Penetrance of the fragile X-associated tremor/ataxia syndrome in a premutation carrier population.
BACKGROUND
Premutation expansions (55-200 CGG repeats) of the fragile X mental retardation 1 (FMR1) gene are frequent in the general population, with estimated prevalences of 1 per 259 females and 1 per 813 males. Several articles have recently described the presence of late-onset neurological symptoms in male carriers of premutation (FMR1) alleles. The main clinical features described in this newly identified syndrome are cerebellar ataxia and intention tremor. Additional documented symptoms include short-term memory loss, executive functional deficits, cognitive decline, parkinsonism, peripheral neuropathy, lower-limb proximal muscle weakness, and autonomic dysfunction.


OBJECTIVE
To study the penetrance of the fragile X-associated tremor/ataxia syndrome (FXTAS) among premutation carriers.


METHODS
Family-based study of 192 individuals (premutation carriers and controls) whose families belong to the Northern or Southern California Fragile X Associations. Data were collected (March 2002-April 2003) through a survey and a standardized neurological examination, which was videotaped and subsequently scored in a blinded fashion.


METHODS
Penetrance of intention tremor and ataxia among adult carriers (aged > or =50 years) of premutation expansions of the FMR1 gene.


RESULTS
Data from the survey of 192 individuals demonstrated an age-related penetrance of the combination of reported intention tremor and gait ataxia in male carriers (17%, 38%, 47%, and 75% [lower-bound estimates] for participants aged 50-59, 60-69, 70-79, and > or =80 years, respectively). The male carrier group had an age-adjusted 13-fold increased risk (95% confidence interval, 3.9-25.4; P =.003) of combined intention tremor and gait ataxia when compared with male controls. The clinical examination data from 93 individuals demonstrated that male carriers experienced more difficulties on each of 3 standardized neurological rating scales compared with controls (P<.05). Female carrier scores were also higher than those of female controls (P<.05) on 2 of the 3 neurological rating scales, but no participant was identified with probable or definite FXTAS.


CONCLUSIONS
The study demonstrates that older male carriers of premutation alleles of the FMR1 gene are at high risk of developing FXTAS. Since male premutation carriers are relatively common in the general population, older men with ataxia and intention tremor should be screened for the FMR1 mutation, especially if these signs are accompanied by parkinsonism, autonomic dysfunction, or cognitive decline, regardless of family history.
Jacquemont
Sébastien
S
MIND Institute, University of California Davis Medical Center, Sacramento, USA.
Hagerman
Randi J
RJ
Leehey
Maureen A
MA
Hall
Deborah A
DA
Levine
Richard A
RA
Brunberg
James A
JA
Zhang
Lin
L
Jardini
Tristan
T
Gane
Louise W
LW
Harris
Susan W
SW
Herman
Kristin
K
Grigsby
James
J
Greco
Claudia M
CM
Berry-Kravis
Elizabeth
E
Tassone
Flora
F
Hagerman
Paul J
PJ
D000368:Aged; D000369:Aged, 80 and over; D001259:Ataxia / Q000235:genetics*; D002140:California; D042622:DNA Repeat Expansion; D005260:Female; D051860:Fragile X Messenger Ribonucleoprotein 1; D005600:Fragile X Syndrome / Q000235:genetics*; D005684:Gait; D005838:Genotype; D006579:Heterozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009460:Neurologic Examination; D010375:Pedigree; D016601:RNA-Binding Proteins; D014202:Tremor / Q000235:genetics*
D051860:Fragile X Messenger Ribonucleoprotein 1; D009419:Nerve Tissue Proteins; D016601:RNA-Binding Proteins; C497683:FMR1 protein, human