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LRRK2-Related Parkinson Disease

Synonyms: LRRK2-Associated Parkinson Disease, PARK8

, PhD and , PhD.

Author Information
, PhD
Center of Applied Neurogenetics
University of British Columbia
Vancouver, British Columbia
, PhD
Department of Neuroscience
Mayo Clinic
Jacksonville, Florida

Initial Posting: ; Last Update: September 13, 2012.

Summary

Disease characteristics. LRRK2-related Parkinson disease (PD) is characterized by features consistent with idiopathic PD: initial motor features of slowly progressive asymmetric tremor at rest and/or bradykinesia, cog-wheel muscle rigidity, postural instability, and gait abnormalities including festination and freezing. Non-motor symptoms in LRRK2-related PD occur with the same frequency as observed in typical idiopathic PD. Onset is generally after age 50 years.

Diagnosis/testing. The diagnosis of LRRK2-related PD relies on clinical findings and the identification of a disease-causing mutation in LRRK2.

Management. Treatment of manifestations: Pharmacologic replacement of dopamine, most commonly accomplished with the precursor of dopamine, L-dopa, combined with carbi-dopa. Dopamine agonists may also be used, as well as inhibitors of catechol-O-methyltransferase (COMT) or monoamine oxidase-B (MAO-B). Physical, occupational, and speech therapy may help. Neurosurgical procedures such as pallidotomy, deep brain stimulation of the subthalamic nucleus/globus pallidus interna, or fetal brain transplant to the caudate nucleus benefit some individuals.

Surveillance: Annual neurologic examination to assess gait, tremor, rigidity, and cognition.

Agents/circumstances to avoid: Neuroleptic treatment may exacerbate parkinsonism.

Genetic counseling. LRRK2-related PD is inherited in an autosomal dominant manner. De novo gene mutations may occur; their frequency is unknown. Each child of an individual with LRRK2-related Parkinson disease has a 50% chance of inheriting the disease-causing mutation. Prenatal diagnosis for pregnancies at increased risk is possible if disease-causing mutation in the family is known.

Diagnosis

Clinical Diagnosis

The diagnosis of LRRK2-related Parkinson disease (PD) relies on clinical findings and the identification of a disease-causing mutation in LRRK2.

Clinical findings

  • Motor features of LRRK2-related PD are indistinguishable from those of idiopathic PD and include the following [Aasly et al 2005, Gosal et al 2005, Ishihara et al 2006]:
    • Asymmetric tremor at rest and/or bradykinesia
    • Muscle rigidity
    • Postural instability
    • Gait abnormalities including festination and freezing
  • Onset is typically after age 50 years.
  • Disease course is slowly progressive.
  • Response to low to moderate doses of levodopa is generally good.

Molecular Genetic Testing

Gene. LRRK2, encoding leucine-rich repeat serine/threonine-protein kinase 2, is the only gene in which mutations are known to cause LRRK2-related PD.

Clinical testing

Table 1. Summary of Molecular Genetic Testing Used in LRRK2-Related Parkinson Disease

Gene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1
LRRK2Targeted mutation analysisp.Arg1441Cys
p.Arg1441Gly
p.Arg1628Pro
p.Tyr1699Cys
p.Gly2019Ser
p.Ile2020Thr
p.Gly2385Arg 2
Varies by ethnicity
Sequence analysisSequence variants including those in targeted mutation panels 3~100% 4
Deletion / duplication analysis 5None known 6Unknown, none reported 6

1. The ability of the test method used to detect a mutation that is present in the indicated gene

2. Known pathologic mutations; for targeted mutation analysis, the testing panel may vary by laboratory. Some panels may include less penetrant pathogenic variants (twofold risk) specific to Asian communities which are also seen in >1% of the healthy population. At least seven mutations are known to be pathogenic (see Table 3, Tables 4-5 [pdf]) [Paisan-Ruiz et al 2004, Zimprich et al 2004, Di Fonzo et al 2005, Gilks et al 2005, Kachergus et al 2005, Nichols et al 2005, Di Fonzo et al 2006b, Ross et al 2008]. Mutation detection rates vary by ethnicity.

3. Other LRRK2 substitutions including p.Arg1441His, p.Ala1442Pro, and p.Ile2012Thr are likely to be pathogenic. Two risk factors (p.Arg1628Pro and p.Gly2385Arg) have been confirmed in Asian populations [Di Fonzo et al 2006b, Tan et al 2006, Tomiyama et al 2006, Farrer et al 2007, Lu et al 2008, Ross et al 2008, Tan et al 2008]. At least 100 other coding variants have been observed, with at least 80 leading to nonsynonymous amino acid substitutions. For many of these, little or no evidence in support of the variants being pathologic is available.

4. LRRK2-related PD is defined by the presence of a mutation in LRRK2; thus the mutation detection rate approaches 100% for nucleotide changes, small deletions/insertions, and mutations in splice site consensus motifs.

5. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

6. To date, no deletions or duplications involving LRRK2 have been reported to cause LRRK2-related Parkinson disease [Mata et al 2005a, Di Fonzo et al 2006a]..

Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.

Information on specific allelic variants may be available in Molecular Genetics (see Table A. Genes and Databases and/or Pathologic allelic variants).

Testing Strategy

To confirm/establish the diagnosis in a proband. A diagnosis of LRRK2-related Parkinson disease is confirmed when an individual has one of the known LRRK2 pathogenic mutations.

Single gene testing. One strategy for molecular diagnosis of a proband suspected of having LRRK2-related Parkinson disease is analysis of a single gene.

  • Given the population-specific nature of LRRK2 variants and the large number of exons that need to be sequenced, it may be cost-effective to begin with targeted mutation analysis based on ethnicity:
    • p.Arg1441Gly appears to be restricted to those with Spanish or Hispanic ancestors.
    • p.Gly2019Ser should be tested first in those of Jewish or North African Berber ancestry.
    • p.Arg1441Cys is most frequent in those with Belgian ancestry.
    • Other, rarer LRRK2 variants appear to have more global distribution.
  • If targeted mutation analysis does not identify the ethnic-specific mutation or if ethnicity is unknown, sequence analysis of the entire coding region should be performed.

Multi-gene panels. Another strategy for molecular diagnosis of a proband suspected of having LRRK2-related Parkinson disease is use of a multi-gene panel. Note: The genes included and the methods used in multi-gene panels vary by laboratory and over time; a panel may not include a specific gene of interest. See Differential Diagnosis.

Predictive testing for at-risk asymptomatic adult family members requires prior identification of the disease-causing mutations in the family. See Penetrance for issues of age of onset and disease penetrance.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.

Clinical Description

Natural History

LRRK2-related Parkinson disease (PD) is characterized by features consistent with idiopathic PD: initial motor features of asymmetric tremor at rest and/or bradykinesia, cog-wheel muscle rigidity, postural instability and gait abnormalities including festination and freezing.

Onset is insidious and the disease course is slowly progressive. Age at onset is variable, even within a family. The mean age at onset is approximately 60 years, typical of late-onset Parkinson disease. The reported range in age of onset is 28 to 82 years [Ishihara et al 2006, Kay et al 2006]. Men and women are affected equally.

Non-motor symptoms in LRRK2-related PD, seen as frequently as in typical idiopathic PD, may include constipation, seborrhea, hyposmia/anosmia, sympathetic denervation of the heart, cognitive decline, and dementia. They may appear prior to the movement disorder or emerge during the disease progression. Both constipation and olfactory dysfunction are potential preclinical markers of PD. Virtually all individuals with PD demonstrate some sleep disruption, which may manifest very early in the disease course. Dementia or depression is quite common and can occur in up to 40% of affected individuals [Chaudhuri et al 2006, Langston 2006].

Seven members of one family (the 'Lincolnshire kindred,' in which the mutation p.Tyr1699Cys is segregating) presented with a behavioral disorder characterized by depression and anxiety [Khan et al 2005]. The initial family identified with the p.Tyr1699Cys mutation ('Family A') [Zimprich et al 2004] also presented with atypical symptoms of dementia and amyotrophy.

Cognitive impairment does not appear to be more common in LRRK2-related PD than in typical sporadic disease; however, one report of individuals with the p.Gly2019Ser mutation suggested that Mini-Mental State Examination scores were lower than expected [Lesage et al 2005]. These findings, however, do not reflect the vast majority of individuals with LRRK2-related PD and further clinical studies suggest that cognitive impairment may occur less frequently in LRRK2 p.Gly2019Ser heterozygotes [Healy et al 2008]

Neuroimaging

  • Brain CT and MRI are normal.
  • Positron emission tomography (PET) associated with the LRRK2 mutations p.Gly2019Ser, p.Tyr1699Cys, and p.Arg1441Cys shows significant reduction in 18F-dopa uptake compared to controls; as typical of late-onset PD, the reduced uptake is asymmetric with a rostrocaudal gradient and the putamen more affected than the caudate [Adams et al 2005, Hernandez et al 2005, Khan et al 2005, Paisan-Ruiz et al 2005]. Comparable reduction in uptake may also be observed for the presynaptic membrane dopamine transporter (SLCA3) and vesicular monoamine transporter (SLC18A2) [Adams et al 2005]. Similar findings may be seen in asymptomatic individuals with one of the same LRRK2 mutations [Adams et al 2005]. In a recent study of a LRRK2 kindred with the p.Arg1441Cys mutation, PET studies with a variety of pre- and postsynaptic tracers revealed progressive dopaminergic dysfunction in motor-impaired affected individuals as well as young asymptomatic heterozygotes [Nandhagopal et al 2008].

Neuropathology. The hallmark pathologic features of the common idiopathic form of PD are neuronal loss and gliosis in the substantia nigra and the presence of intracytoplasmic inclusions (or Lewy bodies). The majority of individuals with LRRK2-related PD exhibit these characteristics [Ross et al 2006]. However, LRRK2-related PD has also been documented with four alternate pathologies including [Wszolek et al 2004, Zimprich et al 2004, Funayama et al 2005, Ross et al 2006, Covy et al 2009]:

  • Nigral neuronal loss and gliosis without Lewy body inclusions;
  • Neurofibrillary tangles;
  • Ubiquitin-immunopositive inclusions (Marinesco bodies); and
  • TDP-43 inclusions.

Immunostaining for Lrrk2 protein has also been reported within inclusion bodies including Lewy pathology, although the specificity of the antibodies used for immunohistochemistry has not been confirmed [Giasson et al 2006, Miklossy et al 2006, Biskup et al 2007, Higashi et al 2007, Alegre-Abarrategui et al 2008, Perry et al 2008].

LRRK2-related PD has the potential to be the 'Rosetta stone' of parkinsonian disorders because: (1) all the major pathologies associated with parkinsonism have been observed; and (2) the end-stage pathology may differ even in families with the same mutation (see Table 2). For example:

  • p.Arg1441Cys. Four members of Family D with this mutation had variable, pleomorphic pathology:
    • One with diffuse Lewy body disease within the cortex and brain stem;
    • One with Lewy bodies restricted to brain stem, typical of idiopathic PD;
    • One with a 4R-tauopathy with globose neurofibrillary tangles and tufted astrocytes, reminiscent of argyrophilic grains disease and progressive supranuclear palsy (PSP); and
    • One with nigral neuronal degeneration and gliosis, without coexisting pathology [Wszolek et al 2004].
  • p.Tyr1699Cys. Two members of Family A with this mutation had ubiquitin-immunoreactive cytoplasmic and nuclear inclusions (Marinesco bodies), and a third had brain stem Lewy body disease [Zimprich et al 2004].
  • p.Gly2019Ser. As the most common mutation, p.Gly2019Ser is present in the majority of autopsied cases, in which brain stem or transitional, α-synuclein immunopositive Lewy body pathology is observed [Taylor et al 2006]. Rarely, however, nigral neuronal loss and gliosis only or alternate tauopathy or ubiquitin-immunopositive pathology are observed [Giasson et al 2006, Ross et al 2006] (see Table 2).
  • p.Ile2020Thr. In four members of the Sagamihara kindred with this mutation only moderate nigral neuronal degeneration and gliosis with no coexisting intracytoplasmic lesion pathology were observed [Funayama et al 2005]. Tau pathology has also been present in individuals with this mutation [Ujiie et al 2012].

Table 2. Number of Individuals with LRRK2-Related PD with Distinct Pathologic Findings

LRRK2 MutationLewy Bodies and NeuritesTau and NFTsUbiquitinNeuronal Loss Only
p.Arg1441Cys2101
p.Tyr1699Cys1011
p.Gly2019Ser13211
p.Ile2020Thr1404

NFTs=neurofibrillary tangles

Zimprich et al [2004], Funayama et al [2005], Gilks et al [2005], Giasson et al [2006], Rajput et al [2006], Ross et al [2006], Ujiie et al [2012]

In some cases with neuronal loss and otherwise nonspecific findings TDP-43 immunopositive inclusions may be observed [Covy et al 2009; Dennis Dickson, personal communication].

Genotype-Phenotype Correlations

To date, no certain correlations between specific LRRK2 mutations and age at onset, clinical presentation, or disease progression have been found [Haugarvoll et al 2008, Healy et al 2008, Hulihan et al 2008]. Neuropathologic correlations are noted in Table 2.

'Dardarin,' the Basque word for tremor, was initially proposed as a name for the protein encoded by LRRK2, leucine-rich repeat serine/threonine-protein kinase 2 (Lrrk2) to highlight excessive tremor in families from this region with the p.Arg1441Gly mutation; however, individuals with this mutation may also present with bradykinesia [Paisan-Ruiz et al 2004, Mata et al 2005b].

Penetrance

Penetrance of LRRK2 mutations is age dependent but may vary depending on mutation and population ethnicity.

In population-based studies, Ozelius et al [2006] determined the lifetime penetrance of p.Gly2019Ser parkinsonism by two methods:

  • Comparing the frequency of individuals with the p.Gly2019Ser mutation among individuals with PD vs. unrelated controls (penetrance: 35.2%); and
  • Calculating the proportion of the parents of these individuals diagnosed with PD (penetrance: 31.8%). This estimate is similar to that provided by Goldwurm et al [2007].

The lifetime penetrance in the Tunisian Arab-Berber population in which p.Gly2019Ser is most frequent is 45% [Hulihan et al 2008]. However, as penetrance is a function of age, it may be more meaningfully defined as an age-associated cumulative risk. In an Arab-Berber sample with the p.Gly2019Ser mutation, the symptoms of parkinsonism manifest in fewer than 20% of heterozygotes younger than age 50 years but in more than 80% of those age 70 years and older. In this population the odds ratio of disease in p.Gly2019Ser heterozygotes is 22.6 (95% CI 10.2-50.1) [Hulihan et al 2008]. The risk to heterozygotes and rarer homozygotes is equivalent [Ishihara et al 2006].

In contrast, analysis of multiplex families (i.e., families with more than one affected individual) identified a higher lifetime penetrance estimate of around 67% compared to the estimate for simplex cases [Kachergus et al 2005, Healy et al 2008, Latourelle et al 2008]. The initial study for LRRK2 p.Gly2019Ser suggests that the probability of a heterozygote manifesting symptoms is lower than 20% at age 50 years and increases in an almost linear fashion to more than 80% at age 75 years [Kachergus et al 2005]. The most recent study suggests that the risk of manifesting disease is about 8% at 50 years but greater than 55% at 75 years [Latourelle et al 2008]. However, asymptomatic p.Gly2019Ser heterozygotes older than age 80 years have been reported [Kay et al 2005, Carmine Belin et al 2006]. While bias in patient ascertainment and reporting likely contributes to this figure, genetic and/or environmental modifiers of penetrance and disease susceptibility most likely contribute as well.

Penetrance estimates for LRRK2 p.Gly2019Ser are most widely reported, but pedigree-based figures for p. Arg1441Cys are similar [Haugarvoll et al 2008].

Anticipation

Anticipation is a phenomenon whereby the symptoms of a genetic disorder become apparent at an earlier age as it is passed on to the next generation. In most cases, an increase of severity of symptoms is also noted. This usually occurs with unstable repeat disorders, e.g., Huntington disease. Anticipation has not been documented in LRRK2-related PD and is unlikely, although suggested in a few families [Khan et al 2005].

Nomenclature

The term PARK8 refers to the chromosomal region of 12q12 linked to disease in a large Japanese PD kindred [Funayama et al 2002].

Prevalence

In the US, LRRK2-related Parkinson disease causes approximately 1.0% of simplex PD (i.e. single occurrences in a family) and approximately 5%-6% of familial PD.

LRRK2 p.Gly2019Ser is the most common mutation, accounting for the following:

These frequencies have largely been extrapolated from clinic and/or community-based series, but in the US they are in close agreement with incidence-based samples [unpublished data].

Asymptomatic heterozygotes are noted within families, typically ascertained via an affected proband including one person age 91 years [Gaig et al 2006]; however, pathogenic LRRK2 mutations have negligible frequency in age-/gender-matched population controls [Kachergus et al 2005, Mata et al 2005a, Hulihan et al 2008]. Among unselected individuals of Ashkenazi Jewish ancestry, the prevalence of p.Gly2019Ser is likely 1%-2% [Ozelius et al 2006, Saunders-Pullman et al 2006].

The p.Arg1441Gly mutation, present in approximately 8% of individuals with PD from the Basque community in Northern Spain, probably represents a founder mutation as it has not been reported outside of Spanish-speaking communities [Paisan-Ruiz et al 2004, Mata et al 2005b, Deng et al 2006, Simón-Sánchez et al 2006, González-Fernández et al 2007, Mata et al 2009]. It is estimated that the most recent common ancestor lived 1350 (95% CI, 1020-1740) years ago (in approximately the 7th century), suggesting that p.Arg1441Gly originated in the Basque population and that dispersion of the mutation then occurred through short-range gene flow that was largely limited to nearby regions in Spain [Mata et al 2009].

Differential Diagnosis

Parkinson disease multi-gene panels may include testing for a number of the genes associated with disorders discussed in this section.

LRRK2-related Parkinson disease (PD) is indistinguishable from PD of unknown cause (see Parkinson Disease Overview). However, molecular genetic testing provides a definitive diagnosis.

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed LRRK2-related Parkinson disease (PD), neurologic examination should include assessment of the following:

  • Tremor
  • Rigidity
  • Bradykinesia
  • Gait
  • Mental status
  • Medical genetics consultation

Treatment of Manifestations

The mainstay of treatment is pharmacologic replacement of dopamine, most commonly accomplished with the precursor of dopamine, L-dopa, combined with carbi-dopa.

Dopamine agonists may also be used, as well as inhibitors of catechol-O-methyltransferase (COMT) or monoamine oxidase-B (MAO-B).

The motor impairment generally responds well to dopamine therapy (agonists and levodopa). Side effects include dyskinesias, for which deep-brain stimulation has proven helpful [Aasly et al 2005, Gosal et al 2005, Hernandez et al 2005, Goldwurm et al 2006, Ishihara et al 2006, Tomiyama et al 2006].

Other medications include anti-cholinergics, selegiline, and amantadine [Lang & Lozano 1998a, Lang & Lozano 1998b, Hristova & Koller 2000, Marjama-Lyons & Koller 2001, Olanow & Stocchi 2004].

Some persons with Parkinson disease benefit from neurosurgical procedures such as pallidotomy, deep brain stimulation of the subthalamic nucleus/globus pallidus interna, or fetal brain transplant to the caudate nucleus [Esselink et al 2004, Schüpbach et al 2007, Gómez-Esteban et al 2008, Munhoz et al 2009].

Individuals with Parkinson disease may benefit from physical, occupational, and speech therapy.

To date, limited effective treatment exists for non-motor findings, which can be extremely disabling.

Surveillance

Annual neurologic examination should assess gait, tremor, rigidity, and cognition.

Agents/Circumstances to Avoid

Neuroleptic treatment may exacerbate parkinsonism in LRRK2-related PD, as in PD in general.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Lrrk2 protein is a fusion of Rab (Roc) and kinase (MAPK) domains, and mutations are postulated to augment kinase activity [West et al 2005, Gloeckner et al 2006, Greggio et al 2006]. Hence, the development of specific kinase inhibitors offers an attractive therapeutic target for neuroprotection in asymptomatic and affected LRRK2 heterozygotes, and for idiopathic PD [Albrecht 2005, Toft et al 2005]. A number of inhibitors are being developed; however, selectivity, specificity, and delivery into the central nervous system remain difficult issues to address [Lee et al 2010b].

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

LRRK2-related Parkinson disease (PD) is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

  • Individuals with LRRK2-related Parkinson disease have one parent who has a LRRK2 mutation. However, given the reduced penetrance associated with LRRK2-related PD, a high percentage of affected individuals report unaffected parents.
  • De novo gene mutations may occur as some sites within the gene are highly mutable, notably the codon encoding p.Arg1441; the frequency of these events is unknown.
  • The probability that an asymptomatic parent with a mutation will become symptomatic increases with age.
  • Recommendations for the evaluation of parents of a proband with an apparent de novo mutation include molecular genetic testing and clinical neurologic examination.

Note: Even if an individual diagnosed with LRRK2-related PD has a parent who has the LRRK2 mutation, the family history may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, reduced penetrance, or late onset of the disease in the affected parent.

Sibs of a proband

  • The risk to the sibs of the proband depends on the genetic status of the proband's parents.
  • If a parent of the proband is affected or has a disease-causing mutation, the risk to the sibs of inheriting the mutation is 50%. However, the risk to sibs of developing disease is lower than 50% because of age-related penetrance (see Penetrance).
  • The probability that an asymptomatic sib who has the mutation will become symptomatic increases with age.

Offspring of a proband

  • Each child of an individual with LRRK2-related PD has a 50% chance of inheriting the mutation.
  • The probability that an offspring with a mutation will become symptomatic increases with age.

Other family members of a proband. The risk to other family members depends on the status of the proband's parents. If a parent is affected or has a disease-causing mutation, his or her family members may be at risk.

Related Genetic Counseling Issues

Considerations in families with an apparent de novo mutation. When neither parent of a proband with an autosomal dominant condition has the disease-causing mutation or clinical evidence of the disorder, it is likely that the proband has a de novo mutation. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.

Testing of at-risk asymptomatic adults. Testing of at-risk asymptomatic adults for LRRK2-related PD is possible using the techniques described in Molecular Genetic Testing. Results of such testing indicate whether the mutation is present or absent, but for those individuals with the mutation, they do not predict what the age of onset, severity and type of symptoms, or rate of disease progression in asymptomatic individuals will be. When testing at-risk individuals for LRRK2-related PD, an affected family member should be tested first to confirm the molecular diagnosis in the family.

Testing for the disease-causing mutation in the absence of definite symptoms of the disease is predictive testing. At-risk asymptomatic adult family members may seek testing in order to make personal decisions regarding reproduction, financial matters, and career planning. Others may have different motivations including simply the "need to know." Testing of asymptomatic at-risk adult family members usually involves pre-test interviews in which the motives for requesting the test, the individual's knowledge of LRRK2-related PD, the possible impact of positive and negative test results, and neurologic status are assessed. Those seeking testing should be counseled about possible problems that they may encounter with regard to health, life, and disability insurance coverage, employment and educational discrimination, and changes in social and family interaction. Other issues to consider are implications for the at-risk status of other family members. Informed consent should be procured and records kept confidential. Individuals with a positive test result need arrangements for long-term follow-up and evaluations.

Testing of at-risk individuals younger than age 18 years. Consensus holds that asymptomatic individuals younger than age 18 years who are at risk for adult-onset disorders — particularly those for which no preventive treatment is available — should not have testing. The principal arguments against such testing are that it removes the individual’s choice to know or not know this information, it raises the possibility of stigmatization within the family and in other social settings, and it could have serious educational and career implications.

Individuals younger than age 18 years who are symptomatic usually benefit from having a specific diagnosis established. See also the National Society of Genetic Counselors position statement on genetic testing of minors for adult-onset conditions and the American Society of Human Genetics and American College of Medical Genetics points to consider: ethical, legal, and psychosocial implications of genetic testing in children and adolescents.

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy. Similarly, decisions about testing to determine the genetic status of at-risk asymptomatic family members are best made before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15 to 18 weeks' gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks' gestation. The presence of the disease-causing mutation in an affected family member must be confirmed before prenatal testing can be performed.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Requests for prenatal testing for adult-onset conditions such as LRRK2-related PD are not common. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although most centers would consider decisions about prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutation has been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • American Parkinson Disease Association (APDA)
    135 Parkinson Avenue
    Staten Island NY 10305
    Phone: 800-223-2732 (toll-free); 718-981-8001
    Fax: 718-981-4399
    Email: apda@apdaparkinson.org
  • Fox Trial Finder
  • Michael J. Fox Foundation for Parkinson's Research
    Church Street Station
    PO Box 780
    New York NY 10008-0780
    Phone: 800-708-7644 (toll-free)
    Email: info@michaeljfox.org
  • National Library of Medicine Genetics Home Reference
  • National Parkinson Foundation
    1501 Northwest 9th Avenue
    Bob Hope Road
    Miami FL 33136-1494
    Phone: 800-327-4545 (toll-free); 305-243-6666
    Fax: 305-243-6073
    Email: contact@parkinson.org
  • Parkinson's Disease Foundation (PDF)
    1359 Broadway
    Suite 1509
    New York NY 10018
    Phone: 800-457-6676 (Toll-free Helpline); 212-923-4700
    Fax: 212-923-4778
    Email: info@pdf.org

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. LRRK2-Related Parkinson Disease: Genes and Databases

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for LRRK2-Related Parkinson Disease (View All in OMIM)

168600PARKINSON DISEASE, LATE-ONSET; PD
607060PARKINSON DISEASE 8, AUTOSOMAL DOMINANT; PARK8
609007LEUCINE-RICH REPEAT KINASE 2; LRRK2

Allelic variants. LRRK2 comprises 144 kb and 51 exons. Pathologic LRRK2 variants are listed in Table 3; see Table 3a (pdf) for additional information (exon, domain, and rs#).

As the pathogenicity of many LRRK2 variants has not been determined to date, other known variants are listed as nonsynonymous and silent allelic variants (Tables 4 and 5; pdf).

Table 3. Selected LRRK2 Pathologic Allelic Variants

DNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequence
c.4309A>Cp.Asn1437His 1NM_198578​.3
NP_940980​.3
c.4322G>Ap.Arg1441His 2
c.4321C>Tp.Arg1441Cys
c.4321C>Gp.Arg1441Gly
c.4883G>C p.Arg1628Pro 3
c.5096A>Gp.Tyr1699Cys
c.6055G>Ap.Gly2019Ser
c.6059T>Cp.Ile2020Thr
c.7153G>Ap.Gly2385Arg 3

Note on variant classification: Variants listed in the table have been provided by the author(s). GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1. Aasly et al [2010]

2. Ross et al [2009]

3. Less penetrant pathogenic variants (twofold risk) specific to Asian communities which are also common; >1% in the healthy population

Genetic risk factors. Recent large genome-wide association studies have highlighted the LRRK2 locus to contain population-based common risk factors for disease, as previously highlighted by p.Arg1628Pro and p.Gly2385Arg [International Parkinson Disease Genomics Consortium 2011, Lill et al 2012].

A large collaborative effort by the Genetic Epidemiology of Parkinson’s Disease consortium (GEO-PD) that included investigators from 23 sites representing 15 countries on five continents examined the role of LRRK2 coding variants. The investigators contributed clinical samples on 15,540 individuals (8,611 persons with PD and 6,929 controls). The study identified two novel risk factors: p.Ala419Val in Asian populations and Met1646Thr in populations of northern European heritage, and a common LRRK2 protective haplotype (Asp551Lys-Arg1398His-Lys1423Lys), suggesting that the toxic nature of the protein can be manipulated and providing hope for future neuroprotective therapy [Tan et al 2010, Ross et al 2011].

Normal gene product. The normal gene product, leucine-rich repeat serine/threonine-protein kinase 2 (Lrrk2), is a 2527-amino acid protein (286 kd) that shares homology with the Roco family of proteins. The six conserved domains within this class of Roco proteins are: ankyrin repeat, leucine-rich repeat, Roc, COR, MAPKKK, and WD40 (see Figure 1) [Bosgraaf & Van Haastert 2003, Mata et al 2006b]. Given the size, domain composition and organization of Lrrk2, and the potential for protein-protein interactions, it is likely to be part of a higher molecular-weight complex involved in cellular signaling. Monomers of Lrrk2 protein may also dimerize, similar to the conformation adopted by most protein kinases and Ras GTPases [Gloeckner et al 2006, Dächsel et al 2007b, Deng et al 2008, Greggio et al 2008].

Figure 1

Figure

Figure 1. Schematic representation of the 144-kb LRRK2 loci on chromosome 12q12. The estimated start of the Lrrk2 domain structure is indicated by the residue number below the exonic-intronic (Ex1-Ex51) and domain scheme (690). Domains:
ANK = (more...)

Several biochemical studies have since confirmed kinase activity for Lrrk2 wild type protein and a number of substrates or cofactors have been nominated [West et al 2005, Gloeckner et al 2006, Greggio et al 2006, Iaccarino et al 2007]. These include threonine 558 of moesin, a member of the ERM/merlin family that links plasma membrane receptor complexes to the microfilament cytoskeleton [Jaleel et al 2007]. In Drosophila, Lrrk2 has also been shown to interact with the insulin/IGF signaling pathway to enhance 4E-BP phosphorylation at theonine 37/46, a negative regulator of eIF4E-mediated protein translation that is critical in stress response and dopaminergic neuronal maintenance [Imai et al 2008]. Whether these are true substrates in vivo has yet to be demonstrated, as does their relevance to PD.

Several groups have shown that Lrrk2 GTP binding and GTPase activity have a modifying effect on kinase activity [Guo et al 2007, Lewis et al 2007, Li et al 2007, van Egmond et al 2008]. The Roc-COR domain may also require dimerization for optimal GTPase activity [Deng et al 2008, Gotthardt et al 2008, Greggio et al 2008].

Abnormal gene product. It is postulated that mutant leucine-rich repeat serine/threonine-protein kinase 2 proteins augment MAPK activity, resulting in a toxic gain of function; experimental data now provide some support for this pathogenic mechanism [Smith et al 2005, Greggio et al 2006, Mata et al 2006b].

Lrrk2 p.Gly2019Ser is within exon 41 and the ‘activation hinge’ of the MAPK domain and is associated with a two- to threefold increase of intra- and intermolecular phosphorylation [West et al 2005, Greggio et al 2006, MacLeod et al 2006, Smith et al 2006, Jaleel et al 2007, Luzón-Toro et al 2007, Anand et al 2009]. Whether enhanced kinase activity in vivo represents a characteristic feature shared by all pathogenic Lrrk2 variants remains controversial [Jaleel et al 2007, Anand et al 2009]. The Lrrk2 p.Ile2020Thr substitution and the adjacent p.Gly2019Ser also both provide a potential site for phosphorylation [Zimprich et al 2004, Funayama et al 2005]. Lrrk2 p.Arg1441Cys, Gly, and His substitutions affect the same arginine residue in the Roc domain, a ‘Ras-like’ part of the protein, that binds and hydrolyses GTP and appears to be a prerequisite for Lrrk2 kinase activity [Mata et al 2006b, Ito et al 2007, Lewis et al 2007, Greggio et al 2008]. Lrrk2 p.Arg1628Pro and p.Tyr1699Cys are located within the COR domain that bridges Roc and MAPK domains, whereas p.Gly2385Arg is located on the external surface of the C-terminal WD40 ‘barrel’, a motif with multiple binding surfaces that usually facilitates protein-protein interactions [Mata et al 2006b].

In retinoic acid-differentiated SH-SY5Y, primary neuronal cultures, and in the intact rodent CNS the over-expression of Lrrk2 mutants induces a progressive reduction in neuritic length and branching [MacLeod et al 2006, Plowey et al 2008]. In contrast, Lrrk2 knockdown induced by RNA interference, or over-expression of a Lrrk2 variant with deficient kinase activity, confers increased neuritic length and branching [MacLeod et al 2006]. In the same model, expression of pathogenic Lrrk2 variants linked to PD may lead to prominent phospho-tau immuno-positive inclusions, with lysosomal characteristics, concomitant with apoptosis [MacLeod et al 2006]. A BAC mouse model overexpressing the human LRRK2 p.Arg1441Gly mutation has been reported to have a deficit in dopamine release, a progressive movement disorder leading to akinesia, and tau pathology [Li et al 2009].

Recent studies have implicated mutant LRRK2 in a number of different pathways including autophagy, endosomal-lysosomal function, and Wnt signaling [Berwick & Harvey 2011, Berwick & Harvey 2012, Bravo-San Pedro et al 2012, Friedman et al 2012, Gómez-Suaga & Hilfiker 2012, Tong et al 2012].

LRRK2 has also been shown to play an important function at the synapse and may play a role in vesicle recycling [Lee et al 2010a, Piccoli et al 2011].

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Chapter Notes

Author Notes

Dr. Ross currently directs the Division of the Neurogenetics at Mayo Clinic Jacksonville, and the Genetic Core of a Morris K Udall Center of Excellence for the Genetics of Parkinson's disease. Current research is supported through the National Institutes of Health (NINDS), the Michael J Fox Foundation, and the Mayo Foundation.

Dr. Farrer and colleagues' research interests are focused on the genetic analysis of parkinsonism and related movement and memory disorders. Research interests include statistical and molecular genetics, functional genomics, and applied neurobiology, including the creation of animal models of parkinsonism based on molecular etiology. Dr. Farrer reports (a) International Publication Number WO 2006/045392 A2; (b) International Publication Number WO 2006/068492 A1; (c) US Patent Number 7,544,786; and (d) Norwegian patent 323175, related to LRRK2. Dr Farrer reports salary and royalty payment from the Pharmaceutical Industry for sponsored research on Lrrk2 biology and mouse model characterization. As of August 2008, Mayo and Dr. Farrer have received royalties from the licensing of these technologies of greater than $10,000, the US federal threshold for significant financial interest.

Author History

Matthew Farrer, PhD (2006-present)
Owen A Ross, PhD (2006-present)
Jeremy T Stone, BSc; Mayo Clinic (2006-2010)

Acknowledgments

  • Morris K Udall Center of Excellence for the Genetics of Parkinson's disease
  • Current research supported through the National Institutes of Health (NINDS, NIEHS and NIA), the Michael J Fox Foundation, and the Mayo Foundation
  • All the individuals involved in our research including the many scientists, clinicians, and especially the patients and their families

Revision History

  • 13 September 2012 (me) Comprehensive update posted live
  • 29 April 2010 (me) Comprehensive update posted live
  • 2 November 2006 (me) Review posted to live Web site
  • 6 July 2006 (mf) Original submission
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