LRRK2-Related Parkinson Disease

Clinical Diagnosis

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

Molecular Genetic Testing

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Gene.   LRRK2, encoding leucine-rich repeat serine/threonine-protein kinase 2, is the only gene associated with LRRK2-related PD.

Molecular genetic testing: Clinical uses

• Diagnosis

• Predictive testing; possible for asymptomatic persons at risk in families with known mutations in LRRK2, but note issues of age of onset and penetrance in Penetrance.

• Prenatal diagnosis

Note: It is the policy of GeneReviews to include clinical uses of testing available from laboratories listed in the GeneTests Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Molecular genetic testing: Clinical methods

• Targeted mutation analysis.  At least five mutations are known to be pathogenic (see Table 1) [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]. Mutation detection rates vary by ethnicity.

• Sequence analysis.  At least 30 substitutions have been observed, with at least 20 leading to non-synonymous amino acid substitutions [Mata, Kachergus et al 2005; Di Fonzo et al 2006]. Of note, LRRK2 has 51 exons; thus sequencing of the entire gene can be expensive and time-consuming. Targeted mutation analysis is recommended in most cases, depending on ethnicity and family history.

Molecular genetic testing: Research

• Quantitative PCR.  To date, no exonic insertions or deletions have been identified in LRRK2 [Mata, Kachergus et al 2005].

Table 2. Molecular Genetic Testing Used in LRRK2-Related Parkinson Disease

Test Methods	Mutations Detected	Mutation Detection Rate	Test Availability
Targeted mutation analysis	4321C>T, 4321C>G, 5096A>G, 6055G>A, 6059T>C  1	Varies by ethnicity	Clinical
Sequence analysis	LRRK2 sequence variants  2	100%  3

1. Panel may vary by laboratory.
2. Other LRRK2 substitutions including p.R1441H and p.I2012T are likely to be pathogenic. (The recently nominated 'risk factor' p.G2385R is a polymorphism rather than a pathogenic mutation; two studies report evidence that p.G2385R is associated with PD risk in Asia, although the finding has yet to be confirmed by replication [Mata, Kachergus et al 2005; Zabetian et al 2005; Di Fonzo et al 2006; Tan et al 2006; Tomiyama et al 2006].
3.  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.

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

A diagnosis of LRRK2-related Parkinson disease is confirmed when an individual has one of the known LRRK2 pathogenic mutations.

Testing Strategy for a Proband

Given the population-specific nature of LRRK2 variants, it may be more cost-efficient and appropriate to determine genetic testing based on ethnicity:

• p.R1441G appears to be restricted to those with Spanish or Hispanic ancestors

• p.G2019S should be tested first in those of Jewish ancestry.

• Other, rarer LRRK2 variants appear to have more global distribution.

Genetically Related (Allelic) Disorders

No other phenotypes are known to be associated with mutations in LRRK2.

The LRRK2 p.G2019S substitution has been observed in one individual with Alzheimer disease; however, this finding may be coincidental [Ross et al 2006].

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 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 et al 2006].

Seven members of one family (the 'Lincolnshire kindred'), in which the mutation p.Y1699C is segregating, presented with a behavioral disorder characterized by depression and anxiety [Khan et al 2005]. The first family identified with the p.Y1699C 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.G2019S mutation suggested that Mini-Mental State Examination scores were lower than expected [Lesage, Ibanez et al 2005]. These findings, however, do not reflect the vast majority of individuals with LRRK2-related PD and the significance of this observation remains unresolved.

Neuroimaging

• Brain CT and MRI are normal.

• Positron emission tomography (PET) associated with the LRRK2 mutations p.G2019S, p.Y1699C, and p.R1441C 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].

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. However, LRRK2-related PD has also been documented with three alternate pathologies including: 1) nigral neuronal loss and gliosis without Lewy body inclusions, 2) neurofibrillary tangles, and 3) ubiquitin immunopositive inclusions (Marinesco bodies) [Wszolek et al 1997, Wszolek et al 2004, Zimprich et al 2004, Funayama et al 2005, Ross et al 2006].

• p.R1441C.  Four members of Family D with this mutation had variable, pleomorphic pathology: one with diffuse Lewy body disease within the cortex and brainstem; one with Lewy bodies restricted to brainstem, 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.Y1699C.  Two members of Family A with this mutation had ubiquitin-immunoreactive cytoplasmic and nuclear inclusions (Marinesco bodies), and a third had brainstem Lewy body disease [Wszolek et al 1997].

• p.G2019S.  As the most common mutation, p.G2019S is present in the majority of autopsied cases, in which brainstem 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 3.)

• p.I2020T.  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].

Genotype-Phenotype Correlations

'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.R1441G mutation; however, individuals with this mutation are equally likely to present with bradykinesia [Paisan-Ruiz et al 2004; Mata, Taylor et al 2005].

Penetrance

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

A pedigree-based estimate has been made for the most prevalent mutation, LRRK2 c.6055G>A (p.G2019S): 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, but asymptomatic heterozygotes older than age 80 years have been reported [Kachergus et al 2005, Kay et al 2005, Carmine Belin et al 2006].

However, accurate estimates of penetrance are difficult to predict and different groups have reported alternate approaches [Kachergus et al 2005, Lesage et al 2005, Ozelius et al 2006]. Ozelius et al (2006) determined lifetime penetrance by two methods: (1) comparing the frequency of individuals with the p.G2019S mutation among individuals with PD vs. unrelated controls (penetrance, 35.2%), and (2) calculating the proportion of the parents of these individuals diagnosed with PD (penetrance, 31.8%). This calculation, performed in a population with a high frequency of the p.G2019S mutation, is a much lower estimate of penetrance than that proposed by Kachergus et al (2005) and Lesage et al (2005). Given the relative absence of the p.G2019S mutation in controls, the penetrance of this variant is clearly age-related and high. Global collaborative efforts to resolve these issues using population-specific approaches are under way.

The risk to heterozygotes and rarer homozygotes is equivalent [Ishihara et al 2006].

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, although it has been suggested in a few families [Khan et al 2005].

Nomenclature

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

'Dardarin,' the Basque word for tremor, was initially proposed to highlight excessive tremor in families from this region with the R1441G mutation; however, individuals with this mutation are equally likely to present with bradykinesia [Paisan-Ruiz et al 2004; Mata, Taylor et al 2005].

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 c.6055G>A (p.G2019S) is the most common mutation, accounting for the following:

• Approximately 0.5% of simplex PD and 2%-6% of familial PD in the US [Deng et al 2005, Farrer et al 2005, Nichols et al 2005, Kay et al 2006]

• Approximamtely 0.5% of simplex PD in the UK [Williams-Gray et al 2006]

• Approximately 2% in families from central Norway [Aasly et al 2005]

• 0.9% simplex PD and 5.1% familial PD in Italy [Goldwurm et al 2005]

• 2.7%-7.6% in northern Spain [Mata, Ross et al 2006]

• 37% of simplex PD [Gaig et al 2006, Infante et al 2006] and 41% of familial PD in North Africa (Morocco, Algeria, and Tunisia) [Lesage et al 2006]

• Approximately 18% of PD in Ashkenazi Jews (13% of simplex cases and 30% of familial cases) [Ozelius et al 2006]

• 0.4% of simplex PD in Japan [Zabetian et al 2006].

  Note: (1) p.G2019S was reported in a Japanese individual with PD in another study [Tomiyama et al 2006]. In that study, however, the frequency of p.G2019S was reported in a pooled Asian sample and the frequency among Japanese individuals with PD was not specified. (2) p.G2019S has not been identified in over 1,200 PD individuals of Chinese ancestry screened to date [Lu et al 2005, Tan et al 2006, Tomiyama et al 2006]. Combining all Asian populations into a single group is not advisable; therefore, it is quite possible that p.G2019S occurs among the Japanese but not in other Asian populations.

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.

Asymptomatic heterozygotes are noted within families, typically ascertained via an affected proband including a 91-year-old person [Gaig et al 2006]; however, pathogenic LRRK2 mutations have negligible frequency in age-/gender-matched population controls [Kachergus et al 2005; Mata, Kachergus et al 2005]. Among unselected individuals of Ashkenazi Jewish ancestry, the prevalence of p.G2019S is likely 1%-2% [Ozelius et al 2006, Saunders-Pullman et al 2006].

The p.R1441G mutation, present in about 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 countries [Paisan-Ruiz et al 2004; Mata, Taylor et al 2005].

Evaluations at Initial Diagnosis to Establsh the Extent of Disease

Neurologic examination should include assessment of the following:

• Tremor

• Rigidity

• Bradykinesia

• Gait

• Mental status

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; Tomiyama et al 2006; Ishihara et al, in press].

Other medications include anti-cholinergics, selegiline, and amantadine [Lang & Lozano 1998, 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].

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.

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].

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

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 an 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.R1441; the frequency of these events is unknown [Kachergus et al 2005; Mata, Kachergus et al 2005].

• 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: Although individuals diagnosed with LRRK2-related PD have 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 upon 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 sibling 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 upon the status of the proband's parents. If a parent is found to be affected, 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 undisclosed adoption could also be explored.

Testing of at-risk asymptomatic adults.  Testing of at-risk asymptomatic adults for LRRK2-related PD is available using the same techniques described in Molecular Genetic Testing. Results of such testing indicate whether symptoms will occur but 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 during childhood.  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 testing asymptomatic individuals during childhood are that it removes their 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 [Bloch & Hayden 1990, Harper & Clarke 1990].

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 resolution on genetic testing of children 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.)

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. See DNA Banking for a list of laboratories offering this service.

Prenatal Testing

Prenatal diagnosis for pregnancies at increased risk for the p.G2019S mutation is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at about 15-18 weeks' gestation or chorionic villus sampling (CVS) at about ten to 12 weeks' gestation. The presence of the p.G2019S 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.

No laboratories offering molecular genetic testing for prenatal diagnosis for other LRRK2 mutations are listed in the GeneTests Laboratory Directory. However, prenatal testing may be available for families in which the disease-causing mutation has been identified in an affected family member. For laboratories offering custom prenatal testing, see .

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, careful discussion of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutation has been identified in an affected family member. For laboratories offering PGD, see .

Note: It is the policy of GeneReviews to include information on prenatal testing and preimplantation genetic diagnosis available from laboratories listed in the GeneTests Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Literature Cited

Published Statements and Policies Regarding Genetic Testing

No specific guidelines regarding genetic testing for this disorder have been developed.

Author Notes

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 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, NIEHS and NIA), the Michael J Fox Foundation and the Mayo Foundation.

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

• 2 November 2006 (me) Review posted to live Web site

• 6 July 2006 (mf) Original submission