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.

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.

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.

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.

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.

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.

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.