Molecular and imaging correlates of the fragile X-associated tremor/ataxia syndrome.
OBJECTIVE
To assess changes in regional brain volumes associated with the fragile X-associated tremor/ataxia syndrome (FXTAS) and the molecular correlates of these changes.


METHODS
We administered molecular, MRI, and neurocognitive tests to 36 male premutation carriers (ages 51 to 79), 25 affected and 11 unaffected with FXTAS, and to 21 control subjects of similar age and education.


RESULTS
We found differences among the three groups in whole brain, cerebrum, cerebellum, ventricular volume, and whole-brain white matter hyperintensity, with the affected group showing significantly more pathology than the control and unaffected groups. Brainstem volume was significantly smaller in the unaffected group vs controls but did not differ from the affected group. Within the premutation sample, CGG repeat length correlated with reductions in IQ and cerebellar volume and increased ventricular volume and whole-brain white matter hyperintensity.


CONCLUSIONS
The current findings, coupled with recent evidence linking the degree of neuropathology (numbers of intranuclear inclusions) to the size of the premutation allele, provide evidence that the neurodegenerative phenotype in the fragile X-associated tremor/ataxia syndrome is a consequence of the CGG repeat expansion.
Cohen
S
S
Department of Human Development, University of California-Davis Medical Center, 2825 50 St., Sacramento, CA 95817, USA.
Masyn
K
K
Adams
J
J
Hessl
D
D
Rivera
S
S
Tassone
F
F
Brunberg
J
J
DeCarli
C
C
Zhang
L
L
Cogswell
J
J
Loesch
D
D
Leehey
M
M
Grigsby
J
J
Hagerman
P J
PJ
Hagerman
R
R
D000368:Aged; D000483:Alleles; D001259:Ataxia / Q000175:diagnosis* / Q000235:genetics*; D001921:Brain / Q000473:pathology; D002531:Cerebellum / Q000473:pathology; D002552:Cerebral Ventricles / Q000473:pathology; D003071:Cognition; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics / Q000378:metabolism; D005600:Fragile X Syndrome / Q000150:complications* / Q000175:diagnosis*; D006579:Heterozygote; D006801:Humans; D007360:Intelligence; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009483:Neuropsychological Tests; D010641:Phenotype; D012333:RNA, Messenger / Q000378:metabolism; D013577:Syndrome; D014202:Tremor / Q000175:diagnosis* / Q000235:genetics*; D018911:Trinucleotide Repeats
D051860:Fragile X Messenger Ribonucleoprotein 1; D012333:RNA, Messenger; C497683:FMR1 protein, human