New observations in the fragile X-associated tremor/ataxia syndrome (FXTAS) phenotype

Fraint, Avram; Vittal, Padmaja; Szewka, Aimee; Bernard, Bryan; Berry‐Kravis, Elizabeth; Hall, Deborah A.

doi:10.3389/fgene.2014.00365

Cited by 31 publications

(29 citation statements)

References 29 publications

(23 reference statements)

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“…The patient in case 2 in the case reports had both kinetic tremor and cerebellar gait ataxia, in addition to parkinsonian features. Prior to death, he did not meet criteria for any of the atypical parkinsonian disorders and appeared closer phenotypically to those FXTAS patients described in Fraint et al [38], with vertical gaze palsy. Case 3 in the case reports was specifically referred to the screening study by her treating neurologist as her ataxia was out of proportion to that expected in ET.…”

Section: Discussionmentioning

confidence: 87%

Clinical Phenotype of Adult Fragile X Gray Zone Allele Carriers: a Case Series

et al. 2016

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Considerable research has focused on patients with trinucleotide (CGG) repeat expansions in the fragile X mental retardation 1 (FMR1) gene that fall within either the full mutation (>200 repeats) or premutation range (55-200 repeats). Recent interest in individuals with gray zone expansions (41-54 CGG repeats) has grown due to reported phenotypes that are similar to those observed in premutation carriers, including neurological, molecular, and cognitive signs. The purpose of this manuscript is to describe a series of adults with FMR1 alleles in the gray zone presenting with movement disorders or memory loss. Gray zone carriers ascertained in large FMR1 screening studies were identified and their clinical phenotypes studied. Thirty-one gray zone allele carriers were included, with mean age of symptom onset of 53 years in patients with movement disorders and 57 years in those with memory loss. Four patients were chosen for illustrative case reports and had the following diagnoses: early-onset Parkinson disease (PD), atypical parkinsonism, dementia, and atypical essential tremor. Some gray zone carriers presenting with parkinsonism had typical features, including bradykinesia, rigidity, and a positive response to dopaminergic medication. These patients had a higher prevalence of peripheral neuropathy and psychiatric complaints than would be expected. The patients seen in memory clinics had standard presentations of cognitive impairment with no apparent differences. Further studies are necessary to determine the associations between FMR1 expansions in the gray zone and various phenotypes of neurological dysfunction.

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Section: Discussionmentioning

confidence: 87%

Clinical Phenotype of Adult Fragile X Gray Zone Allele Carriers: a Case Series

et al. 2016

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“…cerebellar peduncles) may differentiate FXPC+ from FXPC− before age 50. In addition, certain brainstem structures may be proven important for FXTAS phenotypic representations such as parkinsonism (Scaglione et al , 2008), sensorineural hearing loss (Juncos et al , 2011) and eye movement impairment (Fraint et al , 2014). Further segmentation of the brainstem is needed to determine whether specific structures within the brainstem show prodromal signs of FXTAS.…”

Section: Discussionmentioning

confidence: 99%

Abnormal trajectories in cerebellum and brainstem volumes in carriers of the fragile X premutation

Wang

Hessl

Hagerman

et al. 2017

Neurobiology of Aging

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Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder typically affecting male premutation carriers with 55–200 CGG repeat expansions in the FMR1 gene after age 50. The aim of this study was to examine whether cerebellar and brainstem changes emerge during development or aging in late life. We retrospectively analyzed MRI scans from 322 males (age 8–81 years). Volume changes in the cerebellum and brainstem were contrasted with those in the ventricles and whole brain. Compared to the controls, premutation carriers without FXTAS showed significantly accelerated volume decrease in the cerebellum and whole brain, flatter inverted U-shaped trajectory of the brainstem, and larger ventricles. Compared to both older controls and premutation carriers without FXTAS, carriers with FXTAS exhibited significant volume decrease in the cerebellum and whole brain and accelerated volume decrease in the brainstem. We therefore conclude that cerebellar and brainstem volumes were likely affected during both development and progression of neurodegeneration in premutation carriers, suggesting that interventions may need to start early in adulthood to be most effective.

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“…4 FXTAS is generally slowly progressive with a median survival of 21 years after the onset of symptoms, although some patients have a more precipitous decline in function, often after an illness. 5 There are currently no approved treatments for FXTAS. Symptoms are managed with medications shown to be helpful in other diseases with similar symptoms or those with anecdotal evidence from case reports.…”

Section: Resultsmentioning

confidence: 99%

“…Up to 16% of premutation carrier women develop FXTAS, and the phenotype is milder as a result of X‐inactivation . FXTAS is generally slowly progressive with a median survival of 21 years after the onset of symptoms, although some patients have a more precipitous decline in function, often after an illness …”

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confidence: 99%

Placebo Response in Fragile X‐associated Tremor/Ataxia Syndrome

Hill

Goetz

Stebbins

et al. 2020

Movement Disord Clin Pract

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Background Fragile X‐associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder characterized by intention tremor, cerebellar ataxia, and executive dysfunction in carriers of a CGG repeat expansion premutation (55–200 repeats) in the fragile X mental retardation 1 (FMR1) gene. Given reports of poor insight in FXTAS, we postulated that patients with FXTAS would be less likely to exhibit placebo response. Objective To analyze placebo response from the first randomized controlled trial in FXTAS that evaluated cognitive and motor outcomes after 1 year of treatment with memantine. Methods Data from the placebo arm of the first randomized controlled trial in FXTAS were analyzed. There were 2 coprimary outcomes. Based on studies in Parkinson's disease, placebo responders were defined as individuals with an improvement of at least 50% in the coprimary outcomes. Improvements of 20% and 30% served as secondary cutoff values based on the suggested magnitude of placebo response in other movement disorders. Results A total of 36 participants in the placebo group completed baseline and follow‐up evaluations. The average age was 66 ± 7 years, and 60% were men. Average CGG repeat size was 86 ± 18. A total of 19 participants had stage 3 disease. Only 1 patient showed 50% improvement in both coprimary outcomes. At 30% and 20% improvement, there were 2 and 3 patients showing placebo response in the coprimary outcomes, respectively. Conclusions Patients with FXTAS exhibited low rates of placebo response in a randomized controlled trial. Further studies on the relationship between baseline insight and placebo responsivity are applicable to FXTAS and other disorders exhibiting cognitive impairment.

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New observations in the fragile X-associated tremor/ataxia syndrome (FXTAS) phenotype

Cited by 31 publications

References 29 publications

Clinical Phenotype of Adult Fragile X Gray Zone Allele Carriers: a Case Series

Clinical Phenotype of Adult Fragile X Gray Zone Allele Carriers: a Case Series

Abnormal trajectories in cerebellum and brainstem volumes in carriers of the fragile X premutation

Placebo Response in Fragile X‐associated Tremor/Ataxia Syndrome

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