Clinical heterogeneity of the LRRK2 G2019S mutation.
BACKGROUND
Several pathogenic mutations have been reported in the leucine-rich repeat kinase 2 gene (LRRK2) that cause parkinsonism. The "common" LRRK2 G2019S kinase domain substitution has been reported to account for approximately 5% of familial and 1% of sporadic Parkinson disease.


OBJECTIVE
To observe the clinical heterogeneity presented by LRRK2 kinase mutation carriers.


METHODS
We screened 130 patients with pathologically confirmed Parkinson disease and 85 controls for 3 LRRK2 kinase domain pathogenic substitutions: I2012T, G2019S, and I2020T.


METHODS
Detailed clinical phenotypes for individuals who screened positive for LRRK2 mutations.


RESULTS
Five LRRK2 G2019S carriers were identified, of whom 4 had Parkinson disease (clinically and pathologically confirmed), and the fifth was a control subject who died at age 68 years after an acute myocardial infarction with no evidence of neurodegenerative abnormalities. There was no evidence of the I2012T or I2020T mutation in these participants.


CONCLUSIONS
The underlying disease mechanisms of LRRK2 G2019S-associated parkinsonism are similar to those of typical Parkinson disease. The identification of a control subject raises important questions concerning genetic diagnosis and counseling.
Papapetropoulos
Spiridon
S
Department of Neurology, University of Miami School of Medicine, Miami, FL, USA.
Singer
Carlos
C
Ross
Owen A
OA
Toft
Mathias
M
Johnson
Joseph L
JL
Farrer
Matthew J
MJ
Mash
Deborah C
DC
D000368:Aged; D000369:Aged, 80 and over; D016022:Case-Control Studies; D004252:DNA Mutational Analysis / Q000379:methods; D005260:Female; D005998:Glycine / Q000235:genetics*; D006801:Humans; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D008297:Male; D008958:Models, Molecular; D009154:Mutation; D010300:Parkinson Disease / Q000235:genetics*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D012694:Serine / Q000235:genetics*
D012694:Serine; C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases; D005998:Glycine