Neuroanatomy of fragile X syndrome is associated with aberrant behavior and the fragile X mental retardation protein (FMRP).
OBJECTIVE
To determine how neuroanatomic variation in children and adolescents with fragile X syndrome is linked to reduced levels of the fragile X mental retardation-1 protein and to aberrant cognition and behavior.


METHODS
This study included 84 children and adolescents with the fragile X full mutation and 72 typically developing control subjects matched for age and sex. Brain morphology was assessed with volumetric, voxel-based, and surface-based modeling approaches. Intelligence quotient was evaluated with standard cognitive testing, whereas abnormal behaviors were measured with the Autism Behavior Checklist and the Aberrant Behavior Checklist.


RESULTS
Significantly increased size of the caudate nucleus and decreased size of the posterior cerebellar vermis, amygdala, and superior temporal gyrus were present in the fragile X group. Subjects with fragile X also demonstrated an abnormal profile of cortical lobe volumes. A receiver operating characteristic analysis identified the combination of a large caudate with small posterior cerebellar vermis, amygdala, and superior temporal gyrus as distinguishing children with fragile X from control subjects with a high level of sensitivity and specificity. Large caudate and small posterior cerebellar vermis were associated with lower fragile X mental retardation protein levels and more pronounced cognitive deficits and aberrant behaviors.


CONCLUSIONS
Abnormal development of specific brain regions characterizes a neuroanatomic phenotype associated with fragile X syndrome and may mediate the effects of FMR1 gene mutations on the cognitive and behavioral features of the disorder. Fragile X syndrome provides a model for elucidating critical linkages among gene, brain, and cognition in children with serious neurodevelopmental disorders.
Gothelf
Doron
D
Behavioral Neurogenetics Center, Child Psychiatry Department, Schneider Children's Medical Center of Israel, Petah Tiqwa.
Furfaro
Joyce A
JA
Hoeft
Fumiko
F
Eckert
Mark A
MA
Hall
Scott S
SS
O'Hara
Ruth
R
Erba
Heather W
HW
Ringel
Jessica
J
Hayashi
Kiralee M
KM
Patnaik
Swetapadma
S
Golianu
Brenda
B
Kraemer
Helena C
HC
Thompson
Paul M
PM
Piven
Joseph
J
Reiss
Allan L
AL
D000293:Adolescent; D000328:Adult; D001284:Atrophy / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D001921:Brain / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D002421:Caudate Nucleus / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D002648:Child; D002653:Child Behavior Disorders / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology; D002675:Child, Preschool; D003072:Cognition Disorders / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D004252:DNA Mutational Analysis; D005260:Female; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics*; D005600:Fragile X Syndrome / Q000175:diagnosis* / Q000235:genetics / Q000503:physiopathology; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005820:Genetic Testing; D005838:Genotype; D006801:Humans; D006984:Hypertrophy / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D007223:Infant; D008279:Magnetic Resonance Imaging; D008297:Male; D009154:Mutation / Q000235:genetics*; D009483:Neuropsychological Tests; D012737:Sex Factors
D051860:Fragile X Messenger Ribonucleoprotein 1; C497683:FMR1 protein, human