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Parkin disease: a phenotypic study of a large case series

Naheed L. Khan, Elizabeth Graham, Peter Critchley, Anette E. Schrag, Nicholas W. Wood, Andrew J. Lees, Kailash P. Bhatia, Niall Quinn
DOI: http://dx.doi.org/10.1093/brain/awg142 1279-1292 First published online: 8 April 2003

Summary

Mutations in the parkin gene, PARK2, are a common cause of parkinsonism in familial as well as isolated cases with an age of onset <40 years and should be considered in the diagnostic work up of young‐onset parkinsonism. We report a detailed clinical evaluation of a personal series of 24 patients with mutations in the parkin gene. The clinical presentation of most cases was broadly comparable to that of previous descriptions of autosomal recessive early‐onset or juvenile parkinsonism and young‐onset Parkinson’s disease and also had similarities with phenotypes of dopa‐responsive dystonia. However, our only case with consanguineous parents had an age of onset of 54 years. We report three new phenotypes at presentation: cervical dystonia; autonomic dysfunction and peripheral neuropathy; and pure exercise‐induced dystonia. We emphasize a number of clinical features that can be seen in parkin disease: focal dystonia; early instability; freezing; festination or retropulsion; concurrent autonomic failure; dramatic response to anticholinergics; early or atypical l‐dopa‐induced dyskinesias; exquisite sensitivity to small doses of l‐dopa; and recurrent psychosis, even taking l‐dopa alone. We also report behavioural disorder prior to the onset of parkinsonism. Some relatives carrying a single parkin mutation without extrapyramidal symptoms or signs also had psychiatric symptoms that might be related to their carrier status.

  • Keywords: parkin; PARK2; phenotype; mutation
  • Abbreviations: ARJP = autosomal recessive juvenile parkinsonism; DRD = dopa‐responsive dystonia; IPD = idiopathic Parkinson’s disease; MMSE = Mini‐Mental State Examination; PDI = peripheral dopa decarboxylase inhibitor

Received May 13, 2002. Revised October 20, 2002. Second revision January 14, 2003. Accepted January 15, 2003

Introduction

Autosomal recessive early‐onset parkinsonism, first described in Japan in 1973—where it is also called autosomal recessive juvenile parkinsonism (ARJP)—is often characterized by dystonia at onset, hyperreflexia, early complications from l‐dopa treatment [in contrast to dopa‐responsive dystonia (DRD)] and slow progression (Yamamura et al., 1973). Three loci have been identified: PARK2 on chromosome 6 (Kitada et al., 1998); and PARK6 (Valente et al., 2001) and PARK7 (Bonifati et al., 2003), both of which map to chromosome 1. PARK2 was the first recessive parkinsonism locus to be mapped and the gene, parkin (OMIM 602544), cloned (Kitada et al., 1998). Deletions, multiplications or point mutations in the coding regions have been identified not only in kindreds of different ethnic origins, but also in isolated cases of young onset parkinsonism and familial cases with an age of onset as late as 64 years (Abbas et al., 1999; Klein et al., 2000; Lucking et al., 2000). PARK2 encodes a protein, parkin, which functions as an ubiquitin‐protein ligase through the C‐terminal ring finger domain; mutants have impaired self‐ubiquitination and impaired degradation of both self and synaptic vesicle associated protein (Shimura et al., 2000; Zhang et al., 2000).

Neuropathological examination has been reported in only four parkin cases (Mori et al., 1998; Hayashi et al., 2000; Farrer et al., 2001; van de Warrenburg et al., 2001). In one case, Lewy bodies were present in the substantia nigra and locus coeruleus, but also in the nucleus basalis of Meynert and the amygdalo‐hippocampal region (Farrer et al., 2001); however, in the three remaining cases, there was an absence of Lewy bodies and a severe and generalized loss of dopaminergic neurons from the substantia nigra pars compacta and locus coeruleus. One of these three brains showed additional neurofibrillary tangles and argyrophilic astrocytes in cerebral cortex and brainstem nuclei (Mori et al., 1998), the second showed additional involvement of the substantia nigra pars reticulata (Hayashi et al., 2000), and the third showed neuronal loss in parts of the spinocerebellar system (van de Warrenburg et al., 2001). Thus, parkin disease is a distinct genetic entity whose clinical and pathological features show varying degrees of overlap with those of idiopathic Parkinson’s disease (IPD). In the limited number of [18F]‐dopa PET examinations of parkin cases reported to date (Broussolle et al., 2000; Hilker et al., 2001; Portman et al., 2001; Khan et al 2002), nigrostriatal dysfunction has been noted bilaterally in both caudate and putamen. In addition, clinical and subclinical nigrostriatal dysfunction—revealed by [18F]‐dopa PET—and subtle extrapyramidal signs have been reported in asymptomatic carriers of a single mutant parkin allele (Hilker et al 2001; Khan et al., 2002).

Preliminary studies have shown that parkin mutations account for 45% of autosomal recessive parkinsonism with an age of onset <45 years and 77% of isolated cases of parkinsonism with an age of onset <20 years (Lucking et al., 2000). Thus mutations in PARK2, parkin, are a frequent cause of young‐onset parkinsonism and must be considered in the diagnostic work‐up of early‐onset, and sometimes later‐onset, Parkinson’s disease. We here describe a detailed clinical evaluation of 24 cases of parkin disease.

Methods

Molecular analysis

PARK2: PCR amplification and sequence analysis

The 12 coding exons of the parkin gene were amplified from genomic DNA by the polymerase chain reaction (PCR) using previously described primers (Kitada et al., 1998) except for the primer for exon 3, for which exonic primers Ex3iFor and Ex3iRev were used (Abbas et al., 1999). The same primers were used for sequencing the PCR products of the 12 exons on both strands using a Big Dye Terminator Cycle Sequencing Ready Reaction DNA Sequencing Kit (Applied Biosystems, Foster City, CA, USA) on an ABI 373 automated sequencer with the Sequence Analysis v.3.4.1 software (Applied Biosytems).

PARK2: semi‐quantitative PCR

Exon deletions/duplications were screened using a semi‐quantitative PCR protocol as described previously (Lucking et al., 2000). The PCR products were analysed on an ABI 377/3100 automated sequencer with Genescan v.3.1.2 and Genotype v.2.5.1 software (Applied Biosytems). Deletions and insertions of bases were deduced from the size of the PCR products.

Patients

On the basis of a preliminary screen of a collection of DNA samples from 115 cases with age of onset of parkinsonism <50 years or unusual features, we identified 24 patients with parkin mutations, 23 of whom had disease onset ≤age 35 years. We carried out a detailed clinical study of these subjects using a retrospective review of medical records incorporating a standardized clinical proforma including a review of prior drug exposure, family and clinical history. Cognitive assessment was performed using the Folstein Mini‐Mental State Examination (MMSE) (Folstein et al., 1975) at varying intervals after disease onset. All subjects gave informed consent and the project was approved by the Joint Research Ethics Committee of the National Hospital for Neurology and Neurosurgery and the Institute of Neurology, London, UK. A total of five first and second degree relatives without parkinsonism of five unrelated parkin patients were both examined and screened for parkin mutations.

Results

Molecular analysis

The mutations in four isolated cases and five sibling sets have been reported previously (Lucking et al., 2000); these cases have been rescreened. In addition, eight new cases (seven isolated cases, one of whom was the product of a consanguineous marriage, and one additional member of one of the affected sibships) have been identified (Table 1). Mutations on both alleles were identified in 14 cases, of which only one was a homozygote (Patient 20), the remaining 13 cases being compound heterozygotes carrying a different parkin mutation on each allele (3 isolated, 10 familial cases). In the remaining 10 parkin cases (seven isolated, three familial cases), a single mutant allele was identified. One of the parkin mutations in Patients 2–5, all of whom are siblings, was an intron 5 splice site mutation (+2 T>A), the first intronic mutation to be reported in parkin disease (Khan et al., 2002; West et al., 2002).

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Table 1

Parkin mutations identified in 24 cases with parkinsonism

PatientIsolated/familial caseParkin mutation
Allele 1Allele 2
1Isolatedexon 6/7 deletionuncharacterized
2Familial)exon 8 deletionintron 5 (+2 T>A)
3Familial) sibsexon 8 deletionintron 5 (+2 T>A)
4Familial)exon 8 deletionintron 5 (+2 T>A)
5Familial)exon 8 deletionintron 5 (+2 T>A)
6Familial} sibsexon 9 1101C→T(Arg334Cys)exon 7 939G→A(Asp230Asn)
7Familial}exon 9 1101C→T(Arg334Cys)exon 7 939G→A(Asp230Asn)
8Isolatedexon 5 deletionuncharacterized
9Isolatedexon 12 1390G→A(Gly430Asp)uncharacterized
10Isolatedexon 7 924C→T(Arg275Trp)uncharacterized
11Isolatedexon 7 905T→A(Cys268 stop)exon 2 202–203 AG deletion
12Familial} sibsexon 3 deletionexon 4 deletion
13Familial}exon 3 deletionexon 4 deletion
14Isolated(consanguineous)exon 9 1101C→T(Arg334Cys)uncharacterized
15Familial} sibsexon 7 924C→T(Arg275Trp)exon12 1390G→A(Gly430Asp)
16Familial}exon 7 924C→T(Arg275Trp)exon12 1390G→A(Gly430Asp)
17Isolatedexon 12 1390G→A(Gly430Asp)exon 3 deletion
18Isolatedexon 7 867C→T(Arg256Cys)uncharacterized
19Isolatedexon 5 deletionuncharacterized
20Isolatedexon 2 202–203 AG deletionexon 2 202–203 AG deletion
21Isolatedexon 7 924C→T(Arg275Trp)exon 5/6 deletion
22Familial} sibs }exon 7 905T→A(Cys268 stop)uncharacterized
23Familial} sibs }exon 7 905T→A(Cys268 stop)uncharacterized
24Familial uncle }exon 7 905T→A(Cys268 stop)uncharacterized

} = familial

As a group, mutations occurred most frequently in exon 7. Patients 10 and 21, and siblings 15 and 16, shared point mutation Ex7 924C→T (Arg275Trp). Patients 10 and 17, and siblings 15 and 16 shared point mutation Ex12 1390G→A (Gly430Asp). Patient 6 and his sister, Patient 7, shared point mutation Ex9 1101C→T (Arg334Cys) with Patient 14. Patients 11 and 20 shared exon 2 202–203 AG deletion. Patients 8 and 19 both had a deletion in exon 5. Patients 11 and 21–24 shared Ex9 1101C→T (Arg334Cys).

Patients

In all cases, the pattern of inheritance was compatible with autosomal recessive disease (clinically unaffected parents, who may or may not have been in consanguineous marriage). Eleven patients were isolated cases; 10 of them have young‐onset parkinsonism, but in the eleventh, the only one in the entire series from consanguineous parents, age at onset was 54 years. The remaining 13 patients were from five unrelated families (Table 1). In one of these families, the Burnley kindred (Patients 22–24), young‐onset parkinsonism was observed in two generations (see Fig. 1). All cases, with the exception of Patients 17 and 18, fulfilled the UK Parkinson’s Disease Society Brain Bank diagnostic criteria for idiopathic Parkinson’s disease (Gibb et al., 1988) except for the presence of a family history in 13 of them. Sixteen cases were male and eight female (Table 2). All cases were resident in the UK, but were of differing ethnic origins: Irish (isolated case n = 1, families n = 2); English (isolated cases n = 7, family n = 1); Scottish (isolated case n = 1); Japanese (isolated case n = 1); Indian (family n = 1); Bangladeshi (isolated case n = 1); and Dutch (family n = 1). The age at onset of symptoms in all 24 cases ranged from 7 to 54 years (mean 24.0 ± 9.9SD). Disease duration ranged from 4 to 56 years (mean 24.2 ± 13.0SD) (Table 3). Details of illustrative case histories of each subject are given in Appendix 1. It should be noted that there is considerable overlap between cases.

Fig. 1 Pedigree of the Burnley kindred with parkin disease in two generations. *Individuals with isolated postural tremor. + = individuals with depression.

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Table 2

Clinical characteristics of individual parkin cases

PatientSex/ageEthnic originAge at onset (years)Disease duration (years)Hoehn and Yahr motor scoresAdditional featuresFamily history
ONOFF
1F/34Japanese2311Dramatic response to benzhexol, l‐dopa sensitivity ++
2F/54Irish312334Abduction–adduction oscillatory tremor of lower limbs
3M/60Irish28322.54Abduction–adduction oscillatory tremor of lower limbsSuicide, psychosis,
4M/55Irish262934Abduction–adduction oscillatory tremor of lower limbsdepression, tremor
5M/51Irish321934Abduction–adduction oscillatory tremor of lower limbs
6M/55Indian28272.53Misdiagnosed as DRD at onset
7F/46Indian3016Right‐sided hemiparkinsonism at onset, bilateral STN DBS*
8M/40English291112Left leg tremor at onset, good response to orphenadrine, still l‐dopa naiveTremor
9M/32English72534Cervical dystonia at onset, misdiagnosed as DRD, sensitivity l‐dopa ++, atremulous, panic attacks and self‐mutilation
10M/30Scottish181202.5Paranoia and panic attacks prior to parkinsonism, exercise‐induced dystonia at onset, depression Anorexia nervosa, depression
11F/33English19141.52.5Bilateral akinetic‐rigid, dramatic response to benzhexol, still l‐dopa naiveDepression
12M/77Dutch304723Early falls, atremulous, diagnosed and treated after 20 years, dramatic response to l‐dopa within 2 hSuicide
13M/74Dutch20s>4534Tremor at onset, treated with l‐dopa after > 40 years dramatic response
14M/58Bangladeshi54412Consanguineous parents, prominent orofacial dyskinesias 3 days after starting l‐dopa
15M/51Irish133834DRD considered at onset, psychosis, l‐dopa sensitivity++ (motor)
16F/56Irish342222.5Post‐natal depression prior to onset, l‐dopa sensitivity ++ (motor)
17M/29Irish13162.54Dramatic response to benzhexol, autonomic and axonal peripheral neuropathy, still l‐dopa naive, attempted suicide, depressionDepression
18F/21English138Coincidental cerebral palsy
19M/31English10–1516–2112Coincidental familial motor tics, neck tremor at 12–15, parkinsonism at 30 years oldTremor, depression
20M/57English292812Drug‐induced psychosis, unilateral thalamotomyDepression
21M/52English223014Writer’s cramp at onset, l‐dopa sensitivity++, psychosisDepression, psychosis
22F/36English} 1521Anorexia nervosa, suicide attempts, depression prior to onset, bilateral thalamotomyTremor,
23F/46English} Burnley kindred153134Good response to benzhexol, still l‐dopa naivedepression
24M/80English}2456Dramatic response to l‐dopa

} = familial; – = unavailable motor scores; *STNDBS = subthalamic nucleus deep brain stimulation.

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Table 3

Group clinical characteristics of patients with parkin disease

Age of onset:Number of cases
 <209
 21–3011
 31–403
 41–500
 51–601
Mean age of onset all cases in years (SD, range)24.0 (±9.9, 7–54)
Mean disease duration in years (SD, range)24.5 (±13.1, 4–56)
Symptoms and signs at onset:
 tremor70%
 bradykinesia44%
 rigidity13%
 dystonia41%
 symmetry26%
 micrographia13%
 poor balance23%
Symptoms and signs at examination:
 bradykinesia100%
 rigidity100%
 rest or postural tremor92%
 brisk reflexes8%
 MMSE score28 (range 25–30)
Autonomic symptoms:60%
 urgency45%
 impotence28% of males
 othostatic faintness13%
Freezing episodes63% (8% within first 5 years)
Falls50% (30% within first 5 years)
Excellent response to l‐dopa/anticholinergics:75%
Duration of l‐dopa treatment (n = 16 out of 24 patients)15.9 (9.0 SD)
Dyskinesia in l‐dopa treated patients100%
Fluctuations in l‐dopa treated patients50%

Motor features

At disease onset, bilateral symptoms were reported in 26%, limb tremor in 70%, bradykinesia in 44% and micrographia in 13% of cases. The overall picture was that of slowly progressive parkinsonism. Thus, despite frequently long disease duration, none of the patients was greater than Hoehn and Yahr stage 3 in ‘ON’ or stage 4 in ‘OFF’ at the last evaluation, and Patient 12, despite a disease duration of 47 years, was still stage 2 in ‘ON’ and stage 3 in ‘OFF’ (Table 2). ‘Poor balance’ was reported as an initial symptom by 23% of cases. Sixth‐three percent of cases reported freezing, which developed in 8% of them within 5 years, and in 33% within 10 years of disease onset. Fifty percent of cases reported 1–6 falls per month, 30% of them within 5 years and 50% within 10 years of disease onset. Sleep benefit was reported by 63%. For an example, see the details about Patient 1 in Appendix 1.

Tremor

With the exception of Patients 10 and 12, who still remained atremulous after disease durations of 25 and 47 years, respectively, the remaining 22 (92%) developed a tremor (at rest or postural), which frequently started in, or was restricted to, one or both legs, at some stage of disease. For examples, see the details about Patients 2–8 in Appendix 1.

Dystonia

Dystonia was reported in 41% of cases as a presenting symptom, involving feet in seven (one of whom presented with pure exercise induced dystonia), hands in two, and neck and trunk in one each. Some 78% of cases had developed dystonia at some point prior to treatment, involving hands in three, feet in 18, neck in five, and trunk and gait in one each. Some had involvement of more than one of the above sites. For examples, see the details about Patients 9 and 10 in Appendix 1.

Response to treatment

An excellent and sustained response to drug therapy was reported by 75% of treated patients. For an example of a dramatic response to anticholinergics, see the details about Patient 11 in Appendix 1. For examples of a dramatic response to l‐dopa, see the details about Patients 12 and 13 in Appendix 1.

Treatment‐related complications

Sixteen patients had started l‐dopa therapy, with a mean treatment duration of 15.9 ± 9.0SD years. Half of them reported dose‐related fluctuations, and all reported peak dose dyskinesias, except one patient who reported diphasic dyskinesia. Dyskinesias had developed after a mean interval of 6.7 years (± 7.6SD) (range from 3 days to 21 years) after commencing l‐dopa treatment. Some patients developed atypical or unusual levodopa‐induced dyskinesias, or excessive sensitivity to very low doses of l‐dopa. For examples, see the details about Patients 14–16 in Appendix 1.

Autonomic dysfunction

Autonomic symptoms were present in 60% of patients, with 45% reporting urinary urgency, 28% of male patients reporting impotence, and 13% reporting orthostatic symptoms. For an example, see the details about Patient 17 in Appendix 1.

Other clinical findings

Cognition was normal in all cases, with a mean Mini‐mental test score of 28, except for Patient 18 (see Appendix 1), who had presumed cerebral palsy. Hyperreflexia was present in 8% of cases. Eye movements, sensory testing and co‐ordination were normal in all subjects, except for Patient 18. Patient 18 (see Appendix 1) with presumed cerebral palsy and Patient 19 (see Appendix 1) with a past and family history of tics had other neurological abnormalities that we believe are probably, but not necessarily, coincidental.

Behavioural disorder

Psychiatric/behavioural symptoms were reported by 56% of cases (Table 4). In 25%, these symptoms started prior to, and in 31% after, the onset of parkinsonism. For examples, see the details about Patients 20 and 21 in Appendix 1.

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Table 4

Parkin cases with behavioural disorder and a family history of behavioural disorder

Number of patientsPatient number
Prior to onset of motor symptoms:
 depression211, 16
 paranoia110
 psychosis0
 panic attacks110
 anorexia nervosa122
 suicide attempts0
 self‐harm118
After the onset of motor symptoms:
 depression51, 10, 15, 17, 20
 paranoia0
 psychosis315, 20, 21
 panic attacks52, 4, 9, 10, 21
 anorexia nervosa0
 suicide attempts217, 21
 self‐harm28, 9
Behavioural disorder in first and second degree relatives of parkin patients:
 depression82–5, 10, 11, 17, 19–24
 paranoia0
 psychosis22–5, 21
 panic attacks0
 anorexia nervosa110
 suicide attempts22–5, 12–13
 self‐harm0

Family history

Motor features

Five relatives of index cases (Patients 2, 8, 19, 22) were reported to have isolated tremor, essential tremor or postural tremor. Subtle extrapyramidal signs have been reported in three asymptomatic parkin carriers of the Irish kindred (Patients 2–5) (Khan et al., 2002).

Behavioural features

The 16 unrelated parkin patients reported a total of 12 out of 71 (17%) first or second degree relatives without symptoms of parkinsonism, but with a history of psychiatric illness (Tables 2 and 4). Five of these relatives were screened for parkin mutations: all five were carriers of a single mutation and all had a normal neurological examination except for a sibling of Patient 2, who had subtle extrapyramidal signs that did not fulfil diagnostic criteria for IPD. However, this relative had a history of depression and schizophrenia, and had been treated with neuroleptics (Khan et al., 2002).

The Burnley kindred (see Fig. 1)

This kindred originated from Burnley, a small town in Lancashire, UK. Grandparents I:1, I:2 and parents II:1, II:2 were from the same town, but were reported not to be related and did not have parkinsonism. Patients 22 (III:2), 23 (III:4) and 24 (II:7) were members of this family (see Appendix 1). This family is unusual in that parkinsonism occurred in two generations, with all affected individuals sharing the same parkin mutation on one chromosome, with the other allele being undetermined.

Discussion

Parkinsonism due to mutations in PARK2, parkin, is a distinct genetic entity with a phenotype that is typically characterized by young‐onset (<40 years) parkinsonism, predominant lower limb dystonia, dramatic response to l‐dopa and a benign and slowly evolving course (Khan et al., 2002). Whilst young age of onset is undoubtedly the best clinical indicator of parkin disease, the condition is not confined to young or juvenile cases: we report a familial case with an age of onset of 54 years. In the Burnley kindred, II:6 (genotype unknown), who is deceased, developed parkinsonism aged 65 years. This individual may also have had parkin disease, although IPD could not be excluded. These cases extend previous reports of some familial cases having an age of disease onset closer to the average for IPD (Klein et al., 2000; Lucking et al., 2000). The phenotype can also include a bilateral atremulous, akinetic‐rigid syndrome and unusual tremor such as an abduction–adduction tremor confined to the legs in Patients 2–5 (Khan et al., 2002) or the tremor‐dominant parkinsonism reported in an Italian kindred (Hilker et al., 2001). The clinical presentation of most cases was broadly comparable with that reported in ARJP and young‐onset Parkinson’s disease in addition to the IPD (Klein et al., 2000) and DRD phenotypes (Tassin et al., 2000) that have been reported previously. Due to the difficulty in differentiating between DRD and a DRD‐like presentation of parkin disease and other cases of juvenile parkinsonism, exclu sion of parkin mutations or the use of DaT SPECT or [18F]dopa PET scans may be indicated in DYT‐1 mutation negative patients with young‐onset dystonia‐parkinsonism in order to delay the complications of l‐dopa therapy in young‐onset parkinsonism.

Brisk reflexes may be present in parkin disease. Two previous reports have confirmed combined cerebellar and pyramidal tract dysfunction in parkin subjects (Kuroda et al., 2001; van de Warrenburg et al., 2001). However, in our cases, cerebellar signs were absent, and brisk reflexes were found in only two (8%) of them. Additionally, we report two cases of parkin disease accompanied by presumed coincidental cerebral palsy in one and a familial tic disorder in another.

We also describe three new presentations of the disease. Patient 17 developed early autonomic dysfunction combined with an axonal peripheral neuropathy. The presence of axonal peripheral neuropathy alone has been reported previously in a single parkin case (Tassin et al., 1998). Autonomic symptoms alone are common (Yamamura et al., 2000) and were present in 60% of our patients. Patient 9 presented with cervical, and later developed laryngeal, dystonia. Patient 10 developed pure dystonia of the foot on exercise. We also report a patient with writer’s cramp at onset, a phenotype which has been reported previously (Farrer et al., 2001).

Cognitive function remains normal in the majority of patients (Lucking et al., 2000). All subjects in our series, except for Patient 18 with presumed cerebral palsy, had normal cognition, or at least normal scores on the MMSE. Indeed, we observed normal cognition in Patients 12 and 13 after >45 years of parkin disease, implying that the neurodegeneration probably spares structures critical to cognitive function. Functional or structural abnormalities in the caudate nucleus have been postulated to play a role in frontal symptomatology or subcortical dementia in patients with basal ganglia disease. However, the degree of impairment of [18F]dopa uptake in nigrostriatal terminals in the caudate nucleus has been reported by Portman et al. (2001) to be generally greater in parkin disease than in IPD. Similarly, our own in vivo PET studies of the Irish kindred, Patients 2–5 (Khan et al., 2002), and Patient 10 (Sawle, et al., 1991, Case 7), have also demonstrated severe bilateral impairment of [18F]dopa uptake not only in putamen (as in IPD), but also in the caudate. These findings suggest that more than just dopaminergic denervation of the caudate is necessary to impair cognition.

We did, however, observe the repeated development of psychosis in several of our patients, one of whom was taking l‐dopa preparations alone. In the four parkin cases from elsewhere whose autopsy results have been published, the pathology, as in IPD, has involved the substantia nigra and locus coeruleus, but other brain structures that are involved in IPD are usually spared. Although it is conceivable that the greater degree of nigrostriatal denervation in caudate nucleus in parkin disease might play a role in the behavioural disturbances observed in a number of our patients, it is possible that they may have other pathological or neurochemical abnormalities that remain to be identified. Behavioural disorders in parkin disease have been reported previously (Tassin et al., 1998; Yamamura et al., 2000), but not in detail. Moreover, psychiatric symptoms antedating the onset of parkinsonism have not hitherto been described or emphasized. This may represent another new presentation of parkin disease. However, this would require confirmation by studying a larger series of cases and controls. Psychiatric complications including depression, anxiety and psychosis have been reported in IPD, with rates for depression ranging from 20–50% (Oertel et al., 2001; Schrag et al., 2001), anxiety disorders from 20–40% (Aarsland et al., 1999) and psychosis from 15–20% (Aarsland et al., 1999). However, behavioural disturbances including anorexia nervosa, self‐harm and suicide attempts are rare in Parkinson’s disease but affected 24% of patients in this series.

A dramatic response to treatment with l‐dopa preparations is characteristic of both young‐onset Parkinson’s disease and parkin disease. It is intriguing that we also observed a dramatic response to treatment with anticholinergics alone in both early and advanced stages of disease; this has been reported previously in a single parkin case (Munoz et al., 2000). Although anticholinergics may have a modest effect on tremor in IPD, they do not usually improve rigidity or akinesia. In contrast, our Patients 1, 11 and 17, who reported initial virtually complete resolution of symptoms on low doses of benzhexol, had no or minimal tremor. A dramatic benefit from anticholinergics is also recognized in patients with DRD (Jarman et al., 1997), in which there is also an impairment of central endogenous dopamine production in young subjects.

The dramatic response to l‐dopa usually seen in parkin patients indicates that, despite a generally more severe striatal dopaminergic deficit in uptake and storage of l‐dopa and its metabolites as revealed by [18F]dopa PET, administration of even low dosages of l‐dopa is nonetheless able to restore many subjects motorically almost to normal. The exquisite sensitivity of parkin patients to low doses of l‐dopa may partly reflect post‐synaptic striatal dopamine receptor supersensitivity secondary to their severe presynaptic lesion.

l‐dopa induced dyskinesias are common in parkin cases. In our patients, the average interval from initiating l‐dopa to developing dyskinesias was 6.7 years, which is longer than the average in our two reported series of patients with young‐onset Parkinson’s disease (Quinn et al., 1987; Schrag et al., 1998). We also observed that l‐dopa‐induced dyskinesias in some of our patients were unusual or extremely dose‐sensitive. For example, Patient 14 developed prominent orofacial and mild limb dyskinesias only 2 days after commencing l‐dopa and Patient 15 developed a peak‐dose dystonic scissoring gait after only very small amounts of l‐dopa. Interestingly, only one of our cohort of 16 l‐dopa treated parkin patients reported diphasic dyskinesias compared with 15 of 45 cases of young‐onset Parkinson’s disease treated with l‐dopa for ≥2 years (Quinn et al., 1987).

The usually mild degree and very slow progression of clinical parkinsonism (Khan et al., 2002) in parkin disease is, in some ways, surprising. For example, the [18F]dopa PET scan of Patient 10 was far worse than that seen in IPD patients, yet IPD patients with less impairment of nigrostriatal dysfunction usually develop much more severe akinesia and rigidity over time despite having a less severe nigral lesion. This observation would suggest that, in IPD, the nigrostriatal lesion alone is not sufficient to explain the severity of the parkinsonism itself. Alternatively, parkin disease may involve extra‐nigral compensatory mechanisms.

Freezing, festination, retropulsion, instability and falls are usually considered late features in patients with IPD, and are often assumed to be extra‐nigral or non‐dopaminergic in origin. However, these can be early or presenting features in some parkin patients. This might be due to a more severe nigral lesion affecting the caudate more than in IPD or, alternatively, to additional as yet unrecognized pathology.

Parkin disease is typically autosomal recessive and seen in one generation, among male and female siblings who are equally affected. However, it can also appear in isolated cases. In addition, it has been reported in multiple generations of families with consanguineous marriages (Maruyama et al., 2000) or in isolated populations (Klein et al., 2000; Lucking et al., 2001). The latter, and the finding of parkin disease in two generations in our Burnley kindred, suggests that different parkin mutations are frequent enough in some populations to lead to allellic heterogeneity. However, the frequency of parkin carriers and the frequency of the disease (both typical and atypical phenotypes) in the population at large remain to be accurately determined.

The majority of parkin mutations have arisen from independent mutational events, emphasizing their importance in the aetiology of young onset parkinsonism (Abbas et al., 1999; Lucking et al. 2000). However, recurrence of the same mutation in different patients may reflect a founder effect (i.e. these individuals have a common ancestor and are therefore related), which is particularly the case with respect to point mutations (Periquet et al., 2001). We found different patients from apparently different families sharing the same mutations. Three patients from two families originating from the Indian subcontinent shared exon 9 1101C→T (Arg334Cys), while three patients from two families of Irish descent and one Scottish isolated case shared exon 12 1390G→A (Gly430Asp) and two isolated English cases shared an exon 2 202–203 AG deletion. One isolated English case and all siblings from the Burnley kindred shared exon 9 1101C→T (Arg334Cys). Four cases (two Irish from one family and two isolated English cases) shared exon 7 924 C→T (Arg275Trp), which has been reported to be due to ancient founder effects (Periquet et al., 2001). The majority of mutations in our patients were due to different point mutations, in contrast to the deletions first reported in the Japanese parkin patients (Kitada et al., 1998). We failed to detect a second parkin mutation in 10 of our parkin patients. Possible explanations for this could include: an incomplete mutation screen, which did not include a complete analysis of the parkin promotor and intronic regions; the presence of an unknown coexisting susceptibility allele; or that a single mutant allele is sufficient to cause disease.

With recent genetic advances, we now realise that the clinical heterogeneity of ‘Parkinson’s disease’ is, at least in part, due to the fact that it encompasses a number of different disease entities. Autosomal recessive conditions such as parkin disease can be due to different ‘loss of function’ mutations but, in such cases, the clinical phenotype is usually similar (Strachen and Read, 1999). Although we have described common and overlapping clinical themes in our series of parkin patients, they are nonetheless also clinically heterogeneous. Since a number of different mutations in the parkin gene are responsible, this may be mutation dependent. Although both this and previous studies are too small to confidently identify mutation‐specific phenotypes, it is of interest that in our large Irish kindred all four siblings, Patients 2–5, sharing the same mutations, presented between the ages of 26 and 32 years, and that all four of them had in common an abduction–adduction oscillatory tremor of the legs. By contrast, however, in another sibling set, Patient 13 is atremulous after 47 years of disease and his sibling, Patient 12, had tremor at the onset of disease.

We are not certain of the significance of a 17% rate of psychiatric disturbance reported in relatives by 16 unrelated patients with parkin disease because we have do not have a control cohort. The general population incidence of psychiatric disturbance of 19% (Singleton et al., 2001) was ascertained from a household survey and, therefore, may not be directly comparable. Nigrostriatal dysfunction detected using [18F]dopa PET and the manifestation of subtle extrapyramidal signs that do not fulfil clinical diagnostic criteria for IPD have been reported in carriers of a single parkin mutation (Klein et al., 2001; Khan et al 2002), so‐called ‘manifesting heterozygotes’. Here we report that parkin carriers who do not have parkinsonism, but carry a single parkin mutation might also have susceptibility to psychiatric illness. In this context, it is of interest that a locus for schizophrenia has recently been mapped to chromosome 6q25 adjacent to PARK2 (Lindholm et al., 2001). The manifestation of behavioural disorder in non‐parkinsonian carriers of a single mutant allele may support the hypothesis that, by either haploinsufficiency or a dominant negative effect (Strachen and Read, 1999), having gene products up to 50% of the normal level is not sufficient for normal function. However, the progression to develop parkinsonism in such cases is unclear. The significance of the reported behavioural disorders in otherwise unaffected relatives, either with only one demonstrated mutation or whose genotype is uncharacterized, remains to be determined.

Conclusion

Our data indicate that mutations in the parkin gene represent a frequent cause of early‐onset parkinsonism and should be considered in the diagnostic workup of such cases. Typical clinical features (summarized in Table 5) suggestive of parkin disease include age of onset <40 years, foot dystonia, psychiatric symptoms, dramatic response to treatment and dose‐sensitive motor and psychiatric complications of drug therapy. However, in some cases the age of onset is later. Parkin disease may also present atypically with leg tremor, focal dystonia, exercise‐induced dystonia and autonomic and peripheral neuropathy as well as phenotypes suggestive of DRD or IPD. Behavioural disorder may predate the onset of parkinsonism. Our observation of psychiatric illness in non‐parkinsonian family members carrying a single mutant allele in the parkin gene requires further study in a larger cohort in comparison to appropriate control groups.

View this table:
Table 5

Key features of parkin disease (including our cases)

Age of onset usually <40 years
Typical presenting phenotype: young onset Parkinson’s disease/ARJP
Normal cognition
Frequent foot dystonia
Early instability, freezing, festination or retropulsion in some cases
Excellent response to anticholinergics in some cases
Excellent response to l‐dopa, but frequent development of exquisite sensitivity to low doses
Atypical levodopa‐induced dyskinesias in some cases
Behavioural disorder preceding onset parkinsonism and complicating treatment in some cases
Autonomic symptoms in many cases
Usually benign and slow clinical course
Atypical presenting phenotypes include:
 later onset, mimicking IPD
 exercise‐induced dystonia, DRD‐like
 leg tremor
 atremulous bilateral akinetic rigid syndrome
 focal dystonia (writer’s cramp, cervical)
 autonomic or peripheral neuropathy
 cerebellar and pyramidal tract dysfunction
Coincidental neurological disease does not exclude the diagnosis
Family history of individuals with tremor, subtle extrapyramidal signs and behavioural disorder needs further investigation

Acknowledgements

N.L.K. is funded by the Parkinson’s Disease Society and the Brain Research Trust.

Appendix 1

Patient 1

This Japanese woman developed a limp in her right leg at age 23 years. A year later, her right ankle would invert at rest on the bed, but not on walking and, at age 26 years, she complained of right leg tremor, balance difficulty and retropulsion and was diagnosed with Parkinson’s disease. She was treated with benzhexol 1 mg three times a day and was subjectively 100% better. Because of nausea on benzhexol, she was changed at age 28  years to taking Madopar (l‐dopa plus benserazide). At age 34 years, she was taking 1 tablet of Madopar dispersible 62.5 (12.5/50) in the morning followed by half a tablet (l‐dopa content 25 mg) every hour or so thereafter. Higher individual doses caused unacceptable dyskinesias. At age 29 years, she was treated for symptoms of depression.

Patients 2–5

These four siblings, from an Irish kindred, shared in common a marked resting leg tremor with abduction–adduction oscillations (Khan et al., 2002).

Patient 6

This 55‐year‐old man developed a tremor of the right big toe at age 28 years, which subsequently involved both legs, more on the right, and was present at rest, supine and standing. He reported no diurnal fluctuations. Following a marked response to l‐dopa, he was misdiagnosed as tremor‐dominant DRD. Six years after starting l‐dopa therapy, he developed dose‐dependent peak dose dyskinesias and wearing off, and his diagnosis was revised.

Patient 7

This 46‐year‐old sibling of Patient 6, developed at age 30 years right‐sided hemiparkinsonism with dystonia of the right arm and foot, without diurnal fluctuation, which progressed to a bilateral akinetic‐rigid picture with a coarse rest tremor confined to the legs. At age 35 years, she had subthalamic deep brain stimulators implanted bilaterally with good effect.

Patient 8

This man developed tremor of the left leg at age 29 years, which subsequently involved the right leg and right hand, and was diagnosed to have essential tremor. At age 34 years, he noticed slowness of movement, having to check his balance, and diminution of arm swing on the right. His left toes would claw when sitting or driving. He also reported panic attacks. At age 40 years, he commenced orphenadrine with resolution of all symptoms except tremor: he remains l‐dopa naive. Both his father and his 42‐year‐old sibling (genotype uncharacterized) report an isolated tremor of the arms.

Patient 9

This patient developed stiffness of his trunk and legs, turning and stiffness of his neck, poor balance and an inability to stand upright without toppling backwards at age 7 years. He progressed to an atremulous akinetic rigid syndrome with cervical dystonia and dystonia of both feet. He showed a dramatic response to l‐dopa and was initially suspected to have DRD. However, he developed wearing off and had markedly diminished striatal [18F]dopa uptake on PET scan (Sawle, et al., 1991, Case 7), confirming juvenile parkinsonism. At age 29 years, he developed laryngeal adductor dystonia requiring botulinum toxin injections. Otherwise when ‘ON’, he was physically almost normal. He could not tolerate >50 mg l‐dopa with a peripheral dopa decarboxylase inhibitor (PDI) at each of his 18 daily doses because this worsened his laryngeal dystonia. At age 31 years, he was complaining that during ‘OFF’ periods he had ‘no sense of balance’ and had some freezing, festination and retropulsion, leading to falls. At age 22 years, he developed panic attacks and, at age 32 years, has attempted self‐mutilation in the form of forearm and wrist slashing. He has recently been started, aged 32 years, on an apomorphine pump.

Patient 10

This 30‐year‐old man developed inturning of the right foot at age 18 years whilst playing football. At that time, he also reported occasional paranoia and panic attacks. At age 21 years, he developed a tremor of the right thumb and, by age 26 years, had developed rigidity and bradykinesia that improved subjectively by 50% on amantadine. He was treated for depression at the age of 29 years. One of his parents, who carries a mutant parkin allele, had been treated for depression for >20 years. His 27‐year‐old sister (genotype uncharacterized), who does not have parkinsonism, has a 5‐year history of anorexia nervosa.

Patient 11

This patient reported poor balance, clumsiness and difficulty rising from a seated position beginning at age 19 years. By age 25 years, she had developed a shuffling, small‐stepped gait, especially in confined spaces. Examination revealed a bilateral akinetic rigid syndrome with a very fine postural tremor in all four limbs and brisk reflexes. She also reported severe mood swings and exacerbation of her motor disability by alcohol. Treatment was started with benzhexol and, after 2 days, she said she was ‘100% better’. She reported marked pre‐menstrual worsening of motor disability. She is still, aged 33 years, well controlled on benzhexol 2 mg three times a day, and has not required dopaminergic therapy. She reports severe mood swings during her teenage years and a maternal aunt (genotype uncharacterized) with depression.

Patient 12

This 77‐year‐old man is one of 10 siblings of whom another brother, Patient 13, and a sister (who is not reported in this series) have parkin disease. He noted slowness of day‐to‐day tasks and frequent falls from 30 years of age. At age 50 years, he developed dystonia of both feet and micrographia, and was diagnosed with parkinsonism, 20 years after his first symptoms. He reported a dramatic response within 2 h of taking his first dose of 150 mg of l‐dopa (plus PDI). He remains free of tremor after 47 years of disease, and is currently taking Sinemet (l‐dopa plus carbidopa) 25/100 four times a day.

Patient 13

This 74‐year‐old brother of Patient 12 reported dragging his left foot, a lazy left arm and tremor of all four limbs in his late twenties. He also reported a dramatic improvement of symptoms when he started l‐dopa treatment at age 68 years. His cognitive function remains normal after >45 years of disease. He reports a brother (genotype uncharacterized), who did not have parkinsonism and who committed suicide at age 43 years.

Patient 14

This 58‐year‐old man, whose parents were first cousins, developed asymmetrical parkinsonism with dystonic posturing of the trunk at age 54 years. Within 3 days of commencing l‐dopa therapy, he developed prominent orofacial dyskinesias and mild dyskinesias of the lower limbs.

Patient 15

This 51‐year‐old man developed a fine tremor of his right limbs aged 13 years and, at age 22 years, dystonia of his right foot, which dragged after prolonged walking. At age 26 years, he started Sinemet for his dystonia‐parkinsonism with considerable benefit, but with wearing off from the very beginning of treatment. Although there was no diurnal variation prior to treatment, he was initially considered to have DRD. On l‐dopa, he developed a very bizarre scissoring dystonic gait. When overdosed this gait was even worse and was accompanied by neck bobbing, generalized choreiform and myoclonic movements, and repetitive tongue protrusion. His dosage threshold for developing this gait has become extremely low. At age 47 years, he found that he was overdosed after one tablet of half Sinemet CR 25/100 (containing 70 mg biovailable l‐dopa). However, after a half tablet he was good initially but then overdosed after an hour, and he settled on taking a quarter to a third of a Sinemet CR 50/200 tablet 3–5 times a day. In addition to the sensitivity to dyskinesias, he has twice developed hypomania. On the first occasion, aged 36 years, he was taking Sinemet 10/100 six times day and no other medication, and on the second occasion, aged 46 years, he was on Sinemet 25/100 six tablets a day together with Madopar dispersible 25/100 six tablets a day.

Patient 16

The 56‐year‐old sister of Patient 15 developed parkinsonism at age 22 years after being treated for post‐natal depression with chlorpromazine. She reports that she develops marked depressive symptoms if she takes >50 mg of l‐dopa at any time.

Patient 17

This 29‐year‐old man developed parkinsonism at the age of 13 years. At age 16 years, he reported dizzy spells without loss of consciousness, related to orthostatism and exercise. At age 20 years, it was noted that he did not perspire and he reported loose stools and intermittent difficulty with erections and ejaculation. At age 24 years, he developed urgency of micturition. Autonomic function tests confirmed both sympathetic and parasympathetic cardiovascular autonomic impairment. Reflexes were brisk and sensation was normal, but nerve conduction studies and nerve biopsy revealed an axonal peripheral neuropathy. After an initial dramatic response to low doses of benzhexol, he continues to show a moderate motor response after 7 years taking benzhexol alone and 17 years of disease. At age 18 years, he attempted suicide by taking an overdose of painkillers and, at age 21 years, was treated for depression. His unaffected sibling, who carries a single mutant parkin allele, has also been treated for depression.

Patient 18

This 21‐year‐old woman, with presumed cerebral palsy secondary to peripartum anoxia, developed a spastic diplegia at age 12 years and, one year later, developed left‐sided parkinsonism presenting with a rest tremor of the left foot and dystonic posturing of both feet. There was some improvement with a trial of l‐dopa. At age 19 years, she developed off periods and a year later started to have grand mal seizures. She also had head banging, biting and scratching and severe cognitive, visual and hearing impairment.

Patient 19

This 32‐year‐old man had developed an intermittent neck‐shuddering tic and a no–no head tremor between the ages of 10 and 15 years, and nose wrinkling and jaw deviation tics at age 29 years. There were no vocalizations, obsessions or other features of Tourette syndrome. A maternal uncle was reported to have a facial twitch. At the age of 30 years, Patient 19 developed right‐sided parkinsonism, without diurnal variation, at which time his tics were noted to have worsened. His mother, who carries a mutant parkin allele, and his sister (genotype uncharacterized) have been treated for depression. A 24‐year‐old maternal first cousin (genotype uncharacterized) had been diagnosed with essential tremor at the age of 14 years.

Patient 20

This 57‐year‐old man reported tremor of the left foot and stiffness and aching of the left leg from age 29 years, which progressed to left hemiparkinsonism. He was treated with Sinemet with a very good result, but developed motor fluctuations and dyskinesias. At age 37 years, he underwent right‐sided thalamotomy with complete resolution of his left‐sided tremor for 5 years. At age 46 years, taking l‐dopa, he developed some features of hypomania, particularly during ‘ON’ periods. At age 47 years, an apomorphine pump was added with benefit. The following year, the day after adding selegiline to his regime, he became psychotic, with paranoid delusions and third person auditory hallucinations, which lasted 3 months until apomorphine was stopped. Later apomorphine was restarted. At age 49 years, he was admitted because of painful ‘OFF’ periods and ‘ON’ period hypomanic symptoms, and again became psychotic. This resolved after again stopping apomorphine and he was abulic and possibly depressed for the next 5 years, but then spontaneously emerged from this state. When he was reviewed at age 58 years, he had no further psychiatric problems other than feeling a bit high in his ‘ON’ periods, despite being on a cocktail of Sinemet (1130 mg l‐dopa plus PDI per day), amantadine, pramipexole and low doses of pergolide, ropinirole and entacapone. He was ‘ON’, with mild to moderate dyskinesias but no functional impairment, for almost all of the time, but when ‘OFF’ was unable to walk. His father (genotype uncharacterized) had a history of mood swings, depression and personality change from age 58 years and died at age 79 years.

Patient 21

This 52‐year‐old man reported difficulty with writing at age 22 years and, 2 years later, was diagnosed with writer’s cramp. At age 26 years, he reported occasional curling of the toes of the left foot solely with exercise, and was treated with orphenadrine with considerable benefit. Over succeeding years, he developed increasing difficulty walking with start hesitation, a tendency to freezing, ‘tottering’ and occasional shuffling, but no falls. On examination, he was noted to have asymmetric parkinsonism with a right ‘striatal toe’. At age 42 years, he was started on an l‐dopa preparation with striking benefit, with the addition of lisuride shortly thereafter and then selegiline. Within 18 months, he had developed some motor fluctuation and his main problem was start hesitation in the evenings. He had also developed some features of hypomania. Increasingly, he developed ‘ON’ period freezing that was absent in the morning before his first dose, and worse the higher the dose of l‐dopa he took, so his optimal regime was just over half a tablet of Sinemet 12.5/50 (containing 25 mg l‐dopa) at each intake. His greatest concern was a combination of start hesitation, freezing and retropulsion. At age 49 years, he developed delusional morbid jealousy and his lisuride was stopped. Subsequently, he stopped Sinemet and was treated with agonists alone with good motor control but again developed morbid jealousy on cabergoline and later on ropinirole. He attempted suicide on one occasion and developed panic attacks. He reports a 64‐year‐old maternal first cousin (genotype uncharacterized) who has a paranoid psychotic illness.

Burnley kindred

Patient 22 (III:2, Fig. 1)

This non‐identical twin was diagnosed with anorexia nervosa at age 14 years. At that time, she weighed 3.5 stone, became socially reclusive, attempted suicide on several occasions and was treated with chlorpromazine and orphenadrine. From age 15 years, she developed parkinsonism, presenting with an asymmetrical (left > right) tremor of all four limbs, which occurred both at rest and with movement. At age 27 years, she had a right‐sided thalamotomy without benefit and, at age 28 years, underwent left‐sided thalamotomy with clinical improvement. At 37 years, following a suicide attempt, she died of bronchopneumonia. The coroner’s autopsy did not provide useful information about the brain.

Patient 23 (III:4, Fig. 1)

This 46‐year old housewife, the youngest sister of patient 22 developed a tremor of the right hand at the age of 15 years. At age 17 years, she noted inturning of both feet on walking and progressed to right‐sided hemiparkinsonism. She is still l‐dopa naive after 10 years good response to benzhexol.

Patient 24 (II:7, Fig. 1)

This patient developed parkinsonism from age 25 years and died aged 80 years. When seen, he had been taking Sinemet 25/100, half a tablet bd, and benzhexol 2 mg daily for years. This individual had four children, one of whom, III:10 (genotype uncharacterized) has a postural tremor at age 32 years.

Individual II:6 (genotype unknown, Fig. 1)

This individual was reported by relatives to have developed a unilateral coarse rest tremor at the age of 65 years. This progressed to l‐dopa responsive parkinsonism and the patient died aged 77 years. This individual had four children (genotype uncharacterized), two of whom have been treated for depression.

II:3 and II:4 (genotype uncharacterized, Fig. 1)

These individuals were examined aged 70 and 82 years, respectively: a postural tremor was noted with no signs of parkinsonism.

References

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