Bilateral subthalamic stimulation in Parkin and PINK1 parkinsonism.
OBJECTIVE
To study the frequency of different gene mutations in patients with early-onset parkinsonism and bilateral subthalamic nucleus deep brain stimulation (STN-DBS) and the short- and long-term surgical outcome in mutation-positive (MUT+) and -negative (MUT-) patients.


METHODS
Eighty patients with disease onset at age <or= 45 years and bilateral STN-DBS were screened for mutations in the Parkin gene and PINK1 gene and for the recurrent p.G2019S mutation in the LRRK2 gene. The Unified Parkinson's Disease Rating Scale (UPDRS) and Hoehn and Yahr (H-Y) scale were used to compare the on- and off-medication conditions preoperatively and in the off-medication/on-stimulation condition postoperatively.


RESULTS
We identified 12 mutation carriers (11 Parkin [6 with 2 mutated alleles, 5 with 1 mutated allele], 1 homozygous PINK1). There were no clinical differences between the MUT- and MUT+ patients preoperatively, except for more severe H-Y stage and postural and gait scores in the on-medication state in the MUT+ group. During the first year after surgery, MUT- patients showed better clinical improvement (56% motor UPDRS improvement) compared with MUT+ patients (36%). However, in the long-term follow-up (3-6 years), both groups presented with the same degree of clinical improvement (MUT-: 44% vs MUT+: 42%). Although the MUT+ group showed more severe axial signs preoperatively, MUT- patients developed levodopa- and deep brain stimulation-resistant axial signs within the first 3 to 6 years postoperatively, which diminished the initial benefit soon after surgery.


CONCLUSIONS
Patients with Parkin or PINK1 mutations benefit from subthalamic nucleus deep brain stimulation. However, the clinical response is not superior to non-mutation carriers and might be limited by more advanced axial motor symptoms at a relatively early disease stage.
Moro
E
E
Movement Disorder Centre, Toronto Western Hospital, University of Toronto, Ontario, Canada.
Volkmann
J
J
König
I R
IR
Winkler
S
S
Hiller
A
A
Hassin-Baer
S
S
Herzog
J
J
Schnitzler
A
A
Lohmann
K
K
Pinsker
M O
MO
Voges
J
J
Djarmatic
A
A
Seibler
P
P
Lozano
A M
AM
Rogaeva
E
E
Lang
A E
AE
Deuschl
G
G
Klein
C
C
D000328:Adult; D000368:Aged; D004252:DNA Mutational Analysis; D004599:Electric Stimulation Therapy / Q000379:methods / Q000706:statistics & numerical data*; D005260:Female; D005500:Follow-Up Studies; D007839:Functional Laterality / Q000235:genetics; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005820:Genetic Testing; D005838:Genotype; D006579:Heterozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D010300:Parkinson Disease / Q000235:genetics* / Q000503:physiopathology / Q000628:therapy*; D011446:Prospective Studies; D011494:Protein Kinases / Q000235:genetics*; D020127:Recovery of Function / Q000235:genetics; D020531:Subthalamic Nucleus / Q000503:physiopathology / Q000601:surgery*; D016896:Treatment Outcome; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*; D000099202:PTEN-Induced Putative Kinase
D011494:Protein Kinases; D044767:Ubiquitin-Protein Ligases; D000099202:PTEN-Induced Putative Kinase; C111567:parkin protein