Volumetric brain changes in females with fragile X-associated tremor/ataxia syndrome (FXTAS).
BACKGROUND
Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder occurring in male and rare female carriers of a premutation expansion (55 to 200 CGG repeats) of the fragile X mental retardation 1 (FMR1) gene.


METHODS
Volumetric MRI studies, clinical staging, cognitive testing, and molecular analysis were conducted in 15 female premutation carriers affected by FXTAS (age 59.5 +/- 10.3 years), 20 unaffected female carriers (43.3 +/- 11.2 years), 11 genetically normal female controls (51.0 +/- 10.3 years), 36 affected male carriers (65.0 +/- 5.6 years), 25 unaffected male carriers (53.5 +/- 12.5 years), and 39 male controls (58.0 +/- 15.0 years). Female and male carriers with FXTAS were matched on duration of disease.


RESULTS
We found less pronounced reductions of cerebellar volume and a lower incidence of involvement (symmetric high T2 signal) of the middle cerebellar peduncles (MCP sign) in females affected by FXTAS (13%) compared with affected males (58%). We found reduced brain volumes and increased white matter disease associated with the presence of FXTAS in females compared with female controls. We also observed significant associations between reduced cerebellar volume and both increased severity of FXTAS symptoms and increased length of the CGG repeat expansion in male premutation carriers, but not in females.


CONCLUSIONS
Females affected by fragile X-associated tremor/ataxia syndrome (FXTAS) demonstrated milder brain changes than affected males, although they showed a similar pattern of radiologic findings consistent with brain atrophy and white matter disease. FXTAS should be considered (by ordering fragile X DNA testing) in females who present with late-onset ataxia, action tremor, or neuropathy, particularly in those with a family history of mental retardation, autism, or premature ovarian failure.
Adams
J S
JS
M.I.N.D. Institute, University of California, Davis, CA, USA.
Adams
P E
PE
Nguyen
D
D
Brunberg
J A
JA
Tassone
F
F
Zhang
W
W
Koldewyn
K
K
Rivera
S M
SM
Grigsby
J
J
Zhang
L
L
DeCarli
C
C
Hagerman
P J
PJ
Hagerman
R J
RJ
D000328:Adult; D000368:Aged; D001259:Ataxia / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology; D001284:Atrophy / Q000235:genetics / Q000473:pathology*; D002526:Cerebellar Diseases / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology; D004252:DNA Mutational Analysis; D005260:Female; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics; D005600:Fragile X Syndrome / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005820:Genetic Testing; D005838:Genotype; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009413:Nerve Fibers, Myelinated / Q000473:pathology; D012727:Sex Characteristics; D014202:Tremor / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology; D019680:Trinucleotide Repeat Expansion / Q000235:genetics
D051860:Fragile X Messenger Ribonucleoprotein 1; C497683:FMR1 protein, human