Effect of simvastatin on cognitive functioning in children with neurofibromatosis type 1: a randomized controlled trial.
BACKGROUND
Neurofibromatosis type 1 (NF1) is among the most common genetic disorders that cause learning disabilities. Recently, it was shown that statin-mediated inhibition of 3-hydroxy-3-methylglutaryl coenzyme A reductase restores the cognitive deficits in an NF1 mouse model.


OBJECTIVE
To determine the effect of simvastatin on neuropsychological, neurophysiological, and neuroradiological outcome measures in children with NF1.


METHODS
Sixty-two of 114 eligible children (54%) with NF1 participated in a randomized, double-blind, placebo-controlled trial conducted between January 20, 2006, and February 8, 2007, at an NF1 referral center at a Dutch university hospital.


METHODS
Simvastatin or placebo treatment once daily for 12 weeks.


METHODS
Primary outcomes were scores on a Rey complex figure test (delayed recall), cancellation test (speed), prism adaptation, and the mean brain apparent diffusion coefficient based on magnetic resonance imaging. Secondary outcome measures were scores on the cancellation test (standard deviation), Stroop color word test, block design, object assembly, Rey complex figure test (copy), Beery developmental test of visual-motor integration, and judgment of line orientation. Scores were corrected for baseline performance, age, and sex.


RESULTS
No significant differences were observed between the simvastatin and placebo groups on any primary outcome measure: Rey complex figure test (beta = 0.10; 95% confidence interval [CI], -0.36 to 0.56); cancellation test (beta = -0.19; 95% CI, -0.67 to 0.29); prism adaptation (odds ratio = 2.0; 95% CI, 0.55 to 7.37); and mean brain apparent diffusion coefficient (beta = 0.06; 95% CI, -0.07 to 0.20). In the secondary outcome measures, we found a significant improvement in the simvastatin group in object assembly scores (beta = 0.54; 95% CI, 0.08 to 1.01), which was specifically observed in children with poor baseline performance (beta = 0.80; 95% CI, 0.29 to 1.30). Other secondary outcome measures revealed no significant effect of simvastatin treatment.


CONCLUSIONS
In this 12-week trial, simvastatin did not improve cognitive function in children with NF1. Trial Registration isrctn.org Identifier: ISRCTN14965707.
Krab
Lianne C
LC
Department of General Pediatrics, Erasmus MC University Medical Center, Sophia Children's Hospital, Rotterdam, The Netherlands.
de Goede-Bolder
Arja
A
Aarsen
Femke K
FK
Pluijm
Saskia M F
SM
Bouman
Marlies J
MJ
van der Geest
Jos N
JN
Lequin
Maarten
M
Catsman
Coriene E
CE
Arts
Willem Frans M
WF
Kushner
Steven A
SA
Silva
Alcino J
AJ
de Zeeuw
Chris I
CI
Moll
Henriëtte A
HA
Elgersma
Ype
Y
D000293:Adolescent; D002648:Child; D002784:Cholesterol / Q000097:blood; D003071:Cognition / Q000187:drug effects*; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D008279:Magnetic Resonance Imaging; D008297:Male; D009456:Neurofibromatosis 1 / Q000188:drug therapy* / Q000523:psychology; D009483:Neuropsychological Tests; D019821:Simvastatin / Q000009:adverse effects / Q000627:therapeutic use*
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D002784:Cholesterol; D019821:Simvastatin