James A. Bourgeois

Fragile X-associated tremor/ataxia syndrome: clinical features, genetics, and testing guidelines.

Fragile X‐associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder with core features of action tremor and cerebellar gait ataxia. Frequent associated findings include parkinsonism, executive function deficits and dementia, neuropathy, and dysautonomia. Magnetic Resonance Imaging studies in FXTAS demonstrate increased T2 signal intensity in the middle cerebellar peduncles (MCP sign) in the majority of patients. Similar signal alterations are seen in deep and subependymal cerebral white matter, as is general cortical and subcortical atrophy. The major neuropathological feature of FXTAS is the presence of intranuclear, neuronal, and astrocytic, inclusions in broad distribution throughout the brain and brainstem. FXTAS is caused by moderate expansions (55–200 repeats; premutation range) of a CGG trinucleotide in the fragile X mental retardation 1 (FMR1) gene, the same gene which causes fragile X syndrome when in the full mutation range (200 or greater CGG repeats). The pathogenic mechanism is related to overexpression and toxicity of the FMR1 mRNA per se. Although only recently discovered, and hence currently under‐diagnosed, FXTAS is likely to be one of the most common single‐gene disorders leading to neurodegeneration in males. In this report, we review information available on the clinical, radiological, and pathological features, and prevalence and management of FXTAS. We also provide guidelines for the practitioner to assist with identifying appropriate patients for DNA testing for FXTAS, as well as recommendations for genetic counseling once a diagnosis of FXTAS is made.

A Review of Fragile X Premutation Disorders: Expanding the Psychiatric Perspective

CONTEXT Fragile X premutation conditions are associated with a significant degree of psychopathology and thus are of interest to the psychiatrist. Remarkable advances at the molecular level have enhanced our understanding of fragile X premutation disorders. OBJECTIVE The authors review the genetic, molecular, neuroimaging, and clinical (systemic, neurologic, and psychiatric) manifestations of the premutation carrier state (55-200 CGG repeats) of the fragile X mental retardation 1 (FMR1) gene. DATA SOURCES The search for the psychiatric clinical manifestations of fragile X-associated conditions was accomplished by PubMed for clinical papers published between 1970 and 2008 with the following search terms: Fragile X syndrome, depression, psychosis, anxiety, and dementia. STUDY SELECTION Articles addressing psychiatric symptoms in premutation carriers based on review of the abstracts were reviewed. As the majority of the literature on this topic is based on case reports and small case series, these were included in the database. RESULTS Reported clinical manifestations of psychiatric illness in premutation carriers include an apparently significant rate of cognitive, mood, anxiety, and other psychiatric disorders. Fragile X premutation-associated conditions are part of the clinical differential diagnosis of several psychiatric syndromes, particularly in pedigrees with known fragile X syndrome cases. CONCLUSIONS Fragile X-associated psychiatric manifestations serve as a useful model for a molecular genesis of neuropsychiatric illness. Because of the multigenerational expression of fragile X-associated neuropsychiatric illness, there is a prominent role for genetic testing and genetic counseling of patients and their relatives. Genetic testing is confirmatory of the FMR1 premutation and is an essential component of the clinical evaluation. Psychopharmacologic and psychotherapeutic treatment of fragile X-associated psychiatric illnesses may improve patient function and assist in adaptation to the burden of a genetic neuropsychiatric illness.

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.

Treatment of fragile X-associated tremor ataxia syndrome (FXTAS) and related neurological problems.

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a progressive neurological disorder that affects older adult carriers, predominantly males, of premutation alleles (55 to 200 CGG repeats) of the fragile X (FMR1) gene. Principal features of FXTAS are intention tremor, ataxia, parkinsonism, cognitive decline, and peripheral neuropathy; ancillary features include, autonomic dysfunction, and psychiatric symptoms of anxiety, depression, and disinhibition. Although controlled trials have not been carried out in individuals with FXTAS, there is a significant amount of anecdotal information regarding various treatment modalities. Moreover, there exists a great deal of evidence regarding the efficacy of various medications for treatment of other disorders (eg, Alzheimer disease) that have substantial phenotypic overlap with FXTAS. The current review summarizes what is currently known regarding the symptomatic treatment, or potential for treatment, of FXTAS.

Dementia in fragile X-associated tremor/ataxia syndrome (FXTAS): Comparison with Alzheimer's disease†

Neurocognitive deficits in fragile X‐associated tremor/ataxia syndrome (FXTAS) involve attentional control, working memory, executive functioning, and declarative and procedural learning. To date, no studies comparing FXTAS with other dementias have been done. We characterize the dementia in FXTAS, comparing it with Alzheimers disease. Retrospective chart review of 68 adults (50 men, 18 women) with FXTAS. 20 men with FXTAS dementia were matched by age, gender, and education to patients with mild Alzheimers dementia (AD). Neuropsychological measures were compared between the two groups: Boston Naming Test (BNT), phonemic fluency (Controlled Oral Word Association Test), digit span forward (DSF) and backward (DSB). Comparisons were based on analysis of covariance and t‐tests to assess significant differences between groups. 50% of men with FXTAS and no women were cognitively impaired. On mean scores of verbal fluency (22.83 in FXTAS vs. 28.83 in AD, P = 0.112), working memory (DSB, 4.80 in AD vs. 5.41 in FXTAS, P = 0.359), and language (BNT, 48.54 in AD vs. 54.20 in FXTAS, P = 0.089), there were no significant differences. Digit span forward, measuring attention, was significantly higher in subjects with FXTAS dementia (8.59, vs. 7.10 in AD, P = 0.010). Individuals with FXTAS have significant cognitive deficits, on the order of those in AD although the cognitive profiles in these dementias are not similar. Further research is needed to outline the neuropsychiatric profile in FXTAS and the correlation of genetic markers with the progression and severity of cognitive loss.

A retrospective analysis of a child and adolescent eMental health program

OBJECTIVE New models of psychiatric intervention are needed to improve the accessibility of mental health care in the primary care setting, particularly in rural areas of the United States and especially for children and adolescents. The aim of this study was to examine the diagnostic characteristics and outcomes for children referred for eMental Health consultations at UC Davis (videoconferencing, telephone, and secure e-mail) from 10 primary care clinics in rural northern California. METHOD : A retrospective analysis was conducted on the diagnostic and clinical outcomes of 139 referred children who received a full psychiatric diagnostic evaluation via videoconferencing. Within the group, a convenience sample of 58 initial and 41 three-month follow-up Child Behavior Checklists (CBCLs) was collected. RESULTS Comprehensive eMental Health programs appear to be effective for psychiatric diagnosis and assessment of children. Attention deficit (36.2%) and mood (28.1%) disorders were the most common diagnostic groupings overall. Most children were seen only once, but a statistically significant improvement between initial evaluation and 3-month follow-up in the convenience sample was seen in the Affect and Oppositional domains of the CBCL for girls and boys, respectively. CONCLUSIONS Versatile eMental Health programs, incorporating standardized checklists, may assist in diagnosis and treatment of rural children.

Determination of prevalence of depression in an epilepsy clinic using a brief DSM-IV-based self-report questionnaire

Depression in epilepsy is common, underrecognized, and an indicator of quality of life. The Patient Health Questionnaire nine-item depression scale (PHQ-9) is a self-administered questionnaire based on Diagnostic and Statistical Manual, Fourth Edition (DSM-IV) criteria with high sensitivity and specificity for diagnosing depression. Using the PHQ-9, we determined that one-third of 263 patients seen in an epilepsy clinic had scores consistent with major depression. Seizure-free patients had lower depression scores than those with persistent seizures. Depression scores were not related to the number or type of antiepileptic drugs used. One-half of patients with scores consistent with major depression were not on antidepressant medication. The brevity of the PHQ-9 is conducive to routine screening of patients with epilepsy.

Early onset of neurological symptoms in fragile X premutation carriers exposed to neurotoxins

We present four cases of fragile X premutation carriers with early neurological symptoms, including symptoms consistent with multiple sclerosis (MS) and fragile X-associated tremor/ataxia syndrome (FXTAS). Each patient had significant exposure to one or more environmental neurotoxicants that have documented neurotoxicity (i.e. hexachlorocyclopentadiene or C56, Agent Orange, and 2,4- or 2,6-toluene diisocyanate and dichlormate). We hypothesize that premutation carriers are a vulnerable group to neurotoxins because elevated mRNA in the premutation can lead to early cell death and brain disease, leading to neuropsychiatric and neurological symptoms consistent with FXTAS.

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 Alzheimers 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.

Ages of Onset of Mood and Anxiety Disorders in Fragile X Premutation Carriers

OBJECTIVE FMR1 premutation carriers of both genders have a high lifetime prevalence of anxiety and depressive disorders, however little is known regarding the onset ages of these conditions. This study compared onset ages of mood and anxiety disorders in premutation carriers with typical onset ages of the same disorders in the general population. METHODS Eighty-one premutation carriers (42% men; average age 62, SD 10) with and without FXTAS completed the Structured Clinical Interview for DSM-IV-TR. Onset ages of mood and anxiety disorders were compared to the corresponding typical population onset ages using the signed rank test. RESULTS Overall median onset ages of MDD (46 years old, p < 0.0001), panic disorder (40 years old, p = 0.0067), and specific phobia (11.5 years old, p = 0.0003) were significantly higher in premutation carriers compared to the general population. Median MDD onset ages in male carriers (52 years old) and those with FXTAS (49.5 years old) were significantly higher relative to the general population (median 32, both p < 0.0001). Tremor and ataxia emerged significantly later than MDD and the anxiety disorders studied. CONCLUSION Depressive and anxiety disorders in premutation carriers have a later onset compared to the general population, but precede the onset of motor symptoms. This may be due to progressive mRNA toxicity in the limbic system, white matter changes leading to neuronal dysconnectivity, and interaction with environmental factors. Psychosocial factors may be protective. Further research is needed to understand the full spectrum of psychiatric phenotypes in FMR1 premutation carriers.