IOSCA, two members presented with ataxia, polyneuropathy, athetosis, seizures, hypoacusis, and ophthalmoplegia (see also section “Ataxia”) [30]. The phenotype was due to a novel twinkle mutation [30]. In a study of eight individuals from two unrelated families with a nonsyndromic, multisystem MID presenting with athetosis, truncal hypotonia, epilepsy, developmental delay, psychomotor retardation, optic and retinal atrophy, and visual loss, extensive diagnostic workup revealed progressive prominent cerebellar atrophy, thinning of the corpus callosum, cortical atrophy, and demyelination [71]. The cause of the abnormalities was a mutation in the ACO2 gene encoding the mitochondrial aconitase, a component of the Krebs cycle [71]. Paroxysmal non-kinesigenic dyskinesia (PNKD) is an autosomal dominant movement disorder characterized by attacks of dystonia, chorea, and athetosis (see also sections “Dystonia” and “Chorea”). The disorder is due to mutations in the MR1 gene [64]. Three isoforms of the gene product exist, MR1M, located on the Golgi apparatus, endoplasmatic reticulum, and plasma membrane, and MR1L and MR1S, both located in the mitochondrial matrix [64]. The two latter are imported via the N-terminal mitochondrial-targeting sequence (MTS) [64]. Athetosis was part of the phenotype also in two infants with early-onset encephalopathy, muscle hypotonia, sensory neuropathy, ataxia, hypoacusis, CPEO, intractable epilepsy, and hepatopathy (see also section “Ataxia”) [19]. The phenotype was classified as Alpers syndrome due to mutations in the twinkle gene [19]. Dystonia was one among several other features in a consanguineous Israeli Bedouin family carrying a mutation in the UQCRQ gene resulting in RCCIII deficiency (see also section “Dystonia”) [51].

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