FMR1 premutation in females diagnosed with multiple sclerosis

Zhang, Lin; Coffey, Sarah M.; Lua, Lannah L.; Greco, C.; Schäfer, Jakob; Brunberg, James A.; Borodyanskaya, Mariya; Agius, Mark; Apperson, Michelle; Leehey, Maureen A.; Tartaglia, Nicole; Tassone, Flora; Hagerman, Paul J.; Hagerman, Randi J.

doi:10.1136/jnnp.2008.160960

Cited by 30 publications

(23 citation statements)

References 5 publications

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“…Peripheral neuropathy, seizures and hypertension are also reported to be present more often in females with FXTAS than in controls [18,19]. Presence of FXTAS and other (neurological) disorders such as multiple sclerosis have been described in some carrier women [44,45]. Interestingly, although approximately 20% of carrier women have primary ovarian failure [46], one study reports that it is not associated with later onset of FXTAS [19].…”

Section: Fxtas In Womenmentioning

confidence: 99%

“…A number of post-mortem case studies examining brain tissue from patients with FXTAS have revealed evidence of co-morbid pathologies including multiple sclerosis, AD and dementia with Lewy bodies [44,45,58] in addition to FXTAS inclusions. Atypical cognitive phenotypes or atypical progression of symptoms may suggest the presence of co-morbid neurodegenerative conditions.…”

Section: Emerging Issues In Clinical Classification Of Cognitive Disomentioning

confidence: 99%

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Emerging topics in FXTAS

Hall

Birch

Anheim

et al. 2014

J Neurodevelop Disord

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Section: Fxtas In Womenmentioning

confidence: 99%

Section: Emerging Issues In Clinical Classification Of Cognitive Disomentioning

confidence: 99%

Emerging topics in FXTAS

Hall

Birch

Anheim

et al. 2014

J Neurodevelop Disord

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“…107 In this regard, Qurashi et al, 109 observed an accumulation of transcripts from stress response genes in the Drosophila model of the premutation, suggesting a cellular response to oxidative stress, and/or to mitigate an inflammatory response; such inflammatory or immune-mediated processes do co-occur in those with FXTAS at a higher rate than expected in the general population. 49, 68, 70, 85, 110, 111 …”

Section: Pathogenesis Of Premutation Disorders and Fxtasmentioning

confidence: 99%

Advances in clinical and molecular understanding of the FMR1 premutation and fragile X-associated tremor/ataxia syndrome

Hagerman

2013

The Lancet Neurology

286

312

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Summary Fragile X syndrome, the leading heritable form of cognitive impairment, is caused by epigenetic silencing of the fragile X (FMR1) gene consequent to large expansions (>200 repeats) of a non-coding CGG-repeat element. Smaller, “premutation” expansions (55–200 repeats) can give rise to a family of neurodevelopmental (ADHD, autism spectrum disorder, seizure disorder) and neurodegenerative (FXTAS) clinical phenotypes through an entirely distinct molecular mechanism involving increased FMR1 mRNA production and toxicity. Basic cellular, animal, and human studies have helped to elucidate the underlying RNA toxicity mechanism, while clinical research is providing a more nuanced picture of the spectrum of clinical involvement. Whereas advances on both mechanistic and clinical fronts are driving new approaches to targeted treatment, two important issues/needs are emerging: to define the extent to which the mechanisms contributing to FXTAS also contribute to other neurodegenerative and medical disorders, and to redefine FXTAS in light of its differing presentations and associated features.

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“…MRI features include global brain atrophy and white matter disease with spongiosis involving the MCP sign, periventricular regions, subcortical regions, and pons (Adams et al 2007, 2010; Cohen et al 2006; Brunberg et al 2003). Females are less affected than males, both radiologically and cognitively (Coffey et al 2008; Adams et al 2007; Hagerman et al 2004), but they often have autoimmune problems including hypothyroidism and fibromyalgia (Coffey et al 2008) with the rare occurrence of multiple sclerosis (Zhang et al 2009). …”

Section: Involvement In Carriers Of Premutation Allelesmentioning

confidence: 99%

FMR1 premutation and full mutation molecular mechanisms related to autism

Hagerman

2011

J Neurodevelop Disord

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Fragile X syndrome (FXS) is caused by an expanded CGG repeat (>200 repeats) in the 5′ un-translated portion of the fragile X mental retardation 1 gene (FMR1) leading to a deficiency or absence of the FMR1 protein (FMRP). FMRP is an RNA-binding protein that regulates the translation of a number of other genes that are important for synaptic development and plasticity. Furthermore, many of these genes, when mutated, have been linked to autism in the general population, which may explain the high comorbidity that exists between FXS and autism spectrum disorders (ASD). Additionally, premutation repeat expansions (55 to 200 CGG repeats) may also give rise to ASD through a different molecular mechanism that involves a direct toxic effect of FMR1 mRNA. It is believed that RNA toxicity underlies much of the premutation-related involvement, including developmental concerns like autism, as well as neurodegenerative issues with aging such as the fragile X-associated tremor ataxia syndrome (FXTAS). RNA toxicity can also lead to mitochondrial dysfunction, which is common in older premutation carriers both with and without FXTAS. Many of the problems with cellular dysregulation in both premutation and full mutation neurons also parallel the cellular abnormalities that have been documented in idiopathic autism. Research regarding dysregulation of neurotransmitter systems caused by the lack of FMRP in FXS, including metabotropic glutamate receptor 1/5 (mGluR1/5) pathway and GABA pathways, has led to new targeted treatments for FXS. Preliminary evidence suggests that these new targeted treatments will also be beneficial in non-fragile X forms of autism.

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FMR1 premutation in females diagnosed with multiple sclerosis

Cited by 30 publications

References 5 publications

Emerging topics in FXTAS

Emerging topics in FXTAS

Advances in clinical and molecular understanding of the FMR1 premutation and fragile X-associated tremor/ataxia syndrome

FMR1 premutation and full mutation molecular mechanisms related to autism

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