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Jacquemont S, Hagerman RJ, Leehey MA, et al. Penetrance of the Fragile X–Associated Tremor/Ataxia Syndrome in a Premutation Carrier Population. JAMA. 2004;291(4):460–469. doi:10.1001/jama.291.4.460
Author Affiliations: MIND Institute (Drs Jacquemont, R. Hagerman, and Herman, Mr Jardini, and Mss Gane and Harris) and Departments of Pediatrics (Dr R. Hagerman) and Neurology (Dr Zhang), University of California Davis Medical Center, Sacramento; Departments of Neurology (Drs Leehey and Hall) and Medicine (Dr Grigsby), University of Colorado Health Sciences Center, Denver; Department of Mathematics and Statistics, San Diego State University (Dr Levine), San Diego, Calif; Departments of Radiology (Dr Brunberg), Pathology (Dr Greco), and Biological Chemistry (Drs Tassone and P. Hagerman), University of California, Davis, School of Medicine, Davis; and Department of Pediatrics, Rush-Presbyterian-St Luke's Medical Center, Chicago, Ill (Dr Berry-Kravis).
Context 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.
Design, Setting, and Participants 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.
Main Outcome Measures Penetrance of intention tremor and ataxia among adult carriers (aged
≥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 ≥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
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