Risk Factors for Cognitive Impairment in Fragile X-Associated Tremor/Ataxia Syndrome

Seritan, Andreea L.; Kim, Kyoungmi; Benjamin, Ian; Seritan, Ioana; Hagerman, Randi J.

doi:10.1177/0891988716666379

Cited by 18 publications

(15 citation statements)

References 68 publications

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“…CGG repeat length had previously been associated with FXTAS clinical features, such as the age of onset of tremor and executive dysfunction (Cornish et al, 2011 ). The repeat size is also considered a risk factor for developing FXTAS dementia (Seritan et al, 2016 ). Others reported a correlation between age and CGG repeat length, as they found that male carriers with over 100 CGG repeats are more susceptible to the effects of aging on measures of executive function (Cornish et al, 2011 ).…”

Section: Clinical Manifestations Of Poi In General and Ovarian Dysfunmentioning

confidence: 99%

Fragile X-Associated Diminished Ovarian Reserve and Primary Ovarian Insufficiency from Molecular Mechanisms to Clinical Manifestations

Man

Lekovich

Rosenwaks

et al. 2017

Front. Mol. Neurosci.

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Fragile X syndrome (FXS), is caused by a loss-of-function mutation in the FMR1 gene located on the X-chromosome, which leads to the most common cause of inherited intellectual disability in males and the leading single-gene defect associated with autism. A full mutation (FM) is represented by more than 200 CGG repeats within the FMR1 gene, resulting in FXS. A FM is inherited from women carrying a FM or a premutation (PM; 55–200 CGG repeats) allele. PM is associated with phenotypes distinct from those associated with FM. Some manifestations of the PM are unique; fragile-X-associated tremor/ataxia syndrome (FXTAS), and fragile-X-associated primary ovarian insufficiency (FXPOI), while others tend to be non-specific such as intellectual disability. In addition, women carrying a PM may suffer from subfertility or infertility. There is a need to elucidate whether the impairment of ovarian function found in PM carriers arises during the primordial germ cell (PGC) development stage, or due to a rapidly diminishing oocyte pool throughout life or even both. Due to the possibility of expansion into a FM in the next generation, and other ramifications, carrying a PM can have an enormous impact on one’s life; therefore, preconception counseling for couples carrying the PM is of paramount importance. In this review, we will elaborate on the clinical manifestations in female PM carriers and propose the definition of fragile-X-associated diminished ovarian reserve (FXDOR), then we will review recent scientific findings regarding possible mechanisms leading to FXDOR and FXPOI. Lastly, we will discuss counseling, preventative measures and interventions available for women carrying a PM regarding different aspects of their reproductive life, fertility treatment, pregnancy, prenatal testing, contraception and fertility preservation options.

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Section: Clinical Manifestations Of Poi In General and Ovarian Dysfunmentioning

confidence: 99%

Fragile X-Associated Diminished Ovarian Reserve and Primary Ovarian Insufficiency from Molecular Mechanisms to Clinical Manifestations

Man

Lekovich

Rosenwaks

et al. 2017

Front. Mol. Neurosci.

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“…Clinical presentation, age of onset, and severity of FXTAS are heterogeneous. A larger CGG repeat size in PM carriers predicts earlier age of onset and perhaps earlier death [ 40 , 41 , 65 ]. Symptoms in females are milder since they have two X chromosomes [ 39 , 66 ].…”

Section: Clinical Presentation Of Fxtasmentioning

confidence: 99%

“…Behavioral self-regulation, verbal fluency, working memory, remote recall, declarative verbal learning memory, visuospatial function, temporal sequencing, information processing speed, and general intelligence, specifically nonverbal intellectual quotient, are often found to be impaired in individuals with FXTAS [ 88 , 89 , 90 ]. The impairment is correlated with CGG repeat number [ 65 , 88 , 89 ] and it worsens over time. Milder cognitive impairment can sometimes affect non-FXTAS carriers who are also aging [ 90 ].…”

Section: Clinical Presentation Of Fxtasmentioning

confidence: 99%

Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS): Pathophysiology and Clinical Implications

Cabal-Herrera

Tassanakijpanich

Salcedo-Arellano

et al. 2020

IJMS

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The fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder seen in older premutation (55–200 CGG repeats) carriers of FMR1. The premutation has excessive levels of FMR1 mRNA that lead to toxicity and mitochondrial dysfunction. The clinical features usually begin in the 60 s with an action or intention tremor followed by cerebellar ataxia, although 20% have only ataxia. MRI features include brain atrophy and white matter disease, especially in the middle cerebellar peduncles, periventricular areas, and splenium of the corpus callosum. Neurocognitive problems include memory and executive function deficits, although 50% of males can develop dementia. Females can be less affected by FXTAS because of a second X chromosome that does not carry the premutation. Approximately 40% of males and 16% of female carriers develop FXTAS. Since the premutation can occur in less than 1 in 200 women and 1 in 400 men, the FXTAS diagnosis should be considered in patients that present with tremor, ataxia, parkinsonian symptoms, neuropathy, and psychiatric problems. If a family history of a fragile X mutation is known, then FMR1 DNA testing is essential in patients with these symptoms.

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“…Neuropathic signs were tested using the Total Neuropathy score modified to exclude nerve conduction velocity testing [9]. FXTAS stage was noted at baseline [10].…”

Section: Clinical and Laboratory Evaluationsmentioning

confidence: 99%

Open-label pilot clinical trial of citicoline for fragile X-associated tremor/ataxia syndrome (FXTAS)

Hall

Robertson²,

Leehey

et al. 2020

PLoS ONE

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Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late onset neurodegenerative disorder that is characterized by tremor, cerebellar ataxia, frequent falls, cognitive decline, and progressive loss of motor function. There are currently no approved treatments for this disorder. The purpose of this study was to determine if citicoline was safe for the treatment of tremor and balance abnormalities and to stabilize cognitive decline in patients with FXTAS. Ten participants with diagnosed FXTAS were administered 1000 mg of citicoline once daily for 12 months. Outcome measures and neurological examination were performed at baseline, 3 months, 6 months, and 12 months. The primary outcome was the FXTAS Rating Scale score. Secondary outcomes included change in a battery of neuropsychological tests, an instrumented Timed up and go test, computerized dynamic posturography, 9-hole pegboard test, and balance confidence and psychiatric symptom questionnaires. Safety was also evaluated. Citicoline treatment resulted in minimal adverse events in all but one subject over the course of the study. There was a significant improvement in the Beck Anxiety Inventory (p = 0.03) and the Stroop Color-Word test (p = 0.03), with all other measures remaining stable over the course of 12 months. This open-label pilot trial of citicoline for individuals with FXTAS showed that it is safe and well tolerated in this population. Registration: This trial was registered at ClinicalTrials.gov. Identifier: NCT0219710.

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Risk Factors for Cognitive Impairment in Fragile X-Associated Tremor/Ataxia Syndrome

Cited by 18 publications

References 68 publications

Fragile X-Associated Diminished Ovarian Reserve and Primary Ovarian Insufficiency from Molecular Mechanisms to Clinical Manifestations

Fragile X-Associated Diminished Ovarian Reserve and Primary Ovarian Insufficiency from Molecular Mechanisms to Clinical Manifestations

Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS): Pathophysiology and Clinical Implications

Open-label pilot clinical trial of citicoline for fragile X-associated tremor/ataxia syndrome (FXTAS)

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