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Clinical features of LRRK2-associated Parkinson's disease in central Norway.

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Clinical Features of LRRK2Associated Parkinson’s
Disease in Central Norway
Jan O. Aasly, MD, PhD,1 Mathias Toft, MD,2,3
Ignacio Fernandez-Mata, BSc,2 Jennifer Kachergus, MBA,2
Mary Hulihan, MPH,2 Linda R. White, PhD,3
and Matthew Farrer, PhD2
Several pathogenic mutations in the leucine-rich repeat
kinase 2 (LRRK2; PARK8) gene recently have been identified in familial and sporadic parkinsonism. We screened
435 Norwegian patients diagnosed with Parkinson’s disease and 519 control subjects for the presence of 7
LRRK2 mutations. Nine patients from seven families
were found to be heterozygote carriers of the LRRK2
6055G典A (G2019S) mutation. Twelve of 28 first-degree
relatives also carried the mutation, but only 1 had Parkinson’s disease. The clinical features included asymmetric resting tremor, bradykinesia, and rigidity with a good
response to levodopa and could not be distinguished
from idiopathic Parkinson’s disease.
Ann Neurol 2005;57:762–765
Genetic causes for late-onset Parkinson’s disease (PD)
are rare; despite reports of familial aggregation, most
patients have no family history of PD and are considered to be sporadic cases.1 Only recently have genetic
causes been discovered in familial parkinsonism. The
first gene implicated was ␣-synuclein, for which several
missense and multiplication mutations causing fulminant Lewy body disease have been described.2 Typically, these patients have disease onset in the fifth or
sixth decade of life, rapid progression, cognitive decline, and dementia.3
We, as well as others,4,5 have identified mutations in
a novel gene, leucine-rich repeat kinase 2 (LRRK2), in
families in whom PD was linked to the PARK8 locus.
This locus on chromosome 12 was first described in a
large Japanese kindred with autosomal dominant PD.6
The locus was subsequently confirmed in several Euro-
From the 1Department of Neurology, St. Olav’s Hospital, Trondheim, Norway; 2Department of Neuroscience, Mayo Clinic College
of Medicine, Jacksonville, FL; and 3Department of Neuroscience,
Norwegian University of Science and Technology, Trondheim,
Norway.
Received Jan 3, 2005, and in revised form Feb 7. Accepted for publication Feb 24, 2005.
Published online Apr 25, 2005 in Wiley Interscience (www.
intersvience, wiley.com). DOI: 10.1002/ana.20456
Address correspondence to Dr Aasly, Department of Neurology, St.
Olav’s Hospital, N-7006 Trondheim, Norway.
E-mail: jan.aasly@medisin.ntnu.no
762
pean families.7 Recently, a novel LRRK2 mutation
(G2019S) has been described in familial parkinsonism
originating from different European and American
countries.8,9 This study presents a detailed clinical
study of Norwegian patients with LRRK2-associated
disease.
Patients and Methods
Clinical Investigations
A total of 435 patients have been clinically examined and are
being observed longitudinally by one neurologist (JOA) at
the outpatient clinics of three hospitals in Central Norway.
Table 1 presents demographic data of patients, family members, and unrelated control subjects. A full history, including
family history and neurological examination, was completed
for each patient. Clinical diagnosis of PD required the presence of at least two of three cardinal signs (resting tremor,
bradykinesia, and rigidity), improvement with adequate dopaminergic therapy, and absence of atypical features or other
causes of parkinsonism. Clinical criteria for diagnosis of PD
were consistent with that of Gelb and colleagues.10 MiniMental State Examination and clinical judgment based on
repeated examinations were used to assess cognitive function.
Further neuropsychological testing was not warranted. All
patients underwent routine laboratory blood testing; no significant abnormalities were found. Ethnically matched control subjects (n ⫽ 519), without signs of a movement disorder, were recruited from the same region. The Ethics
Committee of Central Norway approved the study, and informed consent was obtained from all participants.
Genetic Studies
All subjects in this study were screened for LRRK2 3342A典G
(L1114L), 5096A典G (Y1699C), 6055G典A (G2019S), and
6059T典C (I2020T) mutations previously identified in families with autosomal dominant parkinsonism.4,5 A genotype
of amplified products was performed using TaqMan chemistry on an ABI7900 (Applied Biosystems, Foster City, CA).
Pathogenic mutations in codon R1441, including LRRK2
4321C典T (R1441C), 4321C典G (R1441G), and 4322G典A
(R1441H), were assayed by BstUI digestion of an exon 31
polymerase chain reaction product.5 The LRRK2 sequence
and amino acid notation was based on National Center for
Biotechnology Information sequence accession number
AY792511.
LRRK2 mutation carriers were reexamined, and an extensive family history was obtained. Family members who
agreed to participate in the study (n ⫽ 28) were examined
using the clinical assessment tools described earlier.
Results
Genetic Findings
Seven LRRK2 mutations were examined, but only
LRRK2 6055A典A (G2019S) was identified in 9 patients
with PD (6/174 female and 3/261 male patients; Table
2). At the time of their diagnosis, only six of these nine
patients (Patients 1–3, 8 –10) reported a family history
of disease. In the entire series, 15% of subjects reported
© 2005 American Neurological Association
Published by Wiley-Liss, Inc., through Wiley Subscription Services
Table 1. Study Subjects
Group
PD patients
First-degree relatives
Controls
n
Sex (%)
Disease Onset
(yr)
Range
(yr)
Age at Last Examination
(yr)
435
174 F (40)
261 M (60)
7 F (22)
21 M (78)
233 F (45)
286 M (55)
60.3 ⫾ 10.9
57.6 ⫾ 10.9
—
—
—
—
33–88
28–80
49–78
21–74
47–96
46–93
70.2 ⫾ 9.3
66.3 ⫾ 10.8
63.8 ⫾ 11.9
57.2 ⫾ 11.8
65.8 ⫾ 12.2
62.7 ⫾ 10.4
28
519
PD ⫽ Parkinson’s disease; F ⫽ Female; M ⫽ Male.
28 – 88 years; n ⫽ 435) and marginally later than the
mean age of asymptomatic LRRK2 6055A典A (G2019S)
carriers (56 ⫾ 13.0 years; age range, 26 –74 years; n ⫽
11).
Resting tremor was the presenting symptom in 6 of
the 10 patients. All except one patient (Patient 8) subsequently experienced development of resting tremor
during the course of their disease (see Table 2). Postural and action tremor were observed to a moderate
degree, although not more frequently than observed in
older patients with idiopathic PD. Bradykinesia was a
consistent finding in all 10 patients with LRRK2associated disease, and it was the first symptom observed in 3 patients (see Table 2). The poverty of
movement was generally moderate, and episodes of severe akinesia were observed only in off periods in two
patients (Patients 2 and 5). Only one patient initially
had an atypical presentation, with bilateral dystonia of
the lower extremities (Patient 1). Autonomic disturbances were not a problem in any of the 10 patients
with PD. One patient (Patient 7) had a history of anxiety disorder, but no other patient had been treated for
a psychiatric disease.
a family history of parkinsonism. No LRRK2 mutations were identified in the 519 control subjects. The
heterozygous LRRK2 mutation carriers have a total of
36 first-degree relatives, and 28 of them subsequently
volunteered to participate in a family study. Currently,
a diagnosis of PD can be made for only one of these
subjects. This individual and 11 other asymptomatic
family members were LRRK2 6055A典A (G2019S) heterozygous carriers. These patients with LRRK2 mutations originate from seven distinct kindreds, because
three of the nine patients originally identified were relatives (Fig). Thirteen deceased members of these seven
families were reported to have been affected by parkinsonism, though only historical data were available.
Clinical Results
The natural history and clinical features of the 10 patients identified with a heterozygous LRRK2 G2019S
amino acid substitution are detailed later in this article
(see Table 2). The mean age at symptom onset was
59 ⫾ 8 years (age range, 43–70 years; n ⫽ 10), which
is comparable to the mean age at symptom onset
within the entire series (59 ⫾ 11 years; age range,
Table 2. Clinical Data for Patients with LRRK2-Associated Parkinsonism
Age at PD Onset/
Diagnosis
Patient
(yr)
No.
Family Age/Sex
1
2
3
4
5
6
7
8
9
10
P-063
P-089
P-104
P-241
P-369
Sib-183b
F-05
F-05
F-05
P-394
72/F
52/M
73/M
85/F
51/F
69/F
76/F
66/M
80/F
86/F
53/56
43/44
58/60
60/61
43/44
57/60
62/64
61/63
70/76
66/67
Cognitive
Function
L-Dopa Equivalents MMSE
Score
(mg)
Response
L-Dopa
Initial
Symptoms
Resting Tremor/Rigidity/
Bradykinesiaa
Dystonia
Tremor
Tremor
Tremor
Tremor
Tremor
Tremor
Bradykinesia
Bradykinesia
Bradykinesia
All
All
All
All
All
All
All
No tremor
All
All
⫹⫹⫹
⫹⫹⫹
⫹
⫹⫹⫹
⫹⫹⫹
⫹⫹⫹
⫹⫹
⫹⫹⫹
⫹⫹
⫹⫹⫹
400
1500
500
600
700
400
400
400
400
400
30
30
24
25
30
NA
26
30
27
26
Only family F-05 was referred based on a family history of parkinsonism.
a
Symptoms developed during the follow-up period. “All” means that the patient has had tremor, rigidity, and bradykinesia. L-Dopa response is
indicated as ⫹, moderate; ⫹⫹ good; or ⫹⫹⫹, very good.
b
The symptomatic first-degree relative.
PD ⫽ Parkinson’s disease; MMSE ⫽ Mini-Mental State Examination. NA ⫽ not available.
Aasly et al: LRRK2-Associated PD in Norway
763
Fig. Pedigrees of families with leucine-rich repeat kinase 2 (LRRK2) G2019S. Black symbols denote family members affected with
parkinsonism. Patients studied are numbered and marked with an arrow. The sex of some asymptomatic subjects has been hidden
to protect confidentiality.
Initial symptoms in the LRRK2 G2019S patients
were tremor (6/10), bradykinesia (3/10), or dystonia
(1/10). Nine of the 10 LRRK2 G2019S patients had a
good to excellent response to L-dopa or other dopaminergic agents. In one patient (Patient 3), the response
was less profound, although when treated with 500 mg
L-dopa, his tremor disappeared and his bradykinesia
became less prominent. L-dopa–induced dyskinesias
were observed in six patients and were most pronounced in the two patients with early-onset PD.
In the two oldest LRRK2 G2019S patients (Patients
4 and 10), with disease durations of 25 and 20 years,
respectively, a moderate decline in learning and shortterm memory was observed, but dementia had not developed in either patient. The four oldest patients documented mild and intermittent visual hallucinations
but only when their dopaminergic medication was increased.
Discussion
We screened patients and control subjects from Central
Norway for seven LRRK2 mutations. Of the 435 patients and 28 relatives examined, a total of 10 had
LRRK2 G2019S–associated parkinsonism. These 10
patients originate from 7 unrelated families of whom 6
kindreds have evidence for autosomal dominant transmission of disease. Eleven family members carry the
mutation and remain asymptomatic, which may reflect
the age-dependent penetrance typical for neurodegenerative diseases.
In three recent reports,8,9,11 the LRRK2 G2019S
substitution was identified in 1.6% of patients with idiopathic PD and in 5 to 6.6% of those with familial
764
Annals of Neurology
Vol 57
No 5
May 2005
PD. Our study confirms that this mutation is a relatively common cause of PD in Norway. We did not
identify carriers of other mutations, including in the
1441 codon. LRRK2 4321C典G (R1441G) previously
was reported to cause 8% of PD cases in a series of 137
individuals from the Basque population.5 Specific
LRRK2 mutations are therefore likely to be more frequent in certain populations.
The motor deficits of LRRK2 G2019S mutation carriers were indistinguishable from the resting tremor,
bradykinesia, and rigidity observed in patients with
typical late-onset PD. In almost all patients with
LRRK2-associated disease, the motor symptoms showed
sustained benefit with dopaminergic therapy. Two patients with early-onset PD experienced severe L-dopa–
induced dyskinesias. Dyskinesias may be a function of
the age of onset, as noted for early-onset parkinsonism
associated with loss of parkin function and for earlyonset idiopathic PD.12,13 The only uncommon presentation among LRRK2 G2019S patients was L-dopa–
responsive dystonia.
Only one patient with a LRRK2 G2019S substitution showed a decline in the effectiveness of L-dopa
therapy, which was combined with mild cognitive impairment. Overall, the prevalence of cognitive dysfunction and dementia among LRRK2 G2019S patients
was low. This is interesting, because LRRK2 is located
on chromosome 12q12, within a locus previously implicated in late-onset Alzheimer’s disease.14 In patients
with a LRRK2 R1441G substitution, resting tremor has
been described as the predominant feature.5 We observed only mild to moderate tremor in our patients
with the G2019S substitution. Interestingly, the phe-
notypic range of LRRK2 Y1699C is broader, including
amyotrophy and dementia.4,15 These different phenotypic presentations may reflect the different positions
of LRRK2 coding substitutions.
In conclusion, patients with a LRRK2 G2019S substitution present with a L-dopa–responsive parkinsonian syndrome with asymmetric resting tremor, bradykinesia, and rigidity, which are typical of idiopathic
PD. The nonmotor autonomic, psychiatric, and cognitive symptoms are mild, even after many years of disease duration. Currently, LRRK2 G2019S–associated
parkinsonism is the most prevalent cause of genetically
determined PD in Norway.
This study was supported by grants from the Udall Parkinson’s Disease Research Center of Excellence, the NIH (National Institute of
Neurological Disorders and Stroke, P01 NS400256, M.F.; National
Institute on Aging, AG022579, M.F.), Research Council of Norway
(153487/V50, L.R.W., J.O.A., M.T.), Reberg’s legacy (J.O.A.), Sigurd K. Thoresen Foundation (M.T.), and Unger-Vetlesen Medical
Fund (M.T.).
13. Quinn N, Critchley P, Marsden CD. Young onset Parkinson’s
disease. Mov Disord 1987;2:73–91.
14. Scott WK, Grubber JM, Conneally PM, et al. Fine mapping of
the chromosome 12 late-onset Alzheimer disease locus: potential genetic and phenotypic heterogeneity. Am J Hum Genet
2000;66:922–932.
15. Wszolek ZK, Vieregge P, Uitti RJ, et al. German-Canadian
family (Family A) with parkinsonism, amyotrophy, and dementia—longitudinal observations. Parkinsonism Relat Disord
1997;3:125–139.
Torsin A Haplotype
Predisposes to Idiopathic
Dystonia
Jordi Clarimon, PhD,1 Hilmir Asgeirsson, Stud. Med.,2
Andrew Singleton, PhD,1 Finnbogi Jakobsson, Dr. Med.,2
Haukur Hjaltason, Dr. Med.,2 John Hardy, PhD,1
and Sigurlaug Sveinbjornsdottir, MD2
We thank M. Schreiber for technical assistance and Dr K. Aasly for
recruiting control subjects.
References
1. Rocca WA, McDonnell SK, Strain KJ, et al. Familial aggregation of Parkinson’s disease: the Mayo Clinic family study. Ann
Neurol 2004;56:495–502.
2. Polymeropoulos MH, Lavedan C, Leroy E, et al. Mutation in
the alpha-synuclein gene identified in families with Parkinson’s
disease. Science 1997;276:2045–2047.
3. Chartier-Harlin MC, Kachergus J, Roumier C, et al. Alphasynuclein locus duplication as a cause of familial Parkinson’s
disease. Lancet 2004;364:1167–1169.
4. Zimprich A, Biskup S, Leitner P, et al. Mutations in LRRK2
cause autosomal-dominant parkinsonism with pleomorphic pathology. Neuron 2004;44:601– 607.
5. Paisan-Ruiz C, Jain S, Evans E, et al. Cloning of the gene containing mutations that cause PARK8-linked Parkinson’s disease.
Neuron 2004;44:595– 600.
6. Funayama M, Hasegawa K, Kowa H, et al. A new locus for
Parkinson’s disease (PARK8) maps to chromosome 12p11.2q13.1. Ann Neurol 2002;51:296 –301.
7. Zimprich A, Mueller-Myhsok B, Farrer M, et al. The PARK8
locus in autosomal dominant parkinsonism: confirmation of
linkage and further delineation of the disease-containing interval. Am J Hum Genet 2004;74:11–19.
8. Nichols WC, Pankratz N, Hernandez D, et al. Genetic screening for a single common LRRK2 mutation in familial Parkinson’s disease. Lancet 2005;365:410 – 412.
9. Di Fonzo A, Rohé CF, Ferreira J. A frequent LRRK2 gene mutation associated with autosomal dominant Parkinson’s disease.
Lancet 2005;365:412– 415.
10. Gelb DJ, Oliver E, Gilman S. Diagnostic criteria for Parkinson
disease. Arch Neurol 1999;56:33–39.
11. Gilks WP, Abou-Sleiman PM, Gandhi S. A common LRRK2
mutation in idiopathic Parkinson’s disease. Lancet 2005;365:
415– 416.
12. Lohmann E, Periquet M, Bonifati V, et al. How much phenotypic variation can be attributed to parkin genotype? Ann Neurol 2003;54:176 –185.
Previous work has suggested that in many neurological
diseases genetic variability in the loci predisposing subjects to autosomal dominant disease contributes to the
risk of sporadic disease. Here, using a population-based
sample of dystonia cases, we show an association with the
torsin A haplotype and sporadic idiopathic dystonia.
Ann Neurol 2005;57:765–767
The prevalence of idiopathic dystonia is approximately
300 per 106 and, in most populations, is more common than the hereditary forms of the disease.1–3 The
relationship between idiopathic dystonia and the mendelian forms of the disease is not clear,3 and, in this
regard, the situation is similar to many other neurological diseases such as Parkinson’s disease, Alzheimer’s
disease, and the tauopathies in each of which there are
relatively rare mendelian and relatively common idiopathic variants of disease.4 It is important to attempt to
discern the relationship between the idiopathic and
mendelian variants because animal models of these dis-
From the 1Laboratory of Neurogenetics, Porter Building, Bethesda,
MD; and 2University of Iceland, Faculty of Medicine and Landspitali University Hospital, Reykjavik, Iceland.
Received Nov 16, 2004, and in revised form Mar 9, 2005. Accepted
for publication Mar 9, 2005.
Published online Apr 25, 2005, in Wiley InterScience
(www.interscience.wiley.com). DOI: 10.1002/ana.20485
Address correspondence to Dr Sveinbjornsdottir, R & D office,
Landspitali University Hospital, C12 Fossvogur, 10 Reykjavik, Iceland. E-mail: sigurls@landspitali.is
© 2005 American Neurological Association
Published by Wiley-Liss, Inc., through Wiley Subscription Services
765
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