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Original Contribution |

LRRK2 Mutations in Spanish Patients With Parkinson Disease:  Frequency, Clinical Features, and Incomplete Penetrance FREE

Carles Gaig, MD; Mario Ezquerra, PhD; Maria Jose Marti, MD, PhD; Esteban Muñoz, MD, PhD; Francesc Valldeoriola, MD, PhD; Eduardo Tolosa, MD, FRCP
[+] Author Affiliations

Author Affiliation: Movement Disorders Unit, Neurology Service, Institut Clínic de Neurociències, Hospital Clínic, Institut d’Investigacions Biomèdiques August Pi i Sunyer, Universitat de Barcelona, Barcelona, Spain.


Arch Neurol. 2006;63(3):377-382. doi:10.1001/archneur.63.3.377.
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Published online

Background  Several pathogenic mutations in the LRRK2 gene have been implicated in familial and sporadic cases of Parkinson disease (PD). The R1441G mutation is frequent in Spanish patients of Basque ethnicity with PD, and the G2019S mutation is a common mutation found in several populations worldwide.

Objectives  To determine the frequency of the LRRK2G2019S and R1441G mutations in PD patients from the non-Basque northeast region of Spain (Catalonia), and to characterize their family history and clinical features.

Design  We screened patients for the presence of the LRRK2R1441G and G2019S mutations. These LRRK2 mutations were detected by restriction endonuclease digestion, and samples with an abnormal electrophoresis pattern were sequenced to identify the exact nucleotide change. The clinical features and family history of patients with LRRK2 mutations were studied in detail.

Setting  The northeast region of Spain.

Patients  Three hundred two patients with PD.

Main Outcome Measures  Onset age, clinical features, and family history of PD and LRRK2 mutations.

Results  The R1441G mutation was present in 0.7% of total PD cases. The G2019S mutation was found in 6.4% of familial and 3.4% of sporadic cases. Additionally, we found 1 patient with the R1441C mutation. Age at onset ranged from 33 to 78 years. Clinical features were not different from classic PD, except for 1 patient who presented with monosymptomatic leg rest tremor of 8 years' duration. In addition, a 91-year-old unaffected relative of a patient with the G2019S mutation was found to be a mutation carrier.

Conclusions  The G2019S mutation frequency in PD patients from northeast Spain is similar to that reported in other European regions. The R1441G mutation is very uncommon in Catalonia. The presence of an aged unaffected G2019S mutation carrier supports the previously described occurrence of incomplete penetrance in PD patients with LRRK2 mutations.

Figures in this Article

Recently, pathogenic mutations in the leucine-rich repeat kinase 2 (LRRK2) gene have been identified in patients with autosomal dominant forms of Parkinson disease (PD).1,2 The LRRK2 gene has 51 exons, encodes a large protein of 2527 amino acids (dardarin), and has an unknown function, although there are 5 predicted functional domains: a leucine-rich repeat domain, a Roc (Ras guanosine triphosphatase) domain, a C-terminal of Roc domain, a WD40 domain (β-transducin repeats), and a tyrosine kinase catalytic domain.1,2 The clinical features of parkinsonism and the response to levodopa treatment in patients with LRRK2 mutations seem to be indistinguishable from those of classic PD.24 Features like dementia or atypical signs such as amyotrophy or supranuclear gaze palsy are rarely observed.1,2,5,6

Until now, several different missense mutations have been reported in the LRRK2 gene.1,2,4,5,7 One of them, the G2019S mutation, has been found in a significant proportion of patients with PD; it accounts for about 5% to 6% of familial and 1% to 2% of apparently sporadic cases.810 The R1441G mutation has been described only in populations located in the Basque country and its neighboring region of northern Spain, Asturias. This mutation has been found in 8% of Basque PD patients1 and in 2.7% of patients with late-onset PD in Asturias.11 Two more mutations, located in position 1441 within the Roc domain, have been described in other populations: the R1441C and R1441H mutations, emphasizing the importance of this residue for the LRRK2 pathogenic mechanism.2,7

The aims of this study were to determine the frequency of the LRRK2G2019S and R1441G mutations in PD patients included in our PD DNA bank, composed of patients from the non-Basque northeast region of Spain (Catalonia), and to characterize in detail their family history and clinical features.

PATIENTS

The LRRK2 mutations were screened in 302 nonconsecutive and unrelated PD patients (mean ± SD age at onset, 53.8 ± 13.3 years; range, 8-85 years; 170 [56.3%] males; 132 [43.7%] females). All subjects in this study resided in Catalonia and were recruited in the Neurology Service of the Hospital Clínic of Barcelona from January 1, 1997, to June 30, 2005. They all fulfilled commonly accepted diagnostic clinical criteria for PD.12,13

Patients included were observed longitudinally in our Movement Disorders Unit. Their family history of PD was periodically evaluated, and when positive, the conservative criteria of Marder et al14 were used to assess its degree of certainty. Among the 302 PD patients, 94 had a family history (31.1%; mean ± SD age at onset, 53.1 ± 14.0; range, 15-84 years), whereas 208 cases were sporadic (68.9%; mean age at onset, 54.2 ± 13.0; range, 8-85 years). Written informed consent was obtained from all participants, and the local ethics authorities approved the project. The clinical data of patients with LRRK2 mutations were reviewed. In some cases, it was possible to obtain blood samples from affected and unaffected relatives.

GENETIC ANALYSIS

The DNA from peripheral blood was isolated by using standard methods in all subjects. The LRRK2G2019S mutation was detected by restriction endonuclease digestion with the SfcI enzyme as previously described,8 running in an acrylamide gel electrophoresis and subsequently stained with ethidium bromide. The R1441G, R1441C, and R1441H mutations were screened by restriction endonuclease digestion with the BstUI enzyme, and samples with an abnormal electrophoresis pattern were sequenced to identify the exact nucleotide change. Genomic DNA was amplified using polymerase chain reaction and done in 25 μL containing 2.5 μL of polymerase chain reaction buffer, 1.5mM magnesium chloride, 1.25mM concentration of each deoxynucleotide triphosphate (dNTP), 0.4μM forward primer, 0.4μM reverse primer, 2.5 U of Taq DNA polymerase, and 50 ng of genomic DNA. Cycle conditions were as follows: 5 minutes at 94°C, 30 cycles of 30 seconds' denaturation at 94°C, 30 seconds' annealing at 58°C, and 90 seconds' extension at 72°C, with a final extension of 5 minutes at 72°C. The samples were sequenced using the Big Dye Terminator Cycle Sequencing Ready Reaction Kit (Perkin Elmer, Foster City, Calif) and run on an ABI-prism automatic DNA sequencer (Perkin Elmer).

The LRRK2 mutations were found in 16 patients, which represent 5.3% of all PD subjects studied in this cohort. Thirteen patients carrying the G2019S mutation, 2 patients with the R1441G mutation, and 1 patient with the LRRK2R1441C mutation were identified (Table 1). The R1441H mutation was not present in any of our patients. An R1441G mutation was found in a familial PD patient originating from the northwest region of Spain, near Asturias, but the other R1441G mutation carrier had not known ancestors from this geographical area.

Table Graphic Jump LocationTable 1. Patients With PD With or Without LRRK2 Mutations*

Nine patients (56.3%) had a family history of PD (Figure). Two other patients (patients 1 and 8; Table 2) reported tremor in 1 parent, but these families did not meet the conservative criteria of Marder and colleagues for familial PD,14 and the cases were classified as sporadic. The pedigrees of patients with LRRK2 mutations are shown in the Figure. The family of proband 4 showed incomplete penetrance. The proband's mother, who was a confirmed mutation carrier, did not have illness symptoms or signs of parkinsonism at age 91 years. Furthermore, a proband's half-sister, from the same mother but a different father, was affected by PD but was not a mutation carrier.

Place holder to copy figure label and caption
Figure.

Pedigrees of familial patients with LRRK2 mutations. Each proband is indicated by an arrow. Black symbols indicate affected family members; gray symbols, relatives who have only tremor; slash, deceased; circles, females; squares, males; asterisk, genotyped individual, with m for mutation carriers and wt for wild-type LRRK2.

Graphic Jump Location
Table Graphic Jump LocationTable 2 Clinical Features of Patients With LRRK2 Mutations*

Two additional patients carrying the G2019S mutation (patients 17 and 18), relatives of probands 4 and 11, respectively, were identified, and their clinical features are also reported herein (Table 2 and Figure). The mean age at illness onset for the 18 patients with LRRK2 mutations (mean ± SD, 57.1 ± 13.2 years; range, 33-78 years) did not differ significantly from PD patients without these mutations (mean ± SD, 53.7±13.3 years; range, 8-85 years). Early onset (<40 years) was present in 2 patients, aged 33 and 35 years, respectively. One relative of patient 7 developed symptoms of PD at age 26 years, but extensive clinical information and DNA from this individual were not available.

The clinical features of patients with LRRK2 mutations after a mean disease duration of 13 years are shown in Table 2 and Table 3 (mean follow-up at our hospital, 6.3 years). The parkinsonism in patients with LRRK2 mutations usually presented with unilateral rest tremor or motor slowness. During the course of the illness, the 3 cardinal parkinsonian signs of rest tremor, bradykinesia, and rigidity were present in most patients, with frequent persistence of the asymmetry of parkinsonian motor signs (Table 3). Only 1 case (patient 18; Table 2) differed from this clinical picture. At age 57 years this patient developed rest tremor of the left leg, which has remained mild and intermittent and been restricted to the left leg for 8 years, without the presence of other parkinsonian signs. Dementia was present in only 1 patient (patient 16; Table 2) with the R1441G mutation, who developed visual hallucinations and delusions with cognitive decline (Mini-Mental State Examination score, 12/30) and fluctuating attention after 15 years of illness. Atypical features of PD such as supranuclear gaze palsy or early dysautonomia were not observed in any of our patients.

Table Graphic Jump LocationTable 3. Summary of Clinical Features in 18 Patients With LRRK2 Mutations

Response to levodopa was positive in all cases. Treatment-induced motor complications appeared frequently after a mean illness duration of 7 years but in some cases appeared after 10 or as early as 2 years. All patients with treatment-induced motor complications had motor fluctuations, mainly wearing-off but also on-off phenomena (Table 3). Three patients (patients 2, 3, and 11; Table 2) were treated with bilateral subthalamic nuclei deep brain stimulation after 7 to 11 years of illness, with sustained control of motor PD symptoms and functional improvement in all cases.

We have found the LRRK2G2019S mutation in 4.3% of our PD patients, accounting for 6.4% of familial and 3.4% of apparently sporadic cases. This is the first study that reports the frequency of the LRRK2G2019S mutation in Spanish PD patients. The proportion of LRRK2G2019S mutation carriers in both familial and isolated cases of PD is similar to or slightly higher than that reported previously in other studies performed in different populations, where this mutation accounts for about 2% to 6% of familial and 0.6% to 2.0% of apparently sporadic cases.710,15,16

The R1441G mutation was present in 0.7% of our PD patients. This mutation was originally identified in 8% of Spanish families originating from the Basque region1 and later in patients from a neighboring region, Asturias, with a lower frequency (2.7%).11 This mutation has not been found in other world populations, including Portuguese PD patients in the Iberian peninsula,16 suggesting that it is geographically restricted to northern Spain by a founder effect in the Basque people, a relatively homogeneous and historically isolated ethnic group. Haplotype analysis of this chromosomal region in PD patients supports this hypothesis.1,11 We have found a lower R1441G mutation frequency in Catalonia when compared with Basque or Asturian regions, supporting the existence of a geographical gradient for this mutation as previously suggested.11 In our population, 1 patient with an R1441G mutation originated from a region near Asturias, whereas the other patient carrier had not known Basque or Asturian ancestors. Therefore, the presence of this mutation in Catalonia could be explained by the existence of recent or ancient migration from the Basque population. Supporting the hypothesis of an ancient migration is the description of an ancestral gene flow between the Basque people and other populations of Europe, especially with the Catalan people, during the past few thousand years.17

As reported in previous studies,26 the clinical features of parkinsonism in our patients with LRRK2 mutations were similar to classic PD. Age at illness onset was variable, ranging from 33 to 78 years, although mean age at onset was similar to that of idiopathic PD. Onset was frequently asymmetrical, with rest tremor or motor slowness. A significant proportion of our patients had minimal or no rest tremor despite long disease duration. As noted in other studies, dementia was rare in patients with LRRK2 mutations.24 A clinical presentation different from classical PD occurred in 1 G2019S mutation carrier, who had monosymptomatic, mild, intermittent rest tremor in 1 leg for several years without developing additional parkinsonian symptoms or signs. This suggests that in some cases, the LRRK2 mutation phenotype may have a benign course. All patients had a good response to levodopa but frequently developed treatment-induced motor complications, especially fluctuations and freezing of gait, that were disabling for many of them. Three of our patients were treated with chronic bilateral electrical stimulation of the subthalamic nuclei, with an excellent outcome.

Family history of PD was present only in 56.3% of our LRRK2 mutation carriers. Negative family history for this subset of PD patients (43.7%) may be related to several factors, including incomplete penetrance,10 undiagnosed PD in a relative, appearance of a mutation de novo, false paternity, and early death of family members before illness development. We found an unaffected 91-year-old relative who carries the G2019S mutation, supporting the existence of incomplete penetrance in this family. Previous studies have reported a penetrance between 70% and 100% in different families with LRRK2 mutations.1,18 In 1 study, the penetrance of the mutation was found to be age dependent, increasing from 17% at age 50 years to 85% at age 70 years.5 However, the 91-year-old unaffected carrier reported herein, together with the previously reported 89-year-old unaffected subject carrying a similar mutation,19 suggests that other factors besides age are important for LRRK2 incomplete penetrance.

Identification of affected relatives of G2019S PD patients but who do not carry this mutation, as in 1 of our patients, has also been observed in other studies.4,8 Nichols et al8 reported the presence of such phenocopies in 5 of 19 affected sibships with the G2019S mutation. As suggested by Singleton,20 these phenocopies may indicate that some risk factors might be present in other family members, independently of their G2019S status, and consequently increase the lifetime risk of PD.

In light of the high frequency of LRRK2 mutations in PD, it seems likely that the identification of many patients and unaffected relatives with LRRK2 mutations will be possible in the near future. This will facilitate the search of genetic and environmental factors that could condition disease susceptibility and age at disease onset. Furthermore, the detection of presymptomatic mutation carriers will allow researchers to perform studies of putative neuroprotective treatments.

Correspondence: Eduardo Tolosa, MD, FRCP, Hospital Clínic, Service of Neurology, Villarroel 170, Barcelona 08036, Spain (etolosa@clinic.ub.es).

Accepted for Publication: October 5, 2005.

Author Contributions:Study concept and design: Gaig and Ezquerra. Acquisition of data: Gaig, Ezquerra, Marti, Muñoz, Valldeoriola, and Tolosa. Analysis and interpretation of data: Gaig, Ezquerra, and Tolosa. Drafting of the manuscript: Gaig, Ezquerra, and Tolosa. Critical revision of the manuscript for important intellectual content: Marti, Muñoz, Valldeoriola, and Tolosa. Obtained funding: Tolosa. Administrative, technical, and material support: Gaig and Ezquerra. Study supervision: Tolosa. Drs Gaig and Ezquerra contributed equally to this work.

Funding/Support: This project was supported by grants from the Distinció per la Recerca de la Generalitat de Catalunya (Barcelona, Spain) and grant C03/06 from Centro en Red de Investigaciones en Enfermedades Neurologicas, Institut d’Investigacions Biomèdiques August Pi i Sunyer–Instituto de Salud Carlos III, Redes Tematicas de Investigación Cooperativa (Barcelona) to Dr Tolosa.

Acknowledgment: We thank the patients and their families for their participation in this study. We acknowledge technical support provided by Manel Fernandez.

Paisan-Ruiz  CJain  SEvans  EW  et al.  Cloning of the gene containing mutations that cause PARK8-linked Parkinson's disease. Neuron 2004;44595- 600
PubMed
Zimprich  ABiskup  SLeitner  P  et al.  Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology. Neuron 2004;44601- 607
PubMed
Aasly  JOToft  MFernandez-Mata  I  et al.  Clinical features of LRRK2-associated Parkinson's disease in central Norway. Ann Neurol 2005;57762- 765
PubMed
Hernandez  DGPaisan-Ruiz  CMcInerney-Leo  A  et al.  Clinical and positron emission tomography of Parkinson's disease caused by LRRK2. Ann Neurol 2005;57453- 456
PubMed
Kachergus  JMata  IFHulihan  M  et al.  Identification of a novel LRRK2 mutation linked to autosomal dominant parkinsonism: evidence of a common founder across European populations. Am J Hum Genet 2005;76672- 680
PubMed
Paisan-Ruiz  CSaenz  ALopez de Munain  A  et al.  Familial Parkinson's disease: clinical and genetic analysis of four Basque families. Ann Neurol 2005;57365- 372
PubMed
Zabetian  CPSamii  AMosley  AD  et al.  A clinic-based study of the LRRK2 gene in Parkinson disease yields new mutations. Neurology 2005;65741- 744
PubMed
Nichols  WCPankratz  NHernandez  D  et al.  Genetic screening for a single common LRRK2 mutation in familial Parkinson's disease. Lancet 2005;365410- 412
PubMed
Di Fonzo  ARohe  CFFerreira  J  et al.  A frequent LRRK2 gene mutation associated with autosomal dominant Parkinson's disease. Lancet 2005;365412- 415
PubMed
Gilks  WPAbou-Sleiman  PMGandhi  S  et al.  A common LRRK2 mutation in idiopathic Parkinson's disease. Lancet 2005;365415- 416
PubMed
Mata  IFTaylor  JPKachergus  J  et al.  LRRK2 R1441G in Spanish patients with Parkinson's disease. Neurosci Lett 2005;382309- 311
PubMed
Hughes  AJDaniel  SEKilford  LLees  AJ Accuracy of clinical diagnosis of idiopathic Parkinson's disease: a clinico-pathological study of 100 cases. J Neurol Neurosurg Psychiatry 1992;55181- 184
PubMed
Gelb  DJOliver  EGilman  S Diagnostic criteria for Parkinson disease. Arch Neurol 1999;5633- 39
PubMed
Marder  KLevy  GLouis  ED  et al.  Accuracy of family history data on Parkinson's disease. Neurology 2003;6118- 23
PubMed
Deng  HLe  WGuo  YHunter  CBXie  WJankovic  J Genetic and clinical identification of Parkinson's disease patients with LRRK2 G2019S mutation. Ann Neurol 2005;57933- 934
PubMed
Bras  JMGuerreiro  RJRibeiro  MH  et al.  G2019s dardarin substitution is a common cause of Parkinson's disease in a Portuguese cohort. Mov Disord 2005;201653- 1655
Hurles  MEVeitia  RArroyo  E  et al.  Recent male-mediated gene flow over a linguistic barrier in Iberia, suggested by analysis of a Y-chromosomal DNA polymorphism. Am J Hum Genet 1999;651437- 1448
PubMed
Funayama  MHasegawa  KKowa  HSaito  MTsuji  SObata  F A new locus for Parkinson's disease (PARK8) maps to chromosome 12p11.2-q13.1. Ann Neurol 2002;51296- 301
PubMed
Kay  DMKramer  PHiggins  DZabetian  CPPayami  H Escaping Parkinson's disease: a neurologically healthy octogenarian with the LRRK2 G2019S mutation. Mov Disord 2005;201077- 1078
PubMed
Singleton  AB Altered alpha-synuclein homeostasis causing Parkinson's disease: the potential roles of dardarin. Trends Neurosci 2005;28416- 421
PubMed

Figures

Place holder to copy figure label and caption
Figure.

Pedigrees of familial patients with LRRK2 mutations. Each proband is indicated by an arrow. Black symbols indicate affected family members; gray symbols, relatives who have only tremor; slash, deceased; circles, females; squares, males; asterisk, genotyped individual, with m for mutation carriers and wt for wild-type LRRK2.

Graphic Jump Location

Tables

Table Graphic Jump LocationTable 1. Patients With PD With or Without LRRK2 Mutations*
Table Graphic Jump LocationTable 2 Clinical Features of Patients With LRRK2 Mutations*
Table Graphic Jump LocationTable 3. Summary of Clinical Features in 18 Patients With LRRK2 Mutations

References

Paisan-Ruiz  CJain  SEvans  EW  et al.  Cloning of the gene containing mutations that cause PARK8-linked Parkinson's disease. Neuron 2004;44595- 600
PubMed
Zimprich  ABiskup  SLeitner  P  et al.  Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology. Neuron 2004;44601- 607
PubMed
Aasly  JOToft  MFernandez-Mata  I  et al.  Clinical features of LRRK2-associated Parkinson's disease in central Norway. Ann Neurol 2005;57762- 765
PubMed
Hernandez  DGPaisan-Ruiz  CMcInerney-Leo  A  et al.  Clinical and positron emission tomography of Parkinson's disease caused by LRRK2. Ann Neurol 2005;57453- 456
PubMed
Kachergus  JMata  IFHulihan  M  et al.  Identification of a novel LRRK2 mutation linked to autosomal dominant parkinsonism: evidence of a common founder across European populations. Am J Hum Genet 2005;76672- 680
PubMed
Paisan-Ruiz  CSaenz  ALopez de Munain  A  et al.  Familial Parkinson's disease: clinical and genetic analysis of four Basque families. Ann Neurol 2005;57365- 372
PubMed
Zabetian  CPSamii  AMosley  AD  et al.  A clinic-based study of the LRRK2 gene in Parkinson disease yields new mutations. Neurology 2005;65741- 744
PubMed
Nichols  WCPankratz  NHernandez  D  et al.  Genetic screening for a single common LRRK2 mutation in familial Parkinson's disease. Lancet 2005;365410- 412
PubMed
Di Fonzo  ARohe  CFFerreira  J  et al.  A frequent LRRK2 gene mutation associated with autosomal dominant Parkinson's disease. Lancet 2005;365412- 415
PubMed
Gilks  WPAbou-Sleiman  PMGandhi  S  et al.  A common LRRK2 mutation in idiopathic Parkinson's disease. Lancet 2005;365415- 416
PubMed
Mata  IFTaylor  JPKachergus  J  et al.  LRRK2 R1441G in Spanish patients with Parkinson's disease. Neurosci Lett 2005;382309- 311
PubMed
Hughes  AJDaniel  SEKilford  LLees  AJ Accuracy of clinical diagnosis of idiopathic Parkinson's disease: a clinico-pathological study of 100 cases. J Neurol Neurosurg Psychiatry 1992;55181- 184
PubMed
Gelb  DJOliver  EGilman  S Diagnostic criteria for Parkinson disease. Arch Neurol 1999;5633- 39
PubMed
Marder  KLevy  GLouis  ED  et al.  Accuracy of family history data on Parkinson's disease. Neurology 2003;6118- 23
PubMed
Deng  HLe  WGuo  YHunter  CBXie  WJankovic  J Genetic and clinical identification of Parkinson's disease patients with LRRK2 G2019S mutation. Ann Neurol 2005;57933- 934
PubMed
Bras  JMGuerreiro  RJRibeiro  MH  et al.  G2019s dardarin substitution is a common cause of Parkinson's disease in a Portuguese cohort. Mov Disord 2005;201653- 1655
Hurles  MEVeitia  RArroyo  E  et al.  Recent male-mediated gene flow over a linguistic barrier in Iberia, suggested by analysis of a Y-chromosomal DNA polymorphism. Am J Hum Genet 1999;651437- 1448
PubMed
Funayama  MHasegawa  KKowa  HSaito  MTsuji  SObata  F A new locus for Parkinson's disease (PARK8) maps to chromosome 12p11.2-q13.1. Ann Neurol 2002;51296- 301
PubMed
Kay  DMKramer  PHiggins  DZabetian  CPPayami  H Escaping Parkinson's disease: a neurologically healthy octogenarian with the LRRK2 G2019S mutation. Mov Disord 2005;201077- 1078
PubMed
Singleton  AB Altered alpha-synuclein homeostasis causing Parkinson's disease: the potential roles of dardarin. Trends Neurosci 2005;28416- 421
PubMed

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