Functional status of men with the fragile X premutation, with and without the tremor/ataxia syndrome (FXTAS).

BACKGROUND: Fragile X-associated tremor/ataxia syndrome (FXTAS), which occurs in some premutation carriers of the fragile X mental retardation 1 (FMR1) gene, is a neurodegenerative disorder characterized by action tremor, gait ataxia, and impaired executive cognitive functioning. OBJECTIVE: To evaluate the nature and severity of functional limitations among male carriers of the fragile X premutation, both with and without FXTAS. METHODS: Forty-two subjects with FXTAS and 24 asymptomatic premutation carriers were compared to 32 control subjects on measures of physical functioning, activities of daily living (ADLs; e.g. eating, bathing), and instrumental activities of daily living (IADLs; e.g. shopping, managing medications). Ordinary least squares regression, controlling for age, education, medical comorbidity, and pain, was used to examine group differences in physical and functional performance. RESULTS: Men with FXTAS performed significantly worse than control subjects on all dependent measures, showing greater limitations in physical functioning, as well as ADL and IADL performance (p < 0.05). Subsequent analyses suggested that physical and functional impairments among men with FXTAS result largely from deficits in motor and executive functioning and that CGG repeat length is associated with functional impairment. Asymptomatic carriers of the fragile X premutation performed similarly to control subjects on all measures. CONCLUSIONS: This study provides the first comprehensive evaluation of functional status among male premutation carriers. Although carriers without FXTAS performed similarly to control subjects, men with FXTAS showed evidence of significant physical and functional impairment, which appears to result largely from motor and executive deficits characteristic of the syndrome.

Cognitive profile of fragile X premutation carriers with and without fragile X-associated tremor/ataxia syndrome.

Fragile X-associated tremor/ataxia syndrome (FXTAS) develops in a subset of fragile X premutation carriers and involves gait ataxia, action tremor, Parkinsonism, peripheral neuropathy, autonomic disorders, and cognitive impairment. The study was designed to define the nature of cognitive deficits affecting male premutation carriers with and without FXTAS. A sample of 109 men underwent motor, cognitive, genetic, and neurologic testing, as well as brain magnetic resonance imaging. Subjects were classified into 3 groups: (a) asymptomatic premutation carriers, (b) premutation carriers with FXTAS, and (c) normal controls. Men with FXTAS performed worse than controls on mental status, intelligence, executive cognitive functioning (ECF), working memory, remote recall of information, declarative learning and memory, information processing speed, and temporal sequencing, as well as 1 measure of visuospatial functioning. Language and verbal comprehension were spared. Asymptomatic carriers performed worse than controls on ECF and declarative learning and memory. This comprehensive examination of cognitive impairment in male premutation carriers suggests that FXTAS involves substantial executive impairment and diffuse deficits in other cognitive functions. Longitudinal research currently underway will provide insight into the progression of the disorder.

Cognitive, anxiety and mood disorders in the fragile X-associated tremor/ataxia syndrome.

OBJECTIVE: We evaluated patients with fragile X-associated tremor/ataxia syndrome (FXTAS), a neurodegenerative disorder associated with a CGG repeat expansion in the premutation range in the fragile X mental retardation 1 (FMR1) gene. METHODS: Neurological, psychiatric and neuropsychological evaluations were performed on 15 male patients with FXTAS. RESULTS: Seven cases were diagnosed with dementia, and seven others were diagnosed with mood and/or anxiety disorders. Twelve subjects demonstrated deficits on neuropsychological testing. CONCLUSIONS: Physicians assessing dementia patients are urged to consider this newly described syndrome, especially in patients with dementia associated with a movement disorder and in those with a family history of mental retardation. If FXTAS is a possible diagnosis, physicians may carry out FMR1 DNA testing; patients who test positive on DNA testing should undergo magnetic resonance imaging, be referred to neurology and receive genetic counseling.

Psychiatric phenotype of the fragile X-associated tremor/ataxia syndrome (FXTAS) in males: newly described fronto-subcortical dementia.

OBJECTIVE: The authors describe and quantify the neuropsychiatric symptoms present in a cohort of males with the fragile X mental retardation 1 (FMR1) premutation allele who have developed fragile X-associated tremor/ataxia syndrome (FXTAS). METHOD: Fourteen male carriers of the FMR1 premutation who had clinical manifestations of the FXTAS syndrome and 14 age- and education-matched controls were assessed with the Neuropsychiatric Inventory (NPI), formal cognitive testing, and genetic analysis. RESULTS: Males with FXTAS had significantly higher total NPI scores (p < .004) and significantly higher scores on the agitation/aggression (p < .004), depression (p < .004), apathy (p < .004), disinhibition (p < .004), and irritability (p < .004) scales, compared with controls. Cognitive performances on the Mini-Mental State Examination did not correlate with severity of symptoms on the NPI. CONCLUSIONS: The neuropsychiatric manifestations of FXTAS, based on this preliminary report, appear to cluster as a fronto-subcortical dementia. Clinicians encountering patients with clinical dementia with motor symptoms suggesting FXTAS should consider genetic testing to determine whether the patient's dementia syndrome is secondary to a fragile X premutation carrier status.

Impairment in the cognitive functioning of men with fragile X-associated tremor/ataxia syndrome (FXTAS).

Disorders associated with fragile X syndrome involve a trinucleotide (CGG) repeat expansion in the FMR1 gene. Recently, a progressive movement disorder (fragile X-associated tremor/ataxia syndrome [FXTAS]) has been identified in premutation carriers, persons with 55 to 200 CGG repeats. In addition to ataxia, action tremor, and Parkinsonism, early case reports suggested that FXTAS involves impaired cognition, but the precise nature of the impairment has not been elucidated. In this first, preliminary study of the subject, circumscribed aspects of cognitive functioning were examined in 25 men with FXTAS. Subjects' performance on the cognitive tests was compared with normative data. Scores on two measures of executive cognitive functioning showed a high prevalence of substantial impairment. Capacity for inhibition was severely affected in one-quarter of this highly educated sample; information processing speed was profoundly impaired in most subjects. Although mean verbal and performance IQ scores were not significantly different from the general population, they were quite low given the sample's educational level. Cognitive and functional impairment was greater for men with more CGG repeats, although number of repeats was not associated with age of onset of either tremor or ataxia. The results provide evidence that FXTAS involves marked impairment of executive cognitive abilities.

Effect of CX516, an AMPA-modulating compound, on cognition and behavior in fragile X syndrome: a controlled trial.

A Phase II, 4-week randomized, double-blind, placebo-controlled clinical trial was conducted to evaluate the safety and efficacy of the Ampakine compound CX516 as a potential treatment for the underlying disorder in fragile X syndrome (FXS). After baseline screening, subjects with FXS (n = 49) underwent a 1-week placebo lead-in and then were randomized to study drug or placebo for a 4-week period. Cognitive and behavioral outcome measures were administered prior to treatment, at the end of treatment, and 2 weeks posttreatment. There were minimal side effects, no significant changes in safety parameters, and no serious adverse events. There was a 12.5% frequency of allergic rash in the CX516 group and 1 subject developed a substantial rash. There was also no significant improvement in memory, the primary outcome measure, or in secondary measures of language, attention/executive function, behavior, and overall functioning in CX516-treated subjects compared to placebo. This study did demonstrate that many outcome measures were reproducible in this test-retest setting for the FXS population, yet some were too difficult or variable. Adult subjects with FXS were able to complete an intensive clinical trial, and some valid outcome measures were identified for future FXS trial design. Problems with potency of CX516 in other studies have suggested dosing may have been inadequate for therapeutic effect and thus it remains unclear whether modulation of AMPA-mediated neurotransmission is a viable therapeutic strategy for the treatment of FXS.

Memantine for fragile X-associated tremor/ataxia syndrome: a randomized, double-blind, placebo-controlled trial.

OBJECTIVE: Memantine, an uncompetitive N-methyl-d-aspartate receptor antagonist, is currently approved by the US Food and Drug Administration for the treatment of moderate to severe Alzheimer's disease. Anecdotal reports have suggested that memantine may improve neurologic and cognitive symptoms of individuals with the neurodegenerative disease fragile X-associated tremor/ataxia syndrome (FXTAS); however, its efficacy and safety in this population have not been assessed in a controlled trial. METHOD: Individuals with FXTAS aged 34-80 years were enrolled in a randomized, double-blind, placebo-controlled, 1-year trial between September 2007 and August 2012. Inclusion required definite, probable, or possible FXTAS in clinical stages 1-5 according to previously published criteria. Primary outcome measures were the Behavioral Dyscontrol Scale (BDS) score and CATSYS intention tremor severity. RESULTS: Ninety-four participants were randomized from 205 screened; of those, 43 and 45 started treatment with memantine (titrated to 10 mg twice daily) and placebo, respectively. Thirty-four participants receiving memantine and 36 receiving placebo completed the 1-year endpoint assessment (n = 70). Intention-to-treat analysis showed no improvement with respect to intention tremor severity (mean [SD] values with memantine vs placebo: 1.05 [0.73] vs 1.89 [2.19], P = .047) or BDS score (16.12 [5.43] vs 15.72 [3.93], P = .727) at follow-up. Post hoc analyses of participants with early FXTAS (stage ≤ 3), those with late FXTAS (stage > 3), and those in different age groups (≤ 65 years and > 65 years) also indicated no significant improvement. More frequent mild adverse events were observed in the placebo group, while more frequent moderate adverse events occurred in the memantine group (P = .007). CONCLUSION: This randomized, double-blind, placebo-controlled trial of memantine for individuals with FXTAS showed no benefit compared to placebo with respect to the selected outcome measures. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00584948.

COGNITIVE DYSFUNCTION IN FMR1 PREMUTATION CARRIERS.

Premutation carriers of the fragile X mental retardation gene (especially men) older than 50 may develop a neurodegenerative disease, the fragile X-associated tremor/ataxia syndrome (FXTAS). Carriers may present with varied cognitive impairments. Attention, working memory, declarative and procedural learning, information processing speed, and recall are among the cognitive domains affected. Executive dysfunction is a prominent deficit, which has been demonstrated mostly in men with FXTAS. In more advanced stages of FXTAS, both men and women may develop a mixed cortical-subcortical dementia, manifested by psychomotor slowing and deficits in attention, retrieval, recall, visuospatial skills, occasional apraxia, as well as overt personality changes. Studies have shown dementia rates as high as 37-42% in older men with FXTAS, although more research is needed to understand the prevalence and risk factors of dementia in women with FXTAS. Neuropsychiatric symptoms are common and reflect the dysfunction of underlying frontal-subcortical neural circuits, along with components of the cerebellar cognitive affective syndrome. These include labile or depressed mood, anxiety, disinhibition, impulsivity, and (rarely) psychotic symptoms. In this paper we review the information available to date regarding the prevalence and clinical picture of FXTAS dementia. Differential diagnosis may be difficult, given overlapping motor and non-motor signs with several other neurodegenerative diseases. Anecdotal response to cholinesterase inhibitors and memantine has been reported, while symptomatic treatments can address the neuropsychiatric manifestations of FXTAS dementia.

Lifetime prevalence of mood and anxiety disorders in fragile X premutation carriers.

OBJECTIVE: The authors studied the lifetime prevalence of DSM-IV-TR psychiatric disorders in a population of adults with the fragile X premutation. METHOD: The Structured Clinical Interview for DSM-IV was conducted, from 2007-2008, in 85 individuals with the fragile X premutation, 47 with the fragile X-associated tremor/ataxia syndrome (FXTAS; 33 male, 14 female; mean age = 66 years) and 38 without FXTAS (16 male, 22 female; mean age = 52 years). Lifetime prevalence for mood and anxiety disorders among carriers with and without FXTAS was compared to available age-specific population estimates from the National Comorbidity Survey Replication (NCS-R). RESULTS: Among participants with FXTAS, 30 (65%) met lifetime DSM-IV-TR criteria for a mood disorder; 24 (52%) met lifetime DSM-IV-TR criteria for an anxiety disorder. Among the non-FXTAS participants, there were 15 instances of lifetime mood disorder (42%) and 18 of lifetime anxiety disorder (47%). When compared to age-specific NCS-R data, the lifetime prevalences of any mood disorder (P < .0001), major depressive disorder (P < .0001), any anxiety disorder (P < .0001), panic disorder (P = .006), specific phobia (P = .0003), and posttraumatic stress disorder (P = .004) were significantly higher in participants with FXTAS. The lifetime rates of social phobia in individuals with the premutation without FXTAS were significantly higher than NCS-R data (P = .001). CONCLUSIONS: This sample of carriers of the fragile X premutation had a notably high lifetime risk of mood and anxiety disorders. Mood and anxiety disorders may be part of the clinical phenotype of the fragile X premutation conditions, especially in carriers with FXTAS. Clinicians encountering these patients are advised to consider FXTAS as a neuropsychiatric syndrome as well as a neurologic disorder.

The primary cognitive deficit among males with fragile X-associated tremor/ataxia syndrome (FXTAS) is a dysexecutive syndrome.

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder associated with a premutation trinucleotide repeat expansion in the fragile X mental retardation 1 gene. Symptoms include gait ataxia, action tremor, and cognitive impairment. The objectives of the study were to clarify the nature of the dysexecutive syndrome observed in FXTAS and to assess the contribution of executive impairment to deficits in nonexecutive cognitive functions. Compared to controls, men with FXTAS demonstrated significant executive impairment, which was found to mediate group differences in most other cognitive abilities. Asymptomatic premutation carriers performed similarly to controls on all but two measures of executive functioning. These findings suggest that the impairment of nonexecutive cognitive skills in FXTAS is in large part secondary to executive dysfunction.

Neuropathic features in fragile X premutation carriers.

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a progressive neurological condition occurring in fragile X premutation carriers, predominantly males, and resulting in CNS dysfunction including tremor, ataxia, Parkinsonism, and cognitive decline. Neuropathic signs have also been described. The objective of this study was to compare neuropathic signs in fragile X premutation carriers versus controls and determine the relationship of these signs to CGG repeat length and tremor/ataxia. A neuropathy scale was utilized to compare distal tendon reflexes and vibration sense in subjects from a large cohort of carriers and controls undergoing neurological exam and structured videotaping sessions for movement disorder rating. The male carrier group displayed more impairment on total neuropathy, vibration and reflex scores than the corresponding control group, while female carriers were not significantly different from controls. In males, after correction for age effects, there was a correlation between CGG repeat length and both total neuropathy and reflex impairments. Age-adjusted partial correlation analyses showed an association between neuropathy scores and severity of ataxia but not tremor in carrier males and females. These data suggest that neuropathic signs are associated with the fragile X premutation, presumably occurring through the same mechanism proposed for CNS disease, namely, toxicity from expanded-CGG-repeat FMR1 mRNA.

Progression of tremor and ataxia in male carriers of the FMR1 premutation.

Premutation alleles of the fragile X mental retardation 1 (FMR1) gene give rise to a late-onset movement disorder, fragile X-associated tremor/ataxia syndrome (FXTAS), characterized by progressive intention tremor and gait ataxia, with associated dementia and global brain atrophy. The natural history of FXTAS is largely unknown. To address this issue, a family-based, retrospective, longitudinal study was conducted with a cohort of 55 male premutation carriers. Analysis of the progression of the major motor signs of FXTAS, tremor and ataxia, shows that tremor usually occurs first, with median onset at approximately 60 years of age. From the onset of the initial motor sign, median delay of onset of ataxia was 2 years; onset of falls, 6 years; dependence on a walking aid, 15 years; and death, 21 years. Preliminary data on life expectancy are variable, with a range from 5 to 25 years.

Impairment of executive cognitive functioning in males with fragile X-associated tremor/ataxia syndrome.

The fragile X-associated tremor/ataxia syndrome (FXTAS) is a recently identified phenotype associated with trinucleotide repeat expansions in the premutation range of the fragile X mental retardation 1 (FMR1) gene. In addition to progressive gait ataxia, action tremor, peripheral neuropathy, and parkinsonism, FXTAS involves impaired cognition. Our preliminary research suggests that executive cognitive functioning (ECF) is especially affected. In this study, a brief neuropsychological exam was administered to 33 men with FXTAS and 27 healthy controls. Compared with controls, individuals with FXTAS showed statistically significant impairments on measures from the Wechsler Adult Intelligence Scale, third edition (WAIS-III; verbal IQ, performance [nonverbal] IQ, verbal comprehension, perceptual organization, and processing speed). FXTAS subjects scored significantly lower on three of four measures of ECF and on two tests of information processing speed. The results provide evidence that FXTAS involves impairment of general intellectual functioning, with marked impairment of executive cognitive abilities. The pattern of cognitive performance is somewhat similar to that observed in the frontal variant of frontotemporal dementia and several of the spinocerebellar ataxias, but differs from the deficits observed in dementia of the Alzheimer type.