Parkinson syndrome as a manifestationof mitochondriopathy

Mitochondriopathies (MCPs) are usually multisys-tem disorders caused by impaired metabolism ofthe citric acid cycle, b-oxidation of free fatty acidsor the respiratory chain (1–4). Parkinson syn-dromes (PSs), characterized by bradykinesia,rigour, tremor and disturbed postural reflexes,comprise neurodegenerative PS [idiopathic PS orParkinson’s disease (PD) and atypical PS], symp-tomatic PS (drug induced, structural basal ganglialesions), and pseudo-PS (normal pressure hydro-cephalus, arteriosclerotic encephalopathy, AIDSencephalopathy) (5). Although there are a numberof investigations that report a relation betweenMCP and PS in single patients (6–19), little isknown about the frequency of PS in a group ofMCP patients, the phenotype of these patients andtheir response to anti-Parkinson medication.The following study was thus conducted: 1) to

assess the frequency of PS in patients with MCPduring a 1-year observational period, 2) to describetheir phenotype and 3) to investigate whether PSin these patients responds to the established anti-Parkinson medication.

Methods and materials

Included were all in- and out-patients with MCPand clinical features of PS who attended the 2ndNeurological Department of the NeurologicalHospital Rosenhugel, Vienna, between April 1999and March 2000. MCP was diagnosed in thesepatients 1) if there were clinical or instrumentalfindings indicative of a peripheral nervous system,central nervous system, endocrine, cardiac, gastro-intestinal, ophthalmological, otological or renaldisorder alone or in combination, and 2) if musclebiopsy showed typical features of MCP, like >5%ragged-red fibres, reduced or negative staining forcytochrome c-oxidase with normal, increased orreduced nicotinamid-adenine dehydrogenase orsuccinate dehydrogenase reactivity in >5% ofthe fibres, subsarcolemmal accumulation of abnor-mally shaped or structured mitochondria andintramitochondrial inclusions (20). The diagnosiswas further supported by blood chemical inves-tigations [elevated creatine-phosphokinase, rest-ing lactate, fasting blood glucose, glycosilized

Finsterer J. Parkinson syndrome as a manifestation ofmitochondriopathy.Acta Neurol Scand 2002: 105: 384–389. � Blackwell Munksgaard 2002.

Objectives – Although there is growing evidence for a relation betweenParkinson syndrome (PS) and mitochondriopathy (MCP), little isknown about the frequency of PS in MCP.Material and methods – Thisstudy assessed the frequency of PS in patients with MCP, thephenotype of these patients, and their response to anti-Parkinsonmedication, during a 1-year period. Results – Between April 1999 andMarch 2000 PS was diagnosed in nine of 76 patients with MCP (12%).The frequency of MCP among 144 patients with PS attending thedepartment during the investigational period was 6.3%. Systems mostfrequently affected by the MCP in the nine patients were the peripheralnervous system, central nervous system, endocrinium, heart, intestines,eyes, ears and kidneys. PS in MCPs responded well to amantadine,L-DOPA, dopamine agonists and catechole-o-methyl-transferaseinhibitors. Conclusion – Twelve per cent of the patients with MCP havephenotypic features of PS and 6% of the patients with PS have featuresof MCP. MCP patients with PS frequently show multisysteminvolvement. PS in MCP responds well to anti-Parkinsonmedication.

J. FinstererLudwig Boltzmann Institute for Epilepsy andNeuromuscular Disorders, Vienna, Austria

Key words: oxidative phosphorylation;neurodegenerative disease; neuromuscular disorders;myopathy; dopamine; extrapyramidal system

Dr J. Finsterer, Postfach 348, 1180 Vienna, AustriaTel.: +43 1 88000 259Fax: +43 1 4781711e-mail: duarte@jet2web.cc

Accepted for publication November 22, 2001

Acta Neurol Scand 2002: 105: 384–389Printed in UK. All rights reserved

Copyright � Blackwell Munksgaard 2002

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haemoglobin, blood urea nitrogen, creatinine,abnormal thyroid function parameters, lactatestress testing, if physically capable (21)], cereb-rospinal fluid investigations, electrocardiogram,echocardiography, nerve conduction studies,electromyography, ophthalmologic investigations,visually evoked potentials, electroencephalography,cerebral computerized tomography (CT) or mag-netic resonance imaging (MRI) scans, biochemicalinvestigations of themuscle homogenate and screen-ing for mitochondrial DNA (mtDNA) mutations inthe muscle or blood lymphocytes. All patients hadundergone clinical neurological investigation, aCT/MRI scan of the brain and if available, 123J-labelled2b-carbomethoxy-3 b-(4-iodophenyl) tropane(b-CIT) single photon emission computed tomog-raphy (SPECT). All patients gave written, informedconsent prior to these investigations.

Results

During the observational period 76 patients withMCP were seen at the investigational department.Nine of these patients (12%), six women and threemen, aged 67–81 years, presented with features ofPS, besides other neurological and non-neurolo-gical MCP manifestations. In all patients, PS wasclassified as symptomatic. Demographics and clin-ical and instrumental findings of these patients aregiven in Table 1. Creatine-kinase was elevated inthree patients. The lactate-stress test, carried out infive patients, was abnormal in four. CT/MRI scansof the brain were abnormal in eight patients. Nerveconduction studies, carried out in six patients, wereabnormal in all of them. Electroencephalogramswere recorded in two patients and were normal inboth of them. The electromyogram was myogenicin six, neurogenic in one, and unspecificallyabnormal in two patients (Fig. 1). Muscle biopsy

revealed reduced cytochrome c-oxidase reactivityin all patients, abnormal mitochondria in eight,ragged-red fibres in six, abnormal glycogen storagein four, and abnormal lipid storage in one (Fig. 2,Table 1). Biochemical investigations of the musclehomogenate, carried out in a single patient, werenormal. Screening for mtDNA deletions by South-ern blot and for transfer RNA (tRNA) pointmutations at np 3243, 3250, 3271, 3394, 3460, 8344,7472, 7497 and 7512 by single-strand conformationpolymorphism and restriction fragment lengthpolymorphism, carried out in a single patient,was negative.Organs and systems affected by the MCP in the

nine included patients are listed in Table 2.

Table 1 Demographics and findings on instrumental investigations in nine patients with MCP and PS

Patient Sex Age DD CPK ALST NCS EMG GS LS RRF NCOX AMITO CT/MR AVEP

1 f 67 10 n + nd my ) ) + + + PVD, AT, OST +2 f 79 4 n + mtn my + ) ) + + PVD, RST nd3 f 80 45 › + an ne ) ) ) + + PVD, OST nd4 m 76 6 › nd mtn unsp ) ) + + + PVD, AT, OST, DIB nd5 f 76 1 n nd nd my ) + ) + + n nd6 m 68 20 n + nd unsp + ) + + + PVD, AT, OST +7 f 81 0.5 n nd an my ) ) + + + PVD, AT, OST nd8 f 68 8 › nd dn my + ) + + ) AT nd9 m 71 53 n n an my + ) + + + PVD +

Sex: (f: female, m: male), Age: (years, in May 2000), DD: disease duration (years) of MCP, CPK: creatine-kinase (n: normal, ›: increased), ALST: abnormal lactate stress test (+ :yes, nd: not done), NCS: nerve conduction studies (an: axonal neuropathy, dn: demyelinating neuropathy, mtn: mixed type neuropathy), EMG: electromyography (my: myogenic,ne: neurogenic, unsp: unspecifically abnormal), GS: increased glycogen storage, LS: increased lipid storage, RRF: ragged red muscle fibres, NCOX: COX-negative fibres, AMITO:abnormal mitochondria on electron microscopy with paracristalline inclusions, CT/MR: CT/MRI scans of the brain (PVD: periventricular demyelination, AT: atrophy, OST: oldstroke, RST: recent (< 4 weeks) stroke, DIB: disseminated intracerebral bleeding), AVEP: abnormal visually evoked potentials.

Figure 1. Myogenic electromyogram from the right brachialbiceps muscle of patient 6 shows predominantly short, lowamplitude motor unit action potentials with a mean durationof 9.1 ms, a mean amplitude of 261 lV, and a per centpolyphasia of 15%. As the interference pattern was dense withan amplitude of 1 mV, the electromyogram was interpreted asmyogenic.

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All patients hadmyopathy, six had polyneuropathy.Eight patients had dementia, six upper motorneurone signs, five a history of stroke or transitoryischaemic attacks (TIAs), and three ataxia. Allpatients had some sort of endocrine impairment.Eight patients had cardiac abnormalities. Three

patients each had vomiting and diarrhoea of unde-termined cause. In four patients a cataract and inthree a glaucoma had been diagnosed. Threepatients showed prolonged latencies of visuallyevoked potentials. Impaired hearing was found infive patients, tinnitus in two and peripheral vertigoin one. Five patients had renal failure.Clinical and instrumental findings concerning

the manifestations of PS and its response toadequate therapy are given in Table 3. All patientshad bradykinesia, eight had dementia, eight musclerigidity, six resting tremor and six postural insta-bility. According to the Hoehn–Yahr score, onepatient was classified as stage II, four as stage III,and two each as stage IV and stage V. Thefrequency of MCP among the 144 patients withPS attending the department during the observa-tional period was 6.3%. All patients respondedwell to amantadine when given intravenously.Eight patients received L-DOPA, five dopamine-agonists, and two catechole-o-methyltransferaseinhibitors, all with good response.

Discussion

MCPs are caused by impaired mitochondrialmetabolism. In the majority of the cases theoxidative metabolism is impaired because of affec-tion of the respiratory chain enzymes (respiratorychain disorders, RCDs) (1–4). RCDs may becaused by mutations in mtDNA located genes(primary RCDs) or because of nuclear locatedgenes (secondary RCDs) (22). As a result of theunique features of the mtDNA (heteroplasmy,replicate segregation, threshold effects) the pheno-type of MCPs is largely variable (2). In most adultcases, MCPs are multisystem disorders, affectingthe peripheral nervous system, central nervous

Figure 2. Muscle biopsy from the left deltoid muscle of patient9 shows irregular intrasarcoplasmatic distribution of mito-chondria in two muscle fibres (A: modified Gomori trichromestain ·300). In single fibres cytochrome c-oxidase activity wasdeficient (B: cytochrome c-oxidase ·150).

Table 2 Manifestations of MCP in nine patients with MCP and PS

Patient Sex Age PNSI CNSI ECI CI GI OCI OTI RI

1 f 67 MP DE, ST SS, TD AEC, DIL N CA, AVP TI, HA N2 f 79 MP, NP ST, US, AT, DE SS, HN, HL AEC VO, DR N N RF3 f 80 MP, NP DE, US TD, DM, HK HF, AEC N N HA N4 m 76 MP, NP ST, AT, DE OP MT, HT N CA HA N5 f 76 MP ST, US, AT, DE SS, HH, HK N DR AVP N N6 m 68 MP, NP DE, US DM, OP ECA, DIL, HT N N N RF7 f 81 MP US, DP, DE TD, DM, OP AEC, HT VO CA, GL N RF8 f 68 MP, NP US, ST DM, HL, OP DIL, HF, AEC VO, DR CA, GL HA RF9 m 71 MP, NP DE HL, OP, HH, IP HT, DIL, HF, AEC N AVP, GL HA, PVE, TI RF

PNSI: Peripheral nervous system involvement (MP: myopathy, NP: neuropathy), CNSI: central nervous system involvement other than PS (DE: dementia, ST: stroke, TIA:transitory ischaemic attack, US: upper motor neurone signs, AT: ataxia, DP: dysphagia), ECI: endocrinological involvement (SS: short stature, TD: thyroid dysfunction, DM:diabetes mellitus, HL: hyperlipidaemia, HK: hypokaliaemia, HN: hyponatriaemia, HH: hyperhidrosis, OP: osteoporosis, IP: impotentia), CI: cardiac involvement (MT: myocardialthickening, AEC: abnormal ECG, HT: hypertension, AP: anginal chest pain, DIL: dilatation of the cardiac cavities, HF: heart failure, N: normal), GI: gastrointestinal involvement(VO: vomiting, DR: diarrhoea), OCI: ocular involvement (CA: cataract, AVP: abnormal visually evoked potentials, GL: glaucoma), OTI: otological involvement (HA: hypacusis, TI:tinnitus, PVE: peripheral vertigo), RI: renal involvement (RF: renal failure).

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system, endocrinium, heart, gastrointestinal tract,eyes, ears, kidneys, dermis, bone marrow or carti-lage (20, 22). Central nervous system manifesta-tions of MCPs are stroke, epilepsy, dementia,ataxia, myocloni, prolonged latencies of visuallyevoked potentials (20, 23), unspecific white matterlesions or basal ganglia calcification (2, 20, 24). Inthe present investigation the diagnosis of MCP wasbased upon clinical and muscle biopsy findings.Thus, it cannot be excluded, that MCP was causedby impaired mitochondrial metabolic pathwaysother than the respiratory chain. However, thefrequently abnormal lactate stress test and thefrequent presence of cytochrome c-oxidase negativemuscle fibres make RCD as the underlying disorderin all patients quite likely. The negative search forbiochemical defects and mtDNA mutations in onepatient does not necessarily rule out RCD.The most frequent among the PSs is PD, which

accounts for 80% of the PSs (5). The prevalence ofPD is 160/105 (5, 25). PD may be caused bymutations in the a-synuclein gene on chromosome4q21–23, parkin gene on chromosome 6q25–27, anunknown gene on chromosome 2p, or the UCH-L1gene on chromosome 4p15 (25). PD is diagnosedupon the typical clinical features unilateral onset ofsymptoms, persistent side predominance of symp-toms, slow progression, good response to L-DOPAand absence of neuro-radiological abnormalities.For a long time, PD was thought to be because of areduction of dopaminergic neurones in the sub-stantia nigra. Based upon recent results (26), thepathogenic concept of PD is widely changing. Atpresent, PD is conceptualized as a chronic pro-gressive cytoskeletal disease involving varioustypes of projective neurones. The illness devastatesspecific regions of the motor, limbic and autonomicsystem, and progresses slowly and unremittingly.

The lesions engulf not only cortical and subcorticalcomponents of the central nervous system but alsolarge portions of the peripheral nervous system andautonomic nervous system, which is why it ismisleading to reduce PD to a disorder of thesubstantia nigra (26).All of the presently investigated patients were

classified as having symptomatic PS induced byMCP. Only a single patient initially fulfilled thecriteria of PD. However, this patient later devel-oped central nervous system abnormalities otherthan PS, such as upper motor neurone signs, ataxiaand stroke, which is why he was finally alsoclassified as symptomatic PS. In all patients mul-tisystem atrophy, supranuclear palsy and cortico-basal degeneration were excluded, as theyresponded well to L-DOPA. None of the patientshad taken neuroleptics, metoclopramid, calcium-antagonists, or reserpin, known to induce sympto-matic PS (5). Furthermore, none of the patientshad a normal pressure hydrocephalus, an arterio-sclerotic encephalopathy, or AIDS. These disor-ders were excluded by serological and radiologicalinvestigations. None of the patients had a historyof manganese or carbon monoxide poisoning, ormicrobial or non-microbial central nervous systeminflammation. No brain tumour was found in anyof the patients (5). Six patients had a history ofstroke, which preceded the PS in all of them. Noother causes for symptomatic PS were found.Interestingly, risk factors for stroke or embolismwere negative in all patients, suggesting thatstrokes and TIAs were related to MCP. Argumentsfor PS as a manifestation of MCP in the presentlyinvestigated patients are, that all other causes forPS were excluded, that all patients had multisysteminvolvement and that all had central nervoussystem involvement other than PS.

Table 3 Symptoms of PS and responsiveness to anti-Parkinson medication in nine patients with MCP

Patient DD HYS ULORestingtremor

Muscularrigidity Bradykinesia

Posturalinstability Dementia CT/MRI SPECT AMTD DOPA DA COMTI MAOB

1 0.5 III ) + + + + + a n + + + ) )2 3.5 IV ) + + + ) + a a + + ) ) )3 7 II ? + ) + ) + a nd + + ) ) )4 6 V + ) + + + + a nd + + + + +*5 1 V + + + + + + n nd + + ) ) )6 0.5 IV ) ) + + + + a nd + + ) + )7 0.5 III + + + + + + a nd + ) + ) )8 3 III ) ) + + ) ) a a + + + ) )9 8 III ) + + + + + a a + + + ) )

DD: duration (in years) of PS until May 2000, HYS: Hoehn)Yahr score, ULO: unilateral onset, ?: uncertain, CT/MRI: CT/MRI scan of the brain (n: normal, a: abnormal), SPECT:b-CIT single photon emission computed tomography, AMTD: responsiveness to amantadine, DOPA: responsiveness to L-DOPA, DA: responsiveness to Dopamin-receptoragonists, COMTI: responsiveness to catechole-o-methyl-transferase inhibitors, MAOB: responsiveness to mono-amino-oxidase-B inhibitors, +: present, ): absent, a: reducedaffinity to presynaptic dopamin receptors. * Given only until dopamine agonists were begun.

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Several previous studies already suggested arelation between PS and MCP (7, 9, 11, 13, 16,17): 1) mitochondrial ND1 defects can be foundin the substantia nigra and platelets of singlepatients with PD (3, 9–12, 14–16), 2) 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, preferentially sto-red in mitochondria of dopaminergic neuronesof the substantia nigra, inhibits complex-1 of therespiratory chain and destabilizes the D-loopstructure, thereby inhibiting mtDNA replication(27), 3) respiratory chain complexes contain iron–sulphur clusters and PD patients have an ironoverload in their substantia nigra, 4) PD cybridcells increase basal nuclear factor jB activity,which functions as a protective mechanism againstimpaired electron transport (6), 5) mtDNA frompatients with PD induces abnormal mitochondrialultrastructure in cybrids, similar to that of MCPs(18), 6) there are respiratory chain defects in theskeletal muscle of some patients with PD (19) and7) oxidative stress is a major factor for neuronaldegeneration in PD (3, 12). Oxidative stress maybe because of the production of reactive oxygenspecies like O2, H2O2, OH and ONOO by thedopamine metabolites dopamine quinone andhydrogene peroxidase. Oxidative stress is com-pensated by increased expression of antioxidativeenzymes like superoxide dismutase, catalase,glutathione peroxidase and glutathione reductase.In case of impaired compensational mechanisms,oxidative stress reduces the mitochondrial mem-brane potential (6), damages neuronal popula-tions and nucleic acids (i.e. RNA and mtDNA),particularly in the substantia nigra of patientswith PD (28), and alters the function of variousmitochondrial proteins (28, 29). The latter effect isprevented by glutathione, but not superoxide-dismutase or catalase (29). Hydrogen peroxidedecreases active-state-3 respiration, prevented byperquiline and catalase. Dopamine quinone indu-ces swelling of the mitochondria by affecting themitochondrial permeability transition pore, inhib-ited by cyclosporin A and glutathione (29).Depletion of glutathione contributes to neuronalapoptosis in PD (30). Which of these mechanismswas responsible for the abnormalities found in thepresently investigated patients remains specula-tive.Limitations of the study were that the study

group was small, that the diagnosis of MCP wasnot genetically confirmed, and that blood chemical,biochemical, MRI, and SPECT investigations werenot carried in all patients. The lactate stress testcould not be performed in four patients, becausethey were wheelchair-bound or bedridden. Bio-chemical investigations were carried out only in a

single patient, because too few material wasavailable (n ¼ 2) or histological examinationswere unequivocally indicative of MCP (n ¼ 6).Electroencephalograms were recorded in only twopatients because there was no indication forseizures in the others. SPECT was not carried outin five patients because they were already underanti-Parkinson medication. MRI scans were notcarried out in all patients because of claustropho-bia or because of contraindications, like metalimplants or a pacemaker.In conclusion this study shows that features of a

PS may occur in 12% of the patients with MCP.On the other hand, features of MCP can be foundin 6% of the patients with PS. All patients withMCP and PS have multisystem involvement. PSin patients with MCP is sensitive to amantadine,L-DOPA, dopamine agonists and catechole-o-methyl-transferase inhibitors.

AcknowledgementsWe are grateful to Dr C. Haberler, for providing histopatho-logical data.

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