Penetrance of the Fragile X-Associated Tremor/Ataxia Syndrome in a Premutation Carrier Population

Sébastien Jacquemont, Randi J Hagerman, Maureen A. Leehey, Deborah A. Hall, Richard A. Levine, James A Brunberg, Lin Zhang, Tristan Jardini, Louise W. Gane, Susan W. Harris, Kristin Herman, James Grigsby, Claudia M. Greco, Elizabeth Berry-Kravis, Flora Tassone, Paul J Hagerman

Research output: Contribution to journalArticle

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Abstract

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 family history.

Original languageEnglish (US)
Pages (from-to)460-469
Number of pages10
JournalJournal of the American Medical Association
Volume291
Issue number4
DOIs
StatePublished - Jan 28 2004

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Penetrance
Tremor
Intellectual Disability
Population
Gait Ataxia
Parkinsonian Disorders
Ataxia
Alleles
Genes
Cerebellar Ataxia
Fragile X Tremor Ataxia Syndrome
Muscle Weakness
Memory Disorders
Neurologic Examination
Peripheral Nervous System Diseases
Short-Term Memory
Lower Extremity
Age Groups
Outcome Assessment (Health Care)
Confidence Intervals

ASJC Scopus subject areas

  • Medicine(all)

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Penetrance of the Fragile X-Associated Tremor/Ataxia Syndrome in a Premutation Carrier Population. / Jacquemont, Sébastien; Hagerman, Randi J; Leehey, Maureen A.; Hall, Deborah A.; Levine, Richard A.; Brunberg, James A; Zhang, Lin; Jardini, Tristan; Gane, Louise W.; Harris, Susan W.; Herman, Kristin; Grigsby, James; Greco, Claudia M.; Berry-Kravis, Elizabeth; Tassone, Flora; Hagerman, Paul J.

In: Journal of the American Medical Association, Vol. 291, No. 4, 28.01.2004, p. 460-469.

Research output: Contribution to journalArticle

Jacquemont, S, Hagerman, RJ, Leehey, MA, Hall, DA, Levine, RA, Brunberg, JA, Zhang, L, Jardini, T, Gane, LW, Harris, SW, Herman, K, Grigsby, J, Greco, CM, Berry-Kravis, E, Tassone, F & Hagerman, PJ 2004, 'Penetrance of the Fragile X-Associated Tremor/Ataxia Syndrome in a Premutation Carrier Population', Journal of the American Medical Association, vol. 291, no. 4, pp. 460-469. https://doi.org/10.1001/jama.291.4.460
Jacquemont, Sébastien ; Hagerman, Randi J ; Leehey, Maureen A. ; Hall, Deborah A. ; Levine, Richard A. ; Brunberg, James A ; Zhang, Lin ; Jardini, Tristan ; Gane, Louise W. ; Harris, Susan W. ; Herman, Kristin ; Grigsby, James ; Greco, Claudia M. ; Berry-Kravis, Elizabeth ; Tassone, Flora ; Hagerman, Paul J. / Penetrance of the Fragile X-Associated Tremor/Ataxia Syndrome in a Premutation Carrier Population. In: Journal of the American Medical Association. 2004 ; Vol. 291, No. 4. pp. 460-469.
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abstract = "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 family history.",
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T1 - Penetrance of the Fragile X-Associated Tremor/Ataxia Syndrome in a Premutation Carrier Population

AU - Jacquemont, Sébastien

AU - Hagerman, Randi J

AU - Leehey, Maureen A.

AU - Hall, Deborah A.

AU - Levine, Richard A.

AU - Brunberg, James A

AU - Zhang, Lin

AU - Jardini, Tristan

AU - Gane, Louise W.

AU - Harris, Susan W.

AU - Herman, Kristin

AU - Grigsby, James

AU - Greco, Claudia M.

AU - Berry-Kravis, Elizabeth

AU - Tassone, Flora

AU - Hagerman, Paul J

PY - 2004/1/28

Y1 - 2004/1/28

N2 - 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 family history.

AB - 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 family history.

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