Genotype-Phenotype Associations in LRRK2 Parkinson's Disease
February 1, 2006 4 minutes read
Genotype-Phenotype Associations in LRRK2 Parkinson's Disease
Abstracts & Commentary
By Claire Henchcliffe, MD, DPhil, Assistant Professor, Department of Neurology, Weill Medical College, Cornell University. Dr. Henchcliffe is on the speaker's bureau for GlaxoSmithKline, Tivo/Eisai, and Boehringer Ingelheim.
Synopsis: The advances in understanding the genotype-phenotype associations for LRRK2 presented by these articles represent an important step towards this objective.
Sources: Khan NL, et al. Mutations in the Gene LRRK2 Encoding Dardarin (PARK8) Cause Familial Parkinson's Disease: Clinical, Pathological, Olfactory and Functional Imaging and Genetic Data. Brain. 2005;128:2786-2796; Berg D, et al. Type and Frequency of Mutations in the LRRK2 Gene in Familial and Sporadic Parkinson's Disease. Brain. 2005; Epub ahead of print.
Leucine-Rich Repeat Kinase 2 (LRRK2) gene mutations can lead to autosomal dominant Parkinson's disease (PD). These 2 papers present clinical and genetic data on the largest series of LRRK2 kindreds compiled to date. Khan and colleagues describe members of the large original LRRK2 "Lincolnshire kindred". In 117 unrelated individuals from smaller UK autosomal dominant PD kindreds, they determined a LRRK2 mutation frequency of 5.1%, with the G2019S mutation most common (2.5%). They additionally established 2 novel LRRK2 mutations. The typical phenotype was late-onset PD, often beginning in one leg, and 18F-dopa positron emission tomography (PET) scans in a subset of subjects were typical of idiopathic PD. Subjects had a good levodopa response, and dyskinesias were not prominent: one individual maintained a good levodopa response for 25 years, without dyskinesias. Cognition was well preserved as judged by the modified mini-mental status examination. However, 7/20 LRRK2 individuals identified, reported prominent non-motor features (beginning after PD onset in 6), including anxiety attacks, depression, paranoia, and one suicide attempt. Hallucinations were rare. A brain autopsy revealed marked loss of pigmented neurons and gliosis in the substantia nigra, and small numbers of cortical and brainstem Lewy bodies.
Berg and colleagues examined LRRK2 in 53 kindreds with autosomal dominant PD, mostly of Southern or Middle German provenance. They detected a higher frequency of LRRK2 mutations, with 7/53 (13%) affected, and found 4 novel mutations, but not G2019S. Sleep disturbance was common, and detailed neuropsychological testing revealed impaired executive function in many. Both studies revealed incomplete penetrance, in common with prior reports, and significant inter- and intra-familial phenotypic variability (for example, one LRRK2 individual had clinical features of dementia with Lewy bodies). Of note, certain family members of LRRK2 PD individuals were identified with clinical PD, in the absence of the gene mutation.
Commentary
Genetic studies have played a crucial role in rapidly advancing understanding of cellular processes in PD. LRRK2 encodes a protein with multiple domains, including a mitogen-activated kinase kinase kinase (MAPKKK), and mutant LRRK2 expression was recently shown to lead to neuronal demise in vitro.1 However, genetic PD has been considered rare and of little direct relevance to office practice. Commercial genetic testing in PD is currently available for parkin, PINK1, and alpha-synuclein, but seldom used in clinical practice. Now, with increasing recognition of young-onset and familial PD, more patients are asking whether they and their family members should be tested. The answer is not simple, and these 2 papers clearly demonstrate some of the complexities of interpreting PD genetics.
While both provide fascinating descriptions of the phenomenology of LRRK2 familial PD, underlining the similarity to typical idiopathic PD, they raise a number of disquieting issues regarding utility of genetic testing at the present time. First, Khan, Berg, and colleagues report phenocopies, that is, symptomatic members of LRRK2 kindreds who do not have the mutation. Therefore, a LRRK2 mutation cannot be assumed in an untested PD individual of a LRRK2 kindred. Second, LRRK2 mutations were found to have incomplete penetrance in common with previous reports. Therefore, even obligate carriers will not necessarily develop PD. Incomplete penetrance presumably involves variability of other susceptibility factors. It is, therefore, fascinating that in this same journal issue, Adams and colleagues used PET scans detecting 18F-dopa uptake (vesicular monoamine and dopamine transporters VMAT and DAT) to look at LRRK2 carriers.2 Two asymptomatic LRRK2 individuals, with normal 18F-dopa uptake, had altered expression of VMAT and DAT. Although preliminary, they suggest that such changes in the striatum could be compensatory, and modify expression of PD symptoms. Clearly, we have far to go in developing clinical genetic testing, such that appropriate counseling may be given regarding practical, emotional, and ethical concerns. However, the advances in understanding the genotype-phenotype associations for LRRK2 presented by the above articles represent an important step towards this objective.
References
1. Smith WW, et al. Leucine-Rich Repeat Kinase 2 (LRRK2) Interacts with Parkin, and Mutant LRRK2 Induces Neuronal Degeneration. Proc Nat Acad Sci. 2005;102:18676-18681.
2. Adams JR, et al. PET in LRRK2 Mutations: Comparison to Sporadic Parkinson's Disease and Evidence for Presymptomatic Compensation. Brain. 2005;128:2777-2785.
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