Intention tremor, parkinsonism, and generalized brain atrophy in male carriers of fragile X

Hagerman, Randi J; Leehey, Maureen A.; Heinrichs, Wm. LeRoy; Tassone, Flora; Wilson, Rebecca L.; Hills, J.; Grigsby, Jim; Gage, Brian F.; Hagerman, Paul J.

doi:10.1212/wnl.57.1.127

Cited by 856 publications

(787 citation statements)

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“…3 Expansions of about 55-200 repeats, called premutation alleles, are associated with a significant elevation of FMR1 mRNA levels, 4 and it has been known that carriers of FMR1 premutation have a risk of developing fragile X-associated tremor/ataxia syndrome, a late-onset neurodegenerative disorder. 5,6 Premutation alleles are generally unstable, resulting in an expansion of the CGG repeat sequence when passed from mother to child. Offspring of female premutation carriers is at risk of having FXS.…”

Section: Introductionmentioning

confidence: 99%

Intermediate FMR1 alleles and cognitive and/or behavioural phenotypes

et al. 2011

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During the last few years, several studies have reported an excess of intermediate FMR1 alleles in patients with cognitive and/or behavioural phenotypes. Here, we report the frequency of intermediate alleles (IAs) in three pathologies, intellectual disabilities (IDs), attention-deficit/hyperactivity disorder and autism, from different Spanish regions. We found 142 IAs among 9015 patients with ID (1.6%), 4 among the 415 ADHD patients (0.96%) and 4 among the 300 autistic patients (1.3%), similar to the frequency reported in our control population. No evidence was found of an excess of IA at the FRAXA locus in any of the study populations, although geographical variability was detected. Moreover, the analysis of 100 transmissions of IAs showed that 95% of these alleles were stable. Only 3% expanded within the same range and 2% expanded to a full mutation in two generations. No evidence of an association between IAs and behavioural or cognitive phenotypes was found, suggesting that IAs are not clearly implicated in these pathologies.

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Section: Introductionmentioning

confidence: 99%

Intermediate FMR1 alleles and cognitive and/or behavioural phenotypes

et al. 2011

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“…Female carriers of the PM are at increased risk of developing premature ovarian failure (POF) (Sherman, 2000). PM carriers also are at risk for fragile X-associated tremor/ataxia syndrome (FXTAS), which has been observed in elderly men over age 50, and less often in female PM carriers (Hagerman et al, 2001;Hagerman and Hagerman, 2002;Jacquemont et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

Altered hypothalamus–pituitary–adrenal gland axis regulation in the expanded CGG-repeat mouse model for fragile X-associated tremor/ataxia syndrome

Brouwer

Severijnen

Jong

et al. 2008

Psychoneuroendocrinology

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The human FMR1 gene contains an unstable CGG-repeat in its 5′ untranslated region. The repeat length in the normal population is polymorphic (5-54 CGG-repeats). Individuals carrying lengths beyond 200 CGGs (i.e. the full mutation) show hypermethylation and as a consequence gene silencing of the FMR1 gene. The absence of the gene product FMRP causes the fragile X syndrome, the most common inherited form of mental retardation. Elderly carriers of the premutation (PM), which is defined as a repeat length between 55-200 CGGs, can develop a progressive neurodegenerative syndrome: fragile X-associated tremor/ataxia syndrome (FXTAS). The high FMR1 mRNA levels observed in cells from PM carriers have led to the hypothesis that FXTAS is caused by a pathogenic RNA gain-of-function mechanism. Apart from tremor/ataxia, specific psychiatric symptoms have been described in PM carriers with or without FXTAS. Since these symptoms could arise from elevated stress hormone levels, we investigated hypothalamicpituitary-adrenal (HPA) axis regulation using a knock-in mouse model with an expanded CGGrepeat in the PM range (>98 repeats) in the Fmr1 gene, which shows repeat instability, and displays biochemical, phenotypic and neuropathological characteristics of FXTAS. We show elevated levels of corticosterone in serum and ubiquitin-positive inclusions in both the pituitary and adrenal gland of 100-week old animals. In addition, we demonstrate ubiquitin-positive © 2008 Elsevier Ltd. All rights reserved. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Financial disclosuresWe declare no conflict of interest. HHS Public Access Author Manuscript Author ManuscriptAuthor ManuscriptAuthor Manuscript inclusions in the amygdala from aged expanded CGG-repeat mice. We hypothesize that altered regulation of the HPA axis and the amygdala and higher stress hormone levels in the mouse model for FXTAS may explain associated psychological symptoms in humans.

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“…FXTAS was among the first conditions associated with carriers of the premutation [32]. This is a neurodegenerative disease mainly characterized by intention tremor and cerebellar ataxia that tends to occur as a function of age, as evidenced by Jacquemont et al (2004) [33] who found an increased prevalence of FXTAS among men with the premutation in each subsequent decade of life after age 50.…”

Section: Neuropsychiatric and Muscular Involvementmentioning

confidence: 99%

Fragile X premutation in women: recognizing the health challenges beyond primary ovarian insufficiency

Hoyos

Thakur

2016

J Assist Reprod Genet

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Fragile X premutation carriers have 55-200 CGG repeats in the 5' untranslated region of the FMR1 gene. Women with this premutation face many physical and emotional challenges in their life. Approximately 20% of these women will develop fragile X-associated primary ovarian insufficiency (FXPOI). In addition, they suffer from increased rates of menstrual dysfunction, diminished ovarian reserve, reduction in age of menopause, infertility, dizygotic twinning, and risk of having an offspring with a premutation or full mutation. Consequent chronic hypoestrogenism may result in impaired bone health and increased cardiovascular risk. Neuropsychiatric issues include risk of developing fragile X-associated tremor/ataxia syndrome, neuropathy, musculoskeletal problems, increased prevalence of anxiety, depression, and sleep disturbances independent of the stress of raising an offspring with fragile X syndrome and higher risk of postpartum depression. Some studies have reported a higher prevalence of thyroid abnormalities and hypertension in these women. Reproductive health providers play an important role in the health supervision of women with fragile X premutation. Awareness of these risks and correlation of the various manifestations could help in early diagnosis and coordination of care and services for these women and their families. This paper reviews current evidence regarding the possible conditions that may present in women with premutation-sized repeats beyond FXPOI.

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Intention tremor, parkinsonism, and generalized brain atrophy in male carriers of fragile X

Cited by 856 publications

References 10 publications

Intermediate FMR1 alleles and cognitive and/or behavioural phenotypes

Intermediate FMR1 alleles and cognitive and/or behavioural phenotypes

Altered hypothalamus–pituitary–adrenal gland axis regulation in the expanded CGG-repeat mouse model for fragile X-associated tremor/ataxia syndrome

Fragile X premutation in women: recognizing the health challenges beyond primary ovarian insufficiency

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