Metformin as targeted treatment in fragile X syndrome.

BACKGROUND: Individuals with fragile X syndrome (FXS) have both behavioral and medical comorbidities and the latter include obesity in approximately 30% and the Prader-Willi Phenotype (PWP) characterized by severe hyperphagia and morbid obesity in less than 10%. Metformin is a drug used in individuals with type 2 diabetes, obesity or impaired glucose tolerance and it has a strong safety profile in children and adults. Recently published studies in the Drosophila model and the knock out mouse model of FXS treated with metformin demonstrate the rescue of multiple phenotypes of FXS. MATERIALS AND METHODS: We present 7 cases of individuals with FXS who have been treated with metformin clinically. One case with type 2 diabetes, 3 cases with the PWP, 2 adults with obesity and/or behavioral problems and, a young child with FXS. These individuals were clinically treated with metformin and monitored for behavioral changes with the Aberrant Behavior Checklist and metabolic changes with a fasting glucose and HgbA1c. RESULTS: We found consistent improvements in irritability, social responsiveness, hyperactivity, and social avoidance, in addition to comments from the family regarding improvements in language and conversational skills. No significant side-effects were noted and most patients with obesity lost weight. CONCLUSION: We recommend a controlled trial of metformin in those with FXS. Metformin appears to be an effective treatment of obesity including those with the PWP in FXS. Our study suggests that metformin may also be a targeted treatment for improving behavior and language in children and adults with FXS.

Characterising repetitive behaviours in young boys with fragile X syndrome.

BACKGROUND: Repetitive behaviours are frequently observed in individuals with intellectual disability (ID). The present study examined the profile, inter-correlations and predictive correlates of repetitive behaviours in boys with fragile X syndrome (FXS), the leading inherited cause of ID. Specific child characteristics examined as predictors included anxiety, nonverbal cognition and autism social-affective symptomatology. METHOD: Participants were 39 boys with FXS (aged 6-10 years). Repetitive behaviours were measured using the Repetitive Behavior Scale - Revised (RBS-R) - a 43-item caregiver-report measure normed on individuals with ID. RESULTS: Restricted Interests and Sensory Motor behaviours were reported as most problematic for this sample of boys, whereas Self-injurious behaviours were less problematic. All subscales of the RBS-R were significantly inter-correlated. Nonverbal IQ was negatively related, whereas anxiety and social affective symptoms of autism spectrum disorder were positively related, to scores for Restricted Interests. Anxiety was also positively related to scores for Compulsive behaviours and Ritualistic Sameness behaviours. CONCLUSIONS: This study provides a preliminary description of repetitive behaviours in boys with FXS, which may form the groundwork for future research.

Psychological status in female carriers of premutation FMR1 allele showing a complex relationship with the size of CGG expansion.

We utilized a sample of 299 adult females aged between 19 and 86 years, carrying fragile X mental retardation (FMR1) alleles with small CCG expansions ranging from 50 to 141 repeats to analyse the relationships between psychological symptoms as assessed by the Symptom Checklist-90-Revised (SCL-90-R) and the size of the CGG repeat in the FMR1 gene. There were highly significant (negative) correlations between the size of the CGG repeat and a great majority of SCL-90-R subscale scores and all the global indices, suggesting that carriers of premutations in the mid-size CGG repeat range may be at greatest risk for the development of psychiatric disorder.

A family with two female siblings with compound heterozygous FMR1 premutation alleles.

Premutation alleles (55-200 CGG repeats) of the fragile X mental retardation (FMR1) gene have been linked to various types of clinical involvement ranging from mood and anxiety disorders to immunological disorders and executive function deficits. Carrier females typically have a premutation allele and a normal allele (<55 CGG repeats). Although rare, seven cases of females that carry two expanded alleles (compound heterozygous premutation) have been reported. Here, we report on four members of a family including two compound heterozygous premutation sisters with similar CGG allele sizes, affected with different levels of clinical severity.

Prevalence of restless legs syndrome and sleep quality in carriers of the fragile X premutation.

This study examined the relationship between the fragile X premutation and restless legs syndrome (RLS). Demographic, medical history and survey responses related to sleep were collected from 213 participants (127 carriers and 86 age matched controls). Subjects were asked about the presence of the four formal diagnostic criteria for RLS. Individuals with the premutation were 1.9 times as likely to meet criteria for RLS (95% CI 1.1­3.2, p=0.025) as controls. Premutation carriers with RLS also experienced significantly worse symptoms than matched controls with adjusted mean scores of 15.1±8.8 vs 7.9±4.4, respectively on the International Restless Legs Scale (IRLS). As markers for domains of sleep disturbance, all subjects completed the Epworth Sleepiness Scale (ESS), the Insomnia Severity Index (ISA) and the Pittsburgh Sleep Quality Index (PSQI). Premutation carriers demonstrated significantly more pathology on these tests except for the ESS where there was a trend towards increased daytime sleepiness in carriers. RLS joins a host of other conditions that should be carefully screened for in those carrying the fragile X premutation and sleep should be a focus for clinicians providing care to them.

FXTAS in an unmethylated mosaic male with fragile X syndrome from Chile.

Carriers of an FMR1 premutation allele (55-200 CGG repeats) often develop the neurodegenerative disorders, fragile X-associated tremor/ataxia syndrome (FXTAS). Neurological signs of FXTAS, parkinsonism and rapid onset of cognitive decline have not been reported in individuals with an unmethylated full mutation (FM). Here, we report a Chilean family affected with FXS, inherited from a parent carrier of an FMR1 unmethylated full mosaic allele, who presented with a fast progressing FXTAS. This case suggests that the definition of FXTAS may need to be broadened to not only include those with a premutation but also those with an expanded allele in FM range with a lack of methylation leading to elevated FMR1-mRNA expression levels and subsequent RNA toxicity.

Fragile X-associated tremor/ataxia syndrome (FXTAS) in grey zone carriers.

The grey zone (GZ; 45-54 CGG repeats in the FMR1 gene) is considered a normal allele; however, several studies have found a high frequency of GZ in movement disordered populations. Here, we describe neurological features of fragile X-associated tremor/ataxia syndrome (FXTAS) in two carriers of GZ alleles, although FXTAS has been defined as occurring only in premutation carriers (55-200 CGG repeats). Both patients had family members who had premutation and were diagnosed with FXTAS. The presence of relatively high GZ alleles with elevated fragile X mental retardation 1 mRNA (FMR1-mRNA) combined with a family history of FXTAS that may represent a facilitating genetic background for FXTAS are the factors that led to the presence of FXTAS in these individuals with a GZ allele. Further research into clinical involvement of GZ alleles is recommended and the definition of FXTAS may require revision.

Fragile X syndrome: clinical, cytogenetic and molecular screening among autism spectrum disorder children in Indonesia.

Fragile X testing is a priority in the evaluation of autism spectrum disorders (ASD) cases because identification of the FMR1 mutation leads to new treatment options. This study is focused on determining the prevalence of the FMR1 gene mutation among ASD cases in Indonesia. DSM-IV-TR criteria were administered to diagnose ASD; symptom severity was classified using the Childhood Autism Rating Scale. Cytogenetic analysis, polymerase chain reaction, and Southern blot for FMR1 gene analysis were carried out to confirm the diagnosis of fragile X syndrome. The fragile X site and FMR1 full mutation allele were identified in 3 out of 65 (4.6%) and 4 out of 65 (6.15%) children aged 3-17 years (57 boys and 8 girls), respectively. The Fragile X laboratory workup is essential in the evaluation of patients with ASD. Molecular analysis is most accurate, while cytogenetic documentation of the fragile X site can also be useful if molecular testing is not available.

Prevalence and risk of migraine headaches in adult fragile X premutation carriers.

FMR1 premutation carriers are common in the general population (1/130-260 females and 1/250-810 males) and can be affected by fragile X-associated tremor ataxia syndrome, fragile X-associated primary ovarian insufficiency, anxiety, depression, hypertension, sleep apnea, fibromyalgia, and hypothyroidism. Here we report the results of a pilot study to assess the prevalence and risk of migraine in FMR1 premutation carriers. Three hundred fifteen carriers (203 females; 112 males) and 154 controls (83 females; 71 males) were seen sequentially as part of a family study. A standardized medical history, physical examination and confirmation of diagnosis of migraine headaches were performed by a physician. The prevalence of migraine was 54.2% in female carriers (mean age/SD: 49.60/13.73) and 26.79% in male carriers (mean age/SD: 59.94/14.27). This prevalence was higher compared to female (25.3%; mean age/SD: 47.60/15.21; p = 0.0001) and male controls (15.5%; mean age/SD; 53.88/13.31; p = 0.0406) who underwent the same protocol and were confirmed to be negative for the FMR1 mutation by DNA testing. We hypothesize that the increased prevalence of migraine headaches in FMR1 premutation carriers is likely related to the mitochondrial abnormalities that have recently been reported. Screening for migraine should be considered when evaluating FMR1 premutation carriers in the future.

The fragile X-associated tremor ataxia syndrome (FXTAS) in Indonesia.

Fragile X-associated disorders caused by the premutation of the FMR1 gene, includes the fragile X-associated tremor/ataxia syndrome (FXTAS). FXTAS affects more than 40% of premutation males over the age of 50 and 75% over the age of 80. FMR1 molecular analysis was done using PCR and confirmed by Southern Blot. Three premutation males were diagnosed FXTAS using quantification based on the standard neurological examination. Cognitive impairment was assessed using Raven and WAIS-R test. MRI was done to identify the middle cerebellar peduncle (MCP) sign, white matter disease and/or cerebral atrophy. Three cases of FXTAS are identified, of five individuals older than 50 years in one family tree two met criteria for definite FXTAS and the third with sub-clinical symptoms, although cognitive and radiological criteria are met. These cases are the first identified FXTAS cases in rural Indonesia. In addition with lack of routine medical follow-up, complications of FXTAS, such as hypertension may go unrecognized and untreated, which may further exacerbate the central nervous system (CNS) findings of FXTAS.

A white paper on a neurodevelopmental framework for drug discovery in autism and other neurodevelopmental disorders.

In the last decade there has been a revolution in terms of genetic findings in neurodevelopmental disorders (NDDs), with many discoveries critical for understanding their aetiology and pathophysiology. Clinical trials in single-gene disorders such as fragile X syndrome highlight the challenges of investigating new drug targets in NDDs. Incorporating a developmental perspective into the process of drug development for NDDs could help to overcome some of the current difficulties in identifying and testing new treatments. This paper provides a summary of the proceedings of the 'New Frontiers Meeting' on neurodevelopmental disorders organised by the European College of Neuropsychopharmacology in conjunction with the Innovative Medicines Initiative-sponsored AIMS-2-TRIALS consortium. It brought together experts in developmental genetics, autism, NDDs, and clinical trials from academia and industry, regulators, patient and family associations, and other stakeholders. The meeting sought to provide a platform for focused communication on scientific insights, challenges, and methodologies that might be applicable to the development of CNS treatments from a neurodevelopmental perspective. Multidisciplinary translational consortia to develop basic and clinical research in parallel could be pivotal to advance knowledge in the field. Although implementation of clinical trials for NDDs in paediatric populations is widely acknowledged as essential, safety concerns should guide each aspect of their design. Industry and academia should join forces to improve knowledge of the biology of brain development, identify the optimal timing of interventions, and translate these findings into new drugs, allowing for the needs of users and families, with support from regulatory agencies.

Clinical involvement in daughters of men with fragile X-associated tremor ataxia syndrome.

Women with the fragile X mental retardation 1 (FMR1) premutation often have concerns about neurological and medical problems, as they become older and if their fathers experience fragile X-associated tremor/ataxia syndrome (FXTAS). We therefore determined the prevalence of these problems in 110 daughters of men with FXTAS [mean age of 44.8 years (SD 8.2)]. We compared them with 43 female controls with normal FMR1 alleles [mean age of 43.8 years (SD 8.1)] and 36 premutation carrier daughters of parents with the premutation, but without FXTAS [mean age of 43.5 years (SD 7.7)]. Overall, daughters of men with FXTAS have a higher prevalence of neurological symptoms including tremor, balance problems, memory problems, and dizziness, menopausal symptoms, and psychiatric involvement including sleep problems and anxiety when compared with non-carrier female controls. Reported balance problems and menopausal symptoms were significantly higher in daughters of men with FXTAS than in carrier daughters of parents without FXTAS, suggesting the potential influence of background gene effects. Therefore, neurological, psychological and gynecological surveillance should be warranted to better provide appropriate counseling, management and care for daughters of men with FXTAS. Biological markers of additional gene effects that predispose individuals with the premutation to FXTAS need to be developed.

A pilot open label, single dose trial of fenobam in adults with fragile X syndrome.

OBJECTIVE: A pilot open label, single dose trial of fenobam, an mGluR5 antagonist, was conducted to provide an initial evaluation of safety and pharmacokinetics in adult males and females with fragile X syndrome (FXS). METHODS: Twelve subjects, recruited from two fragile X clinics, received a single oral dose of 50-150 mg of fenobam. Blood for pharmacokinetic testing, vital signs and side effect screening was obtained at baseline and numerous time points for 6 h after dosing. Outcome measures included prepulse inhibition (PPI) and a continuous performance test (CPT) obtained before and after dosing to explore the effects of fenobam on core phenotypic measures of sensory gating, attention and inhibition. RESULTS: There were no significant adverse reactions to fenobam administration. Pharmacokinetic analysis showed that fenobam concentrations were dose dependent but variable, with mean (SEM) peak values of 39.7 (18.4) ng/ml at 180 min after the 150 mg dose. PPI met a response criterion of an improvement of at least 20% over baseline in 6 of 12 individuals (4/6 males and 2/6 females). The CPT did not display improvement with treatment due to ceiling effects. CONCLUSIONS: Clinically significant adverse effects were not identified in this study of single dose fenobam across the range of dosages utilised. The positive effects seen in animal models of FXS treated with fenobam or other mGluR5 antagonists, the apparent lack of clinically significant adverse effects, and the potential beneficial clinical effects seen in this pilot trial support further study of the compound in adults with FXS.

Psychological symptoms correlate with reduced hippocampal volume in fragile X premutation carriers.

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder occurring in male and occasional female carriers of a premutation expansion (55-200 CGG repeats) of the fragile X mental retardation 1 gene (FMR1). This study assessed the relationship between hippocampal volume and psychological symptoms in carriers, both with and without FXTAS, and controls. Volumetric MRI measures, clinical staging, cognitive testing, molecular analysis, and measures of psychological symptoms were performed for female premutation carriers both with FXTAS (n = 16, age: 57.50 + or - 12.46) and without FXTAS (n = 17, age: 44.94 + or - 11.23), in genetically normal female controls (n = 8, age: 50.63 + or - 11.43), male carriers with FXTAS (n = 34, age: 66.44 + or - 6.77) and without FXTAS (n = 21, age: 52.38 + or - 12.11), and genetically normal male controls (n = 30, age: 57.20 + or - 14.12). We examined the relationship between psychological symptom severity and hippocampal volume, as well as correlations with molecular data. We found a significant negative correlation between total hippocampal volume and anxiety in female carriers, with and without FXTAS. This finding was mainly driven by the significant negative correlation between right hippocampal volume and anxiety. Other anxiety-related subscales also correlated with the right hippocampus in females. In male carriers with and without FXTAS, only paranoid ideation negatively correlated with hippocampal volume. Female premutation carriers demonstrated a negative association between hippocampal volume and the severity of anxiety-related psychological symptoms. Though the presentation of FXTAS symptoms is less common in females, anxiety-related problems are common both prior to and after the onset of FXTAS, and may be related to hippocampal changes.

Motor abilities of children diagnosed with fragile X syndrome with and without autism.

BACKGROUND: Previous studies suggested that children diagnosed with fragile X syndrome (FXS) often meet criteria for autism or PDD. This study describes the fine motor abilities of children diagnosed with FXS with and without autism spectrum disorder, and compares the motor scores of those groups controlling for cognitive level. METHOD: Forty-eight children, ages 12-76 months (SD = 16) diagnosed with FXS were assessed with the Mullen Scales of Early Learning, and the Autism Diagnostic Observation Schedule. Their parents were interviewed with the Autism Diagnostic Interview-Revised. We used a one-way analysis of variance to determine if the fine motor scale of the Mullen would show group differences based on autism classifications for the sample. In addition, we used Pearson correlation coefficient to examine the relationship between the cognitive level, the autism severity and the motor abilities. Lastly, we conducted a one-way analysis of covariance to determine the difference between the motor abilities of the Autism Spectrum Disorder groups controlling for cognitive level. RESULTS: We found that 60% of the children with FXS met criteria for autism or Pervasive Developmental Disorder - Not otherwise specified (PDD-NOS). Children with FXS with autism and PDD-NOS had lower fine motor scores than those without. However, there was no significant association between degree of motor impairment and communication and social impairments after controlling for cognitive level, indicating that cognitive level contributes to impaired motor abilities of children diagnosed with FXS and autism, more than the severity of autism symptoms. CONCLUSION: children with FXS and autism are at risk for impaired motor abilities. Implications for development and intervention are discussed.

[Fragile X associated tremor/ataxia syndrome: its clinical presentation, pathology, and treatment]. / Sindrome de temblor y ataxia asociado al X fragil: presentacion clinica, patologia y tratamiento.

The fragile X associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disease associated with the repetition of CGG triplets (55-200 CGG repetitions) in the FMR1 gene. The premutation of the FMR1 gene, contrasting with the full mutation (more than 200 CGG repetitions), presents an increased production of messenger and a similar or slightly decreased production of FMRP protein. FXTAS affects 40% of men and 16% of women carriers of the premutation. It presents with a wide constellation of neurological signs such as intention tremor, cerebellar ataxia, parkinsonism, executive function deficits, peripheral neuropathy and cognitive decline leading to dementia among others. In this review, we present what is currently known about the molecular mechanism, the radiological findings and the pathology, as well as the complexity of the diagnosis and management of FXTAS.

TITLE: Sindrome de temblor y ataxia asociado al X fragil: presentacion clinica, patologia y tratamiento.El sindrome de temblor y ataxia asociado al X fragil (FXTAS) es una enfermedad neurodegenerativa relacionada con la premutacion del gen FMR1. Los alelos con premutacion (55-200 repeticiones de CGG), al contrario de los alelos con mutacion completa (mas de 200 repeticiones CGG), tienen una produccion excesiva de ARN mensajero y unos niveles normales o reducidos de proteina. El FXTAS afecta al 40% de los hombres y al 16% de las mujeres portadores de la premutacion de FMR1. Se presenta con una amplia variedad de signos neurologicos, como temblor de intencion, ataxia cerebelosa, parkinsonismo, deficit en la funcion ejecutiva, neuropatia periferica y deterioro cognitivo que conduce a la demencia, entre otros. En esta revision se presenta lo que hasta ahora se conoce del mecanismo molecular, los hallazgos radiologicos y la patologia, asi como tambien la complejidad del diagnostico y el tratamiento del FXTAS.

Altered hypothalamus-pituitary-adrenal gland axis regulation in the expanded CGG-repeat mouse model for fragile X-associated tremor/ataxia syndrome.

The human FMR1 gene contains an unstable CGG-repeat in its 5' untranslated region. The repeat length in the normal population is polymorphic (5-54 CGG-repeats). Individuals carrying lengths beyond 200 CGGs (i.e. the full mutation) show hypermethylation and as a consequence gene silencing of the FMR1 gene. The absence of the gene product FMRP causes the fragile X syndrome, the most common inherited form of mental retardation. Elderly carriers of the premutation (PM), which is defined as a repeat length between 55 and 200 CGGs, can develop a progressive neurodegenerative syndrome: fragile X-associated tremor/ataxia syndrome (FXTAS). The high FMR1 mRNA levels observed in cells from PM carriers have led to the hypothesis that FXTAS is caused by a pathogenic RNA gain-of-function mechanism. Apart from tremor/ataxia, specific psychiatric symptoms have been described in PM carriers with or without FXTAS. Since these symptoms could arise from elevated stress hormone levels, we investigated hypothalamic-pituitary-adrenal (HPA) axis regulation using a knock-in mouse model with an expanded CGG-repeat in the PM range (>98 repeats) in the Fmr1 gene, which shows repeat instability, and displays biochemical, phenotypic and neuropathological characteristics of FXTAS. We show elevated levels of corticosterone in serum and ubiquitin-positive inclusions in both the pituitary and adrenal gland of 100-week-old animals. In addition, we demonstrate ubiquitin-positive inclusions in the amygdala from aged expanded CGG-repeat mice. We hypothesize that altered regulation of the HPA axis and the amygdala and higher stress hormone levels in the mouse model for FXTAS may explain associated psychological symptoms in humans.

Contrast detection in infants with fragile X syndrome.

Studies have reported that a selective deficit in visual motion processing is present in certain developmental disorders, including Williams syndrome and autism. More recent evidence suggests a visual motion impairment is also present in adults with fragile X syndrome (FXS), the most common form of inherited mental retardation. The goal of the current study was to examine low-level cortical visual processing in infants diagnosed with FXS in order to explore the developmental origin of this putative deficit. We measured contrast detection of first-order (luminance-defined) and second-order (contrast-defined) gratings at two levels of temporal frequency, 0 Hz (static) and 4 Hz (moving). Results indicate that infants with FXS display significantly higher detection thresholds only for the second-order, moving stimuli compared to mental age-matched typically developing controls.

The fragile X continuum: new advances and perspectives.

Fragile X syndrome is the world's most common hereditary cause of intellectual disability in men and to a lesser extent in women. The disorder is caused by the silencing of a single gene on the X chromosome, the Fragile X Mental Retardation Gene-1. A substantial body of research across the disciplines of molecular genetics, child psychiatry and developmental neuroscience bears testament to a decade of exciting and innovative science that has advanced our knowledge about the fragile X 'signature' or influence across cognitive and social development. The core aims of this review are to first discuss fragile X syndrome and premutation involvement in the context of current advances that demonstrate the dynamic nature of the genotype on phenotypic outcomes. Second, to discuss the implications of these recent advances for the development of clinical and educational interventions and resource tools that target specific phenotypic 'signatures' within the fragile X continuum.