FMR1 CGG repeat length predicts motor dysfunction in premutation carriers

M. A. Leehey, E. Berry-Kravis, C. G. Goetz, Lin Zhang, D. A. Hall, L. Li, C. D. Rice, R. Lara, J. Cogswell, A. Reynolds, L. Gane, S. Jacquemont, Flora Tassone, J. Grigsby, Randi J Hagerman, Paul J Hagerman

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Abstract

BACKGROUND: Fragile X-associated tremor/ataxia syndrome (FXTAS) is a recently described, underrecognized neurodegenerative disorder of aging fragile X mental retardation 1 (FMR1) premutation carriers, particularly men. Core motor features are action tremor, gait ataxia, and parkinsonism. Carriers have expanded CGG repeats (55 to 200); larger expansions cause fragile X syndrome, the most common heritable cause of mental retardation and autism. This study determines whether CGG repeat length correlates with severity and type of motor dysfunction in premutation carriers. METHODS: Persons aged ≥50 years with a family history of fragile X syndrome underwent structured videotaping. Movement disorder neurologists, blinded to carrier status, scored the tapes using modified standardized rating scales. CGG repeat length analyses for women incorporated the activation ratio, which measures the percentage of normal active chromosome X alleles. RESULTS: Male carriers (n = 54) had significantly worse total motor scores, especially in tremor and ataxia, than age-matched male noncarriers (n = 51). There was a trend toward a difference between women carriers (n = 82) and noncarriers (n = 39). In men, increasing CGG repeat correlated with greater impairment in all motor signs. In women, when activation ratio was considered, increasing CGG correlated with greater ataxia. CONCLUSIONS: CGG repeat size is significantly associated with overall motor impairment in premutation carriers. Whereas this association is most pronounced for men and covers overall motor impairment-tremor, ataxia, and parkinsonism-the association exists for ataxia among women carriers. This is the first report of a significant correlation between the premutation status and a motor feature of fragile X-associated tremor/ataxia syndrome in women.

Original languageEnglish (US)
Pages (from-to)1397-1402
Number of pages6
JournalNeurology
Volume70
Issue number16 PART 2
DOIs
StatePublished - Apr 2008

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Intellectual Disability
Ataxia
Tremor
Fragile X Syndrome
Parkinsonian Disorders
Gait Ataxia
Movement Disorders
X Chromosome
Autistic Disorder
Neurodegenerative Diseases
Alleles
Fragile X Tremor Ataxia Syndrome

ASJC Scopus subject areas

  • Neuroscience(all)

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FMR1 CGG repeat length predicts motor dysfunction in premutation carriers. / Leehey, M. A.; Berry-Kravis, E.; Goetz, C. G.; Zhang, Lin; Hall, D. A.; Li, L.; Rice, C. D.; Lara, R.; Cogswell, J.; Reynolds, A.; Gane, L.; Jacquemont, S.; Tassone, Flora; Grigsby, J.; Hagerman, Randi J; Hagerman, Paul J.

In: Neurology, Vol. 70, No. 16 PART 2, 04.2008, p. 1397-1402.

Research output: Contribution to journalArticle

Leehey, MA, Berry-Kravis, E, Goetz, CG, Zhang, L, Hall, DA, Li, L, Rice, CD, Lara, R, Cogswell, J, Reynolds, A, Gane, L, Jacquemont, S, Tassone, F, Grigsby, J, Hagerman, RJ & Hagerman, PJ 2008, 'FMR1 CGG repeat length predicts motor dysfunction in premutation carriers', Neurology, vol. 70, no. 16 PART 2, pp. 1397-1402. https://doi.org/10.1212/01.wnl.0000281692.98200.f5
Leehey MA, Berry-Kravis E, Goetz CG, Zhang L, Hall DA, Li L et al. FMR1 CGG repeat length predicts motor dysfunction in premutation carriers. Neurology. 2008 Apr;70(16 PART 2):1397-1402. https://doi.org/10.1212/01.wnl.0000281692.98200.f5
Leehey, M. A. ; Berry-Kravis, E. ; Goetz, C. G. ; Zhang, Lin ; Hall, D. A. ; Li, L. ; Rice, C. D. ; Lara, R. ; Cogswell, J. ; Reynolds, A. ; Gane, L. ; Jacquemont, S. ; Tassone, Flora ; Grigsby, J. ; Hagerman, Randi J ; Hagerman, Paul J. / FMR1 CGG repeat length predicts motor dysfunction in premutation carriers. In: Neurology. 2008 ; Vol. 70, No. 16 PART 2. pp. 1397-1402.
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abstract = "BACKGROUND: Fragile X-associated tremor/ataxia syndrome (FXTAS) is a recently described, underrecognized neurodegenerative disorder of aging fragile X mental retardation 1 (FMR1) premutation carriers, particularly men. Core motor features are action tremor, gait ataxia, and parkinsonism. Carriers have expanded CGG repeats (55 to 200); larger expansions cause fragile X syndrome, the most common heritable cause of mental retardation and autism. This study determines whether CGG repeat length correlates with severity and type of motor dysfunction in premutation carriers. METHODS: Persons aged ≥50 years with a family history of fragile X syndrome underwent structured videotaping. Movement disorder neurologists, blinded to carrier status, scored the tapes using modified standardized rating scales. CGG repeat length analyses for women incorporated the activation ratio, which measures the percentage of normal active chromosome X alleles. RESULTS: Male carriers (n = 54) had significantly worse total motor scores, especially in tremor and ataxia, than age-matched male noncarriers (n = 51). There was a trend toward a difference between women carriers (n = 82) and noncarriers (n = 39). In men, increasing CGG repeat correlated with greater impairment in all motor signs. In women, when activation ratio was considered, increasing CGG correlated with greater ataxia. CONCLUSIONS: CGG repeat size is significantly associated with overall motor impairment in premutation carriers. Whereas this association is most pronounced for men and covers overall motor impairment-tremor, ataxia, and parkinsonism-the association exists for ataxia among women carriers. This is the first report of a significant correlation between the premutation status and a motor feature of fragile X-associated tremor/ataxia syndrome in women.",
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AU - Leehey, M. A.

AU - Berry-Kravis, E.

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AU - Hall, D. A.

AU - Li, L.

AU - Rice, C. D.

AU - Lara, R.

AU - Cogswell, J.

AU - Reynolds, A.

AU - Gane, L.

AU - Jacquemont, S.

AU - Tassone, Flora

AU - Grigsby, J.

AU - Hagerman, Randi J

AU - Hagerman, Paul J

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N2 - BACKGROUND: Fragile X-associated tremor/ataxia syndrome (FXTAS) is a recently described, underrecognized neurodegenerative disorder of aging fragile X mental retardation 1 (FMR1) premutation carriers, particularly men. Core motor features are action tremor, gait ataxia, and parkinsonism. Carriers have expanded CGG repeats (55 to 200); larger expansions cause fragile X syndrome, the most common heritable cause of mental retardation and autism. This study determines whether CGG repeat length correlates with severity and type of motor dysfunction in premutation carriers. METHODS: Persons aged ≥50 years with a family history of fragile X syndrome underwent structured videotaping. Movement disorder neurologists, blinded to carrier status, scored the tapes using modified standardized rating scales. CGG repeat length analyses for women incorporated the activation ratio, which measures the percentage of normal active chromosome X alleles. RESULTS: Male carriers (n = 54) had significantly worse total motor scores, especially in tremor and ataxia, than age-matched male noncarriers (n = 51). There was a trend toward a difference between women carriers (n = 82) and noncarriers (n = 39). In men, increasing CGG repeat correlated with greater impairment in all motor signs. In women, when activation ratio was considered, increasing CGG correlated with greater ataxia. CONCLUSIONS: CGG repeat size is significantly associated with overall motor impairment in premutation carriers. Whereas this association is most pronounced for men and covers overall motor impairment-tremor, ataxia, and parkinsonism-the association exists for ataxia among women carriers. This is the first report of a significant correlation between the premutation status and a motor feature of fragile X-associated tremor/ataxia syndrome in women.

AB - BACKGROUND: Fragile X-associated tremor/ataxia syndrome (FXTAS) is a recently described, underrecognized neurodegenerative disorder of aging fragile X mental retardation 1 (FMR1) premutation carriers, particularly men. Core motor features are action tremor, gait ataxia, and parkinsonism. Carriers have expanded CGG repeats (55 to 200); larger expansions cause fragile X syndrome, the most common heritable cause of mental retardation and autism. This study determines whether CGG repeat length correlates with severity and type of motor dysfunction in premutation carriers. METHODS: Persons aged ≥50 years with a family history of fragile X syndrome underwent structured videotaping. Movement disorder neurologists, blinded to carrier status, scored the tapes using modified standardized rating scales. CGG repeat length analyses for women incorporated the activation ratio, which measures the percentage of normal active chromosome X alleles. RESULTS: Male carriers (n = 54) had significantly worse total motor scores, especially in tremor and ataxia, than age-matched male noncarriers (n = 51). There was a trend toward a difference between women carriers (n = 82) and noncarriers (n = 39). In men, increasing CGG repeat correlated with greater impairment in all motor signs. In women, when activation ratio was considered, increasing CGG correlated with greater ataxia. CONCLUSIONS: CGG repeat size is significantly associated with overall motor impairment in premutation carriers. Whereas this association is most pronounced for men and covers overall motor impairment-tremor, ataxia, and parkinsonism-the association exists for ataxia among women carriers. This is the first report of a significant correlation between the premutation status and a motor feature of fragile X-associated tremor/ataxia syndrome in women.

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