07 February 2012
Anheim M, Elbaz A, Lesage S, Durr A, Condroyer
C, Viallet F, Pollak P, Bonaïti B, Bonaïti-Pellié C, Brice A; On behalf of the
French Parkinson Disease Genetic Group
OBJECTIVE: Glucocerebrosidase (GBA) gene mutations represent
a strong risk factor for Parkinson disease (PD). PD penetrance in GBA
mutation carriers, which represents a key issue for genetic counseling,
especially for relatives of patients with Gaucher disease (GD), is
unknown. Our objective was to estimate PD penetrance in a familial study
of GBA mutation carriers.
METHODS: Probands with
familial PD were recruited through the French Parkinson Disease Genetic
Study Group. All GBA exons were sequenced in probands and their
relatives. To estimate the age-specific cumulative PD risk (i.e.,
penetrance) in GBA mutation carriers, we used the proband's phenotype
exclusion likelihood method and corrected for selection of familial
cases by considering the status of one affected relative per family as
unknown.
RESULTS: Of 525 probands with familial PD, 24
(4.6%) were GBA mutation carriers. Of their 256 relatives, 43 (16.8%)
had PD and 26 of 32 affected relatives tested for GBA mutations were
mutation carriers; 213 relatives did not have PD and 31 of 71 of
unaffected relatives tested for GBA mutations were mutation carriers.
Under a dominant model, penetrance was estimated as 7.6%, 13.7%, 21.4%,
and 29.7% at 50, 60, 70, and 80 years, respectively. There was no
significant difference in penetrance at 70 years between N370S carriers,
L444P carriers, and carriers of rarer mutations.
CONCLUSION: The
relatively high penetrance estimate in GBA carriers obtained in this
study should lead to consideration of GBA as a dominant causal gene with
reduced penetrance and should be taken into account for genetic
counseling in relatives of patients with GD and patients with
GBA-associated PD.
