Fragile X Syndrome (FXS) is a trinucleotide repeat disorder that results in the silencing of the Fragile X Mental Retardation 1 gene (FMR1), leading to a lack of the FMR1 protein (FMRP). FMRP is an mRNA-binding protein that regulates the translation of hundreds of mRNAs important for synaptic plasticity. Several of these pathways have been identified and have guided the development of targeted treatments for FXS. Here we present evidence that serotonin is dysregulated in FXS and treatment with the selective serotonin reuptake inhibitor (SSRI) sertraline may be beneficial for individuals with FXS, particularly in early childhood.
Fragile X Syndrome; fragile X mental retardation protein; selective serotonin reuptake inhibitors; sertraline
A debilitating late-onset disorder of the premutation in the FMR1 gene is the neurodegenerative disorder fragile X-associated tremor ataxia syndrome (FXTAS). We report two patients with FXTAS who have a history of substance abuse (opiates, alcohol, and cocaine) which may have exacerbated their rapid neurological deterioration with FXTAS. There has been no case report regarding the role of substance abuse in onset, progression, and severity of FXTAS symptoms. However, research has shown that substance abuse can have a negative impact on several neurodegenerative diseases, and we propose that in these cases, substance abuse contributed to a faster progression of FXTAS as well as exacerbated white matter disease.
Substance abuse; neurological deterioration; FXTAS; premutation; opiates
This report seeks to establish the prevalence of sleep apnea in patients with the FMR1 premutation with and without FXTAS and to determine any correlation between CGG repeat and FMR1 mRNA levels with sleep apnea prevalence. Demographic and medical data from 430 (229 males, 201 females) participants were used in this analysis. Participants included premutation carriers with (n=118) and without FXTAS (n=174) as well as controls without the premutation (n=123). Logistic regression models were employed to estimate the odds ratio of sleep apnea relative to controls, adjusted for age and gender, and also to examine potential association with CGG size and FMR1 mRNA expression level. The observed proportion of sleep apnea in premutation carriers with and without FXTAS and controls are 31.4% (37/118), 8.6% (15/174), and 13.8% (17/123), respectively. The adjusted odds of sleep apnea for premutation carriers with FXTAS is about 3.4 times that compared to controls (odds ratio, OR=3.4, 95% CI 1.8 to 7.4; p=0.001), and similarly relative to premutation carriers without FXTAS (OR=2.9, 95% CI 1.2 to 6.9; p=0.014). The risk of sleep apnea was not different between controls and premutation carriers without FXTAS. The presence of sleep apnea is not associated with CGG repeat numbers nor FMR1 mRNA expression level among premutation carriers. Our data supports a higher prevalence and risk of sleep apnea in patients with FXTAS. We recommend that all patients diagnosed with FXTAS be screened for sleep apnea given the negative and perhaps accelerative impact sleep apnea may have on their FXTAS progression.
sleep apnea; fragile X-associated tremor/ataxia syndrome; trinucleotide repeat diseases; mitochondrial disorders; gait disorders/ataxia
The relative risk of immune-mediated disorders (IMDs) among women carrier of premutation alleles is estimated by a survey for IMDs among 344 carrier women (age 19 to 81 years; mean 46.35 and SD 12.60) and 72 controls (age 18 to 87 years; mean 52.40 and SD 15.40). One hundred fifty four (44.77%) women carrier had at least one IMD, as did 20 controls (27.78%). Among women carrier, autoimmune thyroid disorder was the most common (24.4%), then fibromyalgia (10.2%), irritable bowel syndrome (IBS; 9.9%), Raynaud’s phenomenon (7.6%), rheumatoid arthritis (RA; 3.8%), Sjögren syndrome (2.6%), systemic lupus erythematosus (SLE; 2.03%), multiple sclerosis (1.74%). Of 55 carriers age 40 or older with FXTAS, 72.73% had at least one IMD, compared to 46.54% of those without FXTAS (n=159), and 31.58% of controls (n=57). The estimated odds ratio (OR) for IMD is 2.6 (95% CI 1.2–5.6, p = 0.015) for women with FXTAS relative to those without FXTAS; the likelihood of IMD in carriers without or with FXTAS was also significantly higher than for controls (OR 2.1, 95% CI 1.1–4.2, p = 0.034; OR 5.5, 95% CI 2.4–12.5, p < 0.001 respectively). Similarly, the odds of having an IMD among carriers with FXPOI is about 2.4 times higher when compared to carriers without FXPOI (95% CI 1.1–5.0; p = 0.021). The likelihood of IMD in carriers with or without FXPOI is greater (OR 2.4, 95% CI 1.1–5.0; p = 0.021) compared to that of controls.
Autoimmune; FXTAS; RNA toxicity; ovarian insufficiency
Minocycline can rescue the dendritic spine and synaptic structural abnormalities in the fragile X knock-out mouse. This is a review and preliminary survey to document side effects and potential outcome measures for minocycline use in the treatment of individuals with fragile X syndrome. We surveyed 50 patients with fragile X syndrome who received minocycline for at least 2 weeks and found that the most common reported side effect is gastrointestinal difficulty, including loss of appetite. The families reported an improvement in language and behavioral areas. Outcome measures in the design of future randomized clinical trials should include both behavioral and language measures. As with any other treatments, we emphasize that randomized clinical trials are needed to determine the efficacy of minocycline in fragile X syndrome.
Fragile X-associated tremor ataxia syndrome (FXTAS) is a late onset neurodegenerative disease that affects carriers of the fragile X premutation. This study seeks to assess hypertension risk and susceptibility in male premutation carriers with FXTAS. Although many symptoms and diagnostic criteria have been identified, hypertension risk has not been examined in this population. Data from 92 premutation carriers without FXTAS, 100 premutation carriers with FXTAS, and 186 controls was collected via patient medical interview. Age-adjusted logistic regression analysis was used to examine the relative odds of hypertension. We observed a significantly elevated odds ratio (OR) of hypertension relative to controls for premutation carriers with FXTAS (OR = 3.22, 95% CI: 1.72–6.04; P = 0.0003) among participants over 40-year old. The age-adjusted estimated odds of hypertension in premutation carriers without FXTAS in the over 40-year-old age group was higher compared to controls (OR = 1.61, 95% CI: 0.82–3.16), but was not statistically significant (P = 0.164). Chronic hypertension contributes to cardiovascular complications, dementia, and increased risk of stroke. Our results indicate that the risk of hypertension is significantly elevated in male premutation carriers with FXTAS compared with carriers without FXTAS and controls. Thus, evaluation of hypertension in patients diagnosed with FXTAS should be a routine part of the treatment monitoring and intervention for this disease.
hypertension; FMR1 premutation; fragile X-associated tremor/ataxia syndrome; autonomic disease
Fragile X Syndrome (FXS), the most common inherited cause of intellectual disabilities, is an X-linked dominant disorder caused by the amplification of a CGG repeat in the 5′ untranslated region of the fragile X mental retardation gene 1 (FMR1). Prevalence estimates of the disorder are approximately 1/3600. Psychiatric manifestations of the disorder include anxiety, attention deficit hyperactivity disorder, autism, mood instability and aggression. In this article we review the above psychiatric manifestations and challenges to accurate assessment. We also discuss how the neurobiological underpinnings of these symptoms are beginning to be understood and can help guide treatment.
assessment; fragile X syndrome; neurobiology; psychiatric symptoms; treatment
Carriers of the FMR1 premutation (with 55-200 CGG repeats) may present with multiple medical and psychiatric disorders. Middle-aged carriers (males more often than females) may suffer from fragile X-associated tremor/ataxia syndrome (FXTAS). FXTAS is a newly discovered neurodegenerative disease characterized by intention tremor and ataxia, along with several other neurological features. Psychiatric manifestations are common in premutation carriers of both genders and include attention deficits, anxiety, depression, irritability, impulse dyscontrol, and substance abuse or dependence. Major depressive disorder, panic disorder with or without agoraphobia, generalized anxiety disorder, social phobia, and specific phobia are among the psychiatric diagnoses often encountered in premutation carriers, including those with FXTAS. Later in the course of the illness, cognitive deficits (including dementia) may occur. In this paper, we discuss common psychiatric phenotypes in FXTAS, based on a thorough review of the literature, as well as our own research experience. Symptomatic pharmacologic treatments are available, although disease modifying agents have not yet been developed.
anxiety; depression; FXTAS; FMR1 premutation; psychiatric disorders; substance abuse
Memantine, an NMDA receptor uncompetitive antagonist, is currently approved by the Food and Drug Administration for the treatment of moderate to severe Alzheimer’s disease. Anecdotal reports have suggested that memantine may improve neurological and cognitive symptoms of individuals with the neurodegenerative disease, fragile X-associated tremor tremor/ataxia syndrome (FXTAS); however, its efficacy and safety in this population have not been assessed in a controlled trial.
A randomized, double-blind, placebo-controlled, one-year trial in individuals with FXTAS ages 34–80 years. Primary outcome measures were the Behavioral Dyscontrol Scale (BDS) score and CATSYS intention tremor severity.
Ninety-four participants were randomized from 205 screened; of those, 43 and 45 started memantine (titrated to 10 mg twice daily) and placebo, respectively. Thirty-four participants on memantine and 36 on placebo completed the one-year endpoint assessment (n=70). Intention-to-treat analysis showed that there was no improvement with respect to intention tremor severity (memantine vs. placebo: 1.05 ± 0.73 vs. 1.89 ± 2.19, p=0.047) and BDS score (16.12 ± 5.43 vs. 15.72 ± 3.93, p=0.727) at follow-up. Post hoc analyses of participants with early FXTAS (stage ≤ 3), late FXTAS (stage > 3) and different age groups (≤ 65 years and > 65 years) also indicated no significant improvement. More frequent mild adverse events (AEs) were observed in the placebo group, while more frequent moderate AEs occurred in the memantine group (p=0.007).
This randomized, double-blind, placebo-controlled trial of memantine for individuals with FXTAS showed no benefit with respect to the selected outcome measures compared to placebo.
Young children with fragile X syndrome (FXS) often experience anxiety, irritability, and hyperactivity related to sensory hyperarousal. However, there are no medication recommendations with documented efficacy for children under 5 years old of age with FXS. We examined data through a chart review for 45 children with FXS, 12–50 months old, using the Mullen Scales of Early Learning (MSEL) for baseline and longitudinal assessments. All children had clinical level of anxiety, language delays based on MSEL scores, and similar early learning composite (ELC) scores at their first visit to our clinic. Incidence of autism spectrum disorder (ASD) was similar in both groups. There were 11 children who were treated with sertraline, and these patients were retrospectively compared to 34 children who were not treated with sertraline by chart review. The baseline assessments were done at ages ranging from 18 to 44 months (mean 26.9, SD 7.99) and from 12 to 50 months (mean 29.94, SD 8.64) for treated and not treated groups, respectively. Mean rate of improvement in both expressive and receptive language development was significantly higher in the group who was treated with sertraline (P < 0.0001 and P = 0.0071, resp.). This data supports the need for a controlled trial of sertraline treatment in young children with FXS.
Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability due to an expansion in the full mutation range (>200 CGG repeats) of the promoter region of the FMR1 gene leading to gene silencing. Lack of FMRP, a critical protein for dendritic spine formation and maturation, will cause FXS. Early environmental enrichment combined with pharmacological intervention has been proven to rescue dendritic spine abnormalities in the animal model of FXS. Here we report on 2 young children with FXS who were treated early with a combination of targeted treatment and intensive educational interventions leading to improvement in their cognition and behavior and a normal IQ.
In light of evidence that receptive language may be a relative weakness for individuals with autism spectrum disorder (ASD), this study characterized receptive vocabulary profiles in boys with ASD using cross-sectional developmental trajectories relative to age, nonverbal cognition, and expressive vocabulary. Participants were 49 boys with ASD (4–11 years) and 80 typically developing boys (2–11 years). Receptive vocabulary, assessed with the Peabody Picture Vocabulary Test, was a weakness for boys with ASD relative to age and nonverbal cognition. Relative to expressive vocabulary, assessed with the Expressive Vocabulary Test, receptive vocabulary increased at a lower rate for boys with ASD. Vocabulary trajectories in ASD are distinguished from typical development; however, nonverbal cognition largely accounts for the patterns observed.
Autism; Language development; Comprehension; Production; Vocabulary; Trajectory
Executive dysfunction in fragile X-associated tremor/ataxia syndrome (FXTAS) has been suggested to mediate other cognitive impairments. In the present study, event-related potentials and neuropsychological testing were combined to investigate the brain mechanisms underlying the executive dysfunction in FXTAS. Thirty-two-channel electroencephalography was recorded during an auditory “oddball” task requiring dual responses. FXTAS patients (N= 41, mean age= 62) displayed prolonged latencies of N1 and P3 and reduced amplitudes of P2 and P3, whereas their N2 measures remained within the normal range, indicating relatively preserved early-stage auditory attention but markedly impaired late-stage attention and working memory updating processes (as indexed by P3). Topographical mapping revealed a typical parietal P3 peak preceded by a prominent fronto-central P3 in normal control subjects (N= 32), whereas FXTAS patients had decreased parietal P3 amplitude and diminished fronto-central positivities with a delayed onset (∼50 ms later than controls, P < 0.002). The P3 abnormalities were associated with lower executive function test (e.g., BDS-2) scores. Smaller P3 amplitudes also correlated with increased CGG repeat length of fragile X mental retardation 1 (FMR1) gene and higher FMR1 mRNA levels. These results indicate that abnormal fronto-parietal attentional network dynamics underlie executive dysfunction, the cardinal feature of cognitive impairment in FXTAS.
attention; executive function; FMR1; P300; working memory
The fragile X mental retardation 1 gene (FMR1), which codes for the fragile X mental retardation 1 protein (FMRP), is located at Xp27.3. The normal allele of the FMR1 gene typically has 5 to 40 CGG repeats in the 5′ untranslated region; abnormal alleles of dynamic mutations include the full mutation (> 200 CGG repeats), premutation (55–200 CGG repeats) and the gray zone mutation (45–54 CGG repeats). Premutation carriers are common in the general population with approximately 1 in 130–250 females and 1 in 250–810 males, whereas the full mutation and Fragile X syndrome (FXS) occur in approximately 1 in 4000 to 1 in 7000. FMR1 mutations account for a variety of phenotypes including the most common monogenetic cause of inherited intellectual disability (ID) and autism (FXS), the most common genetic form of ovarian failure, the fragile X-associated primary ovarian insufficiency (FXPOI, premutation); and fragile X-associated tremor/ataxia syndrome (FXTAS, premutation). The premutation can also cause developmental problems including ASD and ADHD especially in boys and psychopathology including anxiety and depression in children and adults. Some premutation carriers can have a deficit of FMRP and some unmethylated full mutation individuals can have elevated FMR1 mRNA that is considered a premutation problem. Therefore the term “Fragile X Spectrum Disorder” (FXSD) should be used to include the wide range of overlapping phenotypes observed in affected individuals with FMR1 mutations. In this review we focus on the phenotypes and genotypes of children with FXSD.
Fragile X syndrome; autism spectrum disorder; intellectual disability; developmental delay; premutation
The use of touchscreen applications for the iPad® allows children with disabilities to improve their personal autonomy and quality of life. In light of this emerging literature and our clinical experience with toddlers and children with Fragile X syndrome (FXS), a randomized clinical trial pilot study was conducted of whether an interactive iPad®-based parent training program was efficacious for both individuals with FXS and autism spectrum disorder aged 2-to-12 compared to wait-listed controls. As a second goal, we assessed the difference between direct person-to-person therapy vs. online therapy sessions through telehealth. In this case series report it is presented preliminary results of four individuals with FXS enrolled in the study and described the innovative experience including qualitative and quantitative data analysis. Furthermore, we provide professionals with specific guidelines about the use of touchscreen devices as in-home learning tools and parent training strategies to actively involve families in educational treatments in conjunction with clinical guidance.
Touchscreen devices; educational applications; parent training; innovative therapy
We report the clinical presentation and laboratory findings of a 69-year-old man with fragile X-associated tremor ataxia syndrome (FXTAS), a progressive neurodegenerative disorder, who was noted to have monoclonal gammopathy of undetermined significance (MGUS), a plasma cell proliferative disorder and a precursor disease of multiple myeloma. Both MGUS and FXTAS are associated with microRNA (miRNA) dysregulation. We speculate that individuals with FXTAS may be predisposed to MGUS and further studies are warranted regarding this association.
The fragile X-associated tremor/ataxia syndrome (FXTAS) is a relatively common cause of balance problems leading to gait disturbances in older males (40%) with the premutation. FXTAS is less common in females. We utilized the CATSYS system, a quantitative measure of movement, in 23 women with FXTAS (mean age 62.7; SD 12.3), 90 women with the premutation without FXTAS (mean age 52.9; SD 9.4), and 37 controls (mean age 56.53; SD 7.8). CATSYS distinguished differences between carriers with and without FXTAS in postural tremor, postural sway, hand coordination, and reaction time tasks. Differences were also seen between carriers without FXTAS and controls in finger tapping, reaction time, and one postural sway task. However, these differences did not persist after statistical correction for multiple comparisons. Notably, there were no differences across groups in intention tremor. This is likely due to the milder symptoms in females compared to males with FXTAS.
Multiple sclerosis (MS) and fragile X–associated tremor/ataxia syndrome (FXTAS) have overlapping clinical signs and symptoms.
To present a case with evidence of both MS and FXTAS and to discuss the relationship of both disorders.
Fragile X Research and Treatment Center at the University of California, Davis, Medical Center.
Woman with the FMR1 premutation who died of MS at the age of 52 years.
Main Outcome Measures
Magnetic resonance imaging, physical examination, and neuropathologic examination results.
Magnetic resonance imaging, physical examination, and autopsy neuropathologic examination revealed diagnostic features of MS and FXTAS.
The molecular mechanism of RNA toxicity, including the elevation of αB-crystallin levels observed in FXTAS, may lead to enhanced predisposition to autoimmune diseases.
Expansions of more than 200 CGG repeats (full mutation) in the FMR1 gene give rise to fragile X syndrome (FXS) through a process that generally involves hypermethylation of the FMR1 promoter region and gene silencing, resulting in absence of expression of the encoded protein, FMRP. However, mosaicism with alleles differing in size and extent of methylation often exist within or between tissues of individuals with FXS. In the current work, CGG-repeat lengths and methylation status were assessed for eighteen individuals with FXS, including 13 mosaics, for which peripheral blood cells (PBMCs) and primary fibroblast cells were available. Our results show that for both PBMCs and fibroblasts, FMR1 mRNA and FMRP expression are directly correlated with the percent of methylation of the FMR1 allele. In addition, Full Scale IQ scores were inversely correlated with the percent methylation and positively correlated with higher FMRP expression. These latter results point toward a positive impact on cognition for full mutation mosaics with lower methylation compared to individuals with fully methylated, full mutation alleles. However, we did not observe a significant reduction in the number of seizures, nor in the severity of hyperactivity or autism spectrum disorder, among individuals with mosaic genotypes in the presentation of FXS. These observations suggest that low, but non-zero expression of FMRP may be sufficient to positively impact cognitive function in individuals with FXS, with methylation mosaicism (lowered methylation fraction) contributing to a more positive clinical outcome.
mosaicism; fragile X; FMR1; FMRP; methylation; premutation
Fragile X syndrome (FXS) is the most common genetic cause of intellectual disability and the most common single-gene cause of autism. It is caused by mutations on the fragile X mental retardation gene (FMR1) and lack of fragile X mental retardation protein, which in turn, leads to decreased inhibition of translation of many synaptic proteins. The metabotropic glutamate receptor (mGluR) hypothesis states that the neurological deficits in individuals with FXS are due mainly to downstream consequences of overstimulation of the mGluR pathway. The main efforts have focused on mGluR5 targeted treatments; however, investigation on the gamma-aminobutyric acid (GABA) system and its potential as a targeted treatment is less emphasized. The fragile X mouse models (Fmr1-knock out) show decreased GABA subunit receptors, decreased synthesis of GABA, increased catabolism of GABA, and overall decreased GABAergic input in many regions of the brain. Consequences of the reduced GABAergic input in FXS include oversensitivity to sensory stimuli, seizures, and anxiety. Deficits in the GABA receptors in different regions of the brain are associated with behavioral and attentional processing deficits linked to anxiety and autistic behaviors. The understanding of the neurobiology of FXS has led to the development of targeted treatments for the core behavioral features of FXS, which include social deficits, inattention, and anxiety. These symptoms are also observed in individuals with autism and other neurodevelopmental disorders, therefore the targeted treatments for FXS are leading the way in the treatment of other neurodevelopmental syndromes and autism. The GABAergic system in FXS represents a target for new treatments. Herein, we discuss the animal and human trials of GABAergic treatment in FXS. Arbaclofen and ganaxolone have been used in individuals with FXS. Other potential GABAergic treatments, such as riluzole, gaboxadol, tiagabine, and vigabatrin, will be also discussed. Further studies are needed to determine the safety and efficacy of GABAergic treatments for FXS.
gamma-aminobutyric acid (GABA) system; targeted treatments; autism; ganaxolone; arbaclofen
Fragile X syndrome is the world’s most common hereditary cause of
developmental delay in males and is now well characterized at the biological,
brain and cognitive levels. The disorder is caused by the silencing of a single
gene on the X chromosome, the FMR1 gene. The premutation
(carrier) status, however, is less well documented but has an emerging
literature that highlights a more subtle profile of executive cognitive
deficiencies that mirror those reported in fully affected males. Rarely,
however, has the issue of age-related declines in cognitive performance in
premutation males been addressed. In the present study we focus specifically on
the cognitive domain of working memory and its sub-components (verbal, spatial
and central executive memory) and explore performance across a broad sample of
premutation males aged 18–69 years matched on age and IQ to unaffected
comparison males. We further tease apart the premutation status into those males
with symptoms of the newly identified neurodegenerative disorder, the fragile
X-associated tremor/ataxia syndrome (FXTAS) and those males currently
symptom-free. Our findings indicate a specific vulnerability in premutation
males on tasks that require simultaneous manipulation and storage of new
information, so-called executive control of memory. Furthermore, this
vulnerability appears to exist regardless of the presence of FXTAS symptoms.
Males with FXTAS symptoms demonstrated a more general impairment encompassing
phonological working memory in addition to central executive working memory.
Among asymptomatic premutation males, we observed the novel finding of a
relationship between increased CGG repeat size and impairment to central
executive working memory.
Fragile X syndrome; Fragile X tremor and ataxia syndrome; premutation status; working memory; central executive; phonological loop; visual-spatial sketchpad; development; aging
The mutations in the FMR1 gene have been described as a family of disorders called fragile X-associated disorders (FXD) including fragile X syndrome (FXS), fragile X-associated tremor/ ataxia syndrome (FXTAS), primary ovarian insufficiency and other problems associated with the premutation, such as hypothyroidism, hypertension, neuropathy, anxiety, depression, attention deficit hyperactivity disorders and autism spectrum disorders. The premutation is relatively common in the general population affecting 1 of 130–250 female individuals and 1 of 250–800 male individuals. Therefore, to provide appropriate treatment and genetic counseling for all of the carriers and affected individuals in a family, a detailed family history that reviews many of the disorders that are related to both the premutation and the full mutation should be carried out as exemplified in these cases.
To facilitate the integration of this knowledge into clinical practice, this is the first case report that demonstrates only premutation involvement across 3 generations.
A premutation (PM) expansion (55–200 CGG) in the fragile X mental retardation gene 1 (FMR1) causes elevated mRNA and reduced FMR1 protein (FMRP). Young PM carriers can develop characteristic physical features and mild cognitive disabilities. In addition, individuals with PM, particularly male carriers, are at high risk to develop Fragile X-associated tremor/ataxia syndrome (FXTAS) with aging. Human post-mortem FXTAS brains show extensive white matter disease in the cerebellum and the presence of intranuclear inclusions throughout the brain, although their etiological significance is unknown. In the current work, expression levels of the metabotropic glutamate (Glu) receptor mGluR5 and the Glu transporter EAAT1, examined by RT-PCR and WB analyses, were found to be reduced in the post-mortem cerebellum of PM carriers with FXTAS compared to age matched controls, with higher CGG repeat number having greater reductions in both proteins. These data suggests a dysregulation of Glu signaling in PM carriers, which would likely contribute to the development and severity of FXTAS.
FMR1; FMRP; premutation; Fragile X Tremor/Ataxia Syndrome; FXTAS; Glu transporters; EAAT1; EAAT2; mGluR5
Fragile X-associated tremor/ataxia syndrome (FXTAS) is generally considered to be uncommon in older female carriers of premutation alleles (55–200 CGG repeats) of the fragile X mental retardation 1 (FMR1) gene; however, neither prevalence, nor the nature of the clinical phenotype, has been well characterized in female carriers. In this study, we evaluated 146 female carriers (mean, 42.3 years; range, 20–75 years) with and without core features of FXTAS (tremor; gait ataxia), and 69 age-matched controls (mean, 45.8 years; range, 21–78 years). Compared with controls, carriers with definite or probable FXTAS had greater medical co-morbidity, with increased prevalence of thyroid disease (P = 0.0096), hypertension (P = 0.0020), seizures (P = 0.0077), peripheral neuropathy (P = 0.0040), and fibromyalgia (P = 0.0097), in addition to the typical symptoms of FXTAS–tremor (P <0.0001) and ataxia (P <0.0001). The non-FXTAS premutation group had more complaints of chronic muscle pain (P = 0.0097), persistent paraesthesias in extremities (P < 0.0001), and history of tremor (P <0.0123) than controls. The spectrum of clinical involvement in female carriers with FXTAS is quite broad, encompassing a number of medical co-morbidities as well as the core movement disorder. The remarkable degree of thyroid dysfunction (17% in the non-FXTAS group and 50% in the FXTAS group) warrants consideration of thyroid function studies in all female premutation carriers, particularly those with core features of FXTAS.
FXTAS; fragile X premutation; neuropathy; hypothyroidism