RESUMO
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.
Assuntos
Transtorno Autístico , Transtornos do Neurodesenvolvimento , Criança , Descoberta de Drogas/métodos , Humanos , Transtornos do Neurodesenvolvimento/tratamento farmacológico , Transtornos do Neurodesenvolvimento/genéticaRESUMO
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.
Assuntos
Ataxia , Síndrome do Cromossomo X Frágil , Tremor , Antidepressivos/uso terapêutico , Ataxia/diagnóstico , Ataxia/diagnóstico por imagem , Ataxia/genética , Ataxia/terapia , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Estimulação Encefálica Profunda , Feminino , Proteína do X Frágil da Deficiência Intelectual/genética , Síndrome do Cromossomo X Frágil/diagnóstico , Síndrome do Cromossomo X Frágil/diagnóstico por imagem , Síndrome do Cromossomo X Frágil/genética , Síndrome do Cromossomo X Frágil/terapia , Humanos , Masculino , Memantina/uso terapêutico , Exame Neurológico , Pregnanolona/uso terapêutico , Avaliação de Sintomas , Tremor/diagnóstico , Tremor/diagnóstico por imagem , Tremor/etiologia , Tremor/genética , Tremor/terapiaRESUMO
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.
Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Síndrome do Cromossomo X Frágil/tratamento farmacológico , Obesidade/tratamento farmacológico , Síndrome de Prader-Willi/tratamento farmacológico , Adulto , Animais , Criança , Pré-Escolar , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/patologia , Feminino , Síndrome do Cromossomo X Frágil/sangue , Síndrome do Cromossomo X Frágil/genética , Síndrome do Cromossomo X Frágil/patologia , Intolerância à Glucose/sangue , Intolerância à Glucose/tratamento farmacológico , Intolerância à Glucose/genética , Intolerância à Glucose/patologia , Hemoglobinas Glicadas/metabolismo , Humanos , Masculino , Transtornos Mentais/sangue , Transtornos Mentais/tratamento farmacológico , Transtornos Mentais/patologia , Metformina/administração & dosagem , Pessoa de Meia-Idade , Obesidade/sangue , Obesidade/genética , Obesidade/patologia , Síndrome de Prader-Willi/sangue , Síndrome de Prader-Willi/genética , Síndrome de Prader-Willi/patologia , Resultado do Tratamento , Adulto JovemRESUMO
Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder affecting approximately 45% of male and 16% of female carriers of the FMR1 premutation over the age of 50 years. Currently, no effective treatment is available. We performed an open-label intervention study to assess whether allopregnanolone, a neurosteroid promoting regeneration and repair, can improve clinical symptoms, brain activity, and magnetic resonance imaging (MRI) measurements in patients with FXTAS. Six patients underwent weekly intravenous infusions of allopregnanolone (2-6 mg over 30 min) for 12 weeks. All patients completed baseline and follow-up studies, though MRI scans were not collected from 1 patient because of MRI contraindications. The MRI scans from previous visits, along with scans from 8 age-matched male controls, were also included to establish patients' baseline condition as a reference. Functional outcomes included quantitative measurements of tremor and ataxia and neuropsychological evaluations. Brain activity consisted of event-related potential N400 word repetition effect during a semantic memory processing task. Structural MRI outcomes comprised volumes of the hippocampus, amygdala, and fluid-attenuated inversion recovery hyperintensities, and microstructural integrity of the corpus callosum. The results of the study showed that allopregnanolone infusions were well tolerated in all subjects. Before treatment, the patients disclosed impairment in executive function, verbal fluency and learning, and progressive deterioration of all MRI measurements. After treatment, the patients demonstrated improvement in executive functioning, episodic memory and learning, and increased N400 repetition effect amplitude. Although MRI changes were not significant as a group, both improved and deteriorated MRI measurements occurred in individual patients in contrast to uniform deterioration before the treatment. Significant correlations between baseline MRI measurements and changes in neuropsychological test scores indicated the effects of allopregnanolone on improving executive function, learning, and memory for patients with relatively preserved hippocampus and corpus callosum, while reducing psychological symptoms for patients with small hippocampi and amygdalae. The findings show the promise of allopregnanolone in improving cognitive functioning in patients with FXTAS and in partially alleviating some aspects of neurodegeneration. Further studies are needed to verify the efficacy of allopregnanolone for treating FXTAS.
Assuntos
Ataxia/tratamento farmacológico , Síndrome do Cromossomo X Frágil/tratamento farmacológico , Pregnanolona/uso terapêutico , Tremor/tratamento farmacológico , Administração Intravenosa , Idoso , Ataxia/psicologia , Encéfalo/diagnóstico por imagem , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Encéfalo/fisiopatologia , Síndrome do Cromossomo X Frágil/psicologia , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Pregnanolona/sangue , Resultado do Tratamento , Tremor/psicologiaRESUMO
Aberrant CGG trinucleotide amplification within the FMR1 gene, which spans approximately 38 Kb of genomic DNA is almost always what leads to fragile X syndrome (FXS). However, deletions of part or the entire FMR1 gene can also cause FXS. Both CGG amplification-induced silencing and deletions result in the absence of the FMR1 gene product, FMRP. Here, we report a rare case of germinal mosaicism of a deletion encompassing approximately 300 Kb of DNA, which by removing the entire FMR1 gene led to FXS. The male proband, carrying the deletion, presented in clinic with the typical features of FXS. His mother was analyzed by FISH on metaphase chromosomes with cosmid probe c22.3 spanning the FMR1 locus, and she was found not to carry the deletion on 30 analyzed cells from peripheral blood lymphocytes. Prenatal examination of the mother's third pregnancy showed that the male fetus also had the same deletion as the proband. Following this prenatal diagnosis, FISH analysis in the mother was expanded to 400 metaphases from peripheral lymphocytes, and a heterozygous FMR1 deletion was found in three. Although this result could be considered questionable from a diagnostic point of view, it indicates that the deletion is in the ovary's germinal cells.
Assuntos
Proteína do X Frágil da Deficiência Intelectual/genética , Síndrome do Cromossomo X Frágil/genética , Deleção de Genes , Mosaicismo , Criança , Feminino , Síndrome do Cromossomo X Frágil/tratamento farmacológico , Aconselhamento Genético , Humanos , Hibridização in Situ Fluorescente , Recém-Nascido , Masculino , Gravidez , Diagnóstico Pré-Natal , Sertralina/uso terapêuticoRESUMO
OBJECTIVE: Clinical observations and a limited number of research studies provide evidence that the fragile X premutation may confer risk for autism, executive dysfunction, and psychopathology. The link to autism spectrum symptoms and social cognition deficits with the premutation remains uncertain, and thus was the focus of the present investigation. METHOD: Our sample included 131 individuals, 42 men/22 women with the FMR1 premutation (mean age = 31.83 ± 8.59 years) with a normal neurological exam, and 48 men/19 women healthy age-matched controls (mean age = 29.48 ± 7.29 years). Individuals completed a comprehensive neuropsychological battery with additional assessments for social cognition, broad autism spectrum, and obsessive-compulsive (OC) symptoms. RESULTS: Premutation carriers self-reported higher rates of autism-related symptoms (Autism Quotient; p = .001). Among males only, premutation carriers showed more atypical social interaction (p < .001) and stereotyped behavior (p = .014) during standardized clinical examination on the Autism Diagnostic Observation Schedule (ADOS) relative to controls. Female premutation carriers reported significantly higher rates of OC symptoms compared to control females (p = .012). Molecular measures defining the expanded premutation (FMR1 CGG repeat length and/or mRNA) were significantly associated with a measure of theory of mind (Reading the Mind in the Eyes Task). CONCLUSIONS: The results of this study indicate a higher rate of broad autism spectrum symptoms in some males with the premutation and provide evidence for an obsessive-compulsive subtype in female premutation carriers.
Assuntos
Transtorno do Espectro Autista/genética , Transtorno do Espectro Autista/psicologia , Proteína do X Frágil da Deficiência Intelectual/genética , Transtorno Obsessivo-Compulsivo/genética , Transtorno Obsessivo-Compulsivo/psicologia , Adulto , Transtorno do Espectro Autista/diagnóstico , Feminino , Síndrome do Cromossomo X Frágil/diagnóstico , Síndrome do Cromossomo X Frágil/genética , Síndrome do Cromossomo X Frágil/psicologia , Humanos , Masculino , Exame Neurológico , Testes Neuropsicológicos , Transtorno Obsessivo-Compulsivo/diagnóstico , Estimulação Luminosa/métodos , Comportamento Social , Adulto JovemRESUMO
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.
Assuntos
Comportamento Infantil/fisiologia , Síndrome do Cromossomo X Frágil/fisiopatologia , Comportamento Estereotipado/fisiologia , Criança , Humanos , MasculinoRESUMO
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.
Assuntos
Proteína do X Frágil da Deficiência Intelectual/genética , Síndrome do Cromossomo X Frágil/genética , Expansão das Repetições de Trinucleotídeos/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Feminino , Síndrome do Cromossomo X Frágil/fisiopatologia , Triagem de Portadores Genéticos , Humanos , Deficiência Intelectual , Pessoa de Meia-Idade , MutaçãoRESUMO
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.
Assuntos
Proteína do X Frágil da Deficiência Intelectual/genética , Mutação/genética , Síndrome das Pernas Inquietas/epidemiologia , Síndrome das Pernas Inquietas/genética , Sono , Fatores Etários , Estudos de Casos e Controles , Demografia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , Síndrome das Pernas Inquietas/fisiopatologia , Índice de Gravidade de Doença , Distúrbios do Início e da Manutenção do Sono/genéticaRESUMO
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.
Assuntos
Proteína do X Frágil da Deficiência Intelectual/genética , Síndrome do Cromossomo X Frágil/genética , Deficiência Intelectual/genética , Mutação , Adulto , Alelos , Feminino , Síndrome do Cromossomo X Frágil/patologia , Testes Genéticos , Heterozigoto , Humanos , Deficiência Intelectual/patologia , Gravidez , Irmãos , Expansão das Repetições de Trinucleotídeos/genéticaRESUMO
Fragile X-associated tremor/ataxia syndrome (FXTAS), a neurodegenerative disorder, affects fragile X (FMR1) gene premutation carriers in late life. Studies have shown cognitive impairments in FXTAS including executive dysfunction, working memory and visuospatial deficits. However, less is known about cognition in females with FXTAS. Thus, we examined semantic processing and verbal memory in female FXTAS patients with event-related potentials (ERPs) and neuropsychological testing. Sixty-one females (34 FXTAS, Mage = 62.7; 27 controls, Mage = 60.4) were studied with 32-channel ERPs during a category judgment task in which semantically congruous (50%) and incongruous items were repeated approximately 10-140 seconds later. N400 and P600 amplitude data were submitted to analysis of covariance. Neuropsychological testing demonstrated lower performance in verbal learning and executive function in females with FXTAS. Event-related potential analyses showed a significant reduction of the N400 congruity effect (incongruous - congruous) in the FXTAS group. The N400 congruity effect reduction in females with FXTAS was mainly due to increased N400 amplitude to congruous new words. No significant abnormalities of the N400 repetition effect or the P600 repetition effect were found, indicating preserved implicit memory and verbal memory, respectively, in females with FXTAS. The decreased N400 congruity effect suggests abnormal semantic expectancy and/or semantic network disorganization in female FXTAS patients. The enhanced N400 amplitude to congruous new words may reflect decreased cognitive flexibility among FXTAS women, making access to less typical category exemplar words more difficult.
Assuntos
Ataxia/fisiopatologia , Potenciais Evocados , Síndrome do Cromossomo X Frágil/fisiopatologia , Transtornos da Linguagem/genética , Diferencial Semântico , Tremor/fisiopatologia , Aprendizagem Verbal , Idoso , Ataxia/genética , Estudos de Casos e Controles , Cognição , Função Executiva , Feminino , Síndrome do Cromossomo X Frágil/genética , Humanos , Transtornos da Linguagem/fisiopatologia , Memória , Pessoa de Meia-Idade , Percepção da Fala/genética , Tremor/genéticaRESUMO
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.
Assuntos
Ataxia/genética , Metilação de DNA/genética , Proteína do X Frágil da Deficiência Intelectual/genética , Síndrome do Cromossomo X Frágil/genética , Tremor/genética , Idoso , Ataxia/complicações , Ataxia/patologia , Chile , Síndrome do Cromossomo X Frágil/complicações , Síndrome do Cromossomo X Frágil/patologia , Humanos , Masculino , Mosaicismo , Tremor/complicações , Tremor/patologiaRESUMO
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.
Assuntos
Proteína do X Frágil da Deficiência Intelectual/genética , Heterozigoto , Transtornos de Enxaqueca/epidemiologia , Transtornos de Enxaqueca/genética , Adulto , Idoso , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Transtornos de Enxaqueca/diagnóstico , Prevalência , Risco , Expansão das Repetições de TrinucleotídeosRESUMO
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.
Assuntos
Síndrome do Cromossomo X Frágil/epidemiologia , Síndrome do Cromossomo X Frágil/genética , Cariótipo Anormal , Adolescente , Criança , Transtornos Globais do Desenvolvimento Infantil/complicações , Transtornos Globais do Desenvolvimento Infantil/diagnóstico , Pré-Escolar , Análise Citogenética , Feminino , Proteína do X Frágil da Deficiência Intelectual/genética , Síndrome do Cromossomo X Frágil/complicações , Testes Genéticos , Humanos , Indonésia/epidemiologia , Masculino , Mutação , Prevalência , Análise de Sequência de DNARESUMO
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.
Assuntos
Ataxia/genética , Proteína do X Frágil da Deficiência Intelectual/genética , Síndrome do Cromossomo X Frágil/genética , Tremor/genética , Idoso , Ataxia/complicações , Saúde da Família , Feminino , Síndrome do Cromossomo X Frágil/complicações , Predisposição Genética para Doença/genética , Humanos , Indonésia , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Linhagem , Síndrome , Tremor/complicações , Expansão das Repetições de Trinucleotídeos/genéticaRESUMO
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.
Assuntos
Ataxia/genética , Proteína do X Frágil da Deficiência Intelectual/genética , Síndrome do Cromossomo X Frágil/genética , Mutação , RNA Mensageiro/genética , Tremor/genética , Repetições de Trinucleotídeos , Idoso de 80 Anos ou mais , Alelos , Ataxia/fisiopatologia , Feminino , Síndrome do Cromossomo X Frágil/fisiopatologia , Frequência do Gene , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Tremor/fisiopatologiaRESUMO
Fragile X-associated tremor/ataxia syndrome (FXTAS) is an adult-onset neurodegenerative disorder associated with premutation alleles of the fragile X mental retardation 1 (FMR1) gene. Approximately 40% of older male premutation carriers, and a smaller proportion of females, are affected by FXTAS; due to the lower penetrance the characterization of the disorder in females is much less detailed. Core clinical features of FXTAS include intention tremor, cerebellar gait ataxia and frequently parkinsonism, autonomic dysfunction and cognitive deficits progressing to dementia in up to 50% of males. In this study, we report the clinical, molecular and neuropathological findings of eight female premutation carriers. Significantly, four of these women had dementia; of the four, three had FXTAS plus dementia. Post-mortem examination showed the presence of intranuclear inclusions in all eight cases, which included one asymptomatic premutation carrier who died from cancer. Among the four subjects with dementia, three had sufficient number of cortical amyloid plaques and neurofibrillary tangles to make Alzheimer's disease a highly likely cause of dementia and a fourth case had dementia with cortical Lewy bodies. Dementia appears to be more common than originally reported in females with FXTAS. Although further studies are required, our observation suggests that in a portion of FXTAS cases there is Alzheimer pathology and perhaps a synergistic effect on the progression of the disease may occur.
Assuntos
Ataxia/genética , Encéfalo/patologia , Demência/genética , Proteína do X Frágil da Deficiência Intelectual/genética , Síndrome do Cromossomo X Frágil/genética , Tremor/genética , Idoso , Idoso de 80 Anos ou mais , Alelos , Ataxia/patologia , Demência/patologia , Feminino , Síndrome do Cromossomo X Frágil/patologia , Humanos , Corpos de Inclusão Intranuclear/genética , Corpos de Inclusão Intranuclear/patologia , Pessoa de Meia-Idade , Neurônios/patologia , Síndrome , Tremor/patologiaRESUMO
Fragile X syndrome (FXS) is the most common form of inherited intellectual disability and autism. The protein (FMRP) encoded by the fragile X mental retardation gene (FMR1), is an RNA-binding protein linked to translational control. Recently, in the Fmr1 knockout mouse model of FXS, dysregulated translation initiation signaling was observed. To investigate whether an altered signaling was also a feature of subjects with FXS compared to typical developing controls, we isolated total RNA and translational control proteins from lymphocytes of subjects from both groups (38 FXS and 14 TD). Although we did not observe any difference in the expression level of messenger RNAs (mRNAs) for translational initiation control proteins isolated from participant with FXS, we found increased phosphorylation of the mammalian target of rapamycin (mTOR) substrate, p70 ribosomal subunit 6 kinase1 (S6K1) and of the mTOR regulator, the serine/threonine protein kinase (Akt), in their protein lysates. In addition, we observed increased phosphorylation of the cap binding protein eukaryotic initiation factor 4E (eIF4E) suggesting that protein synthesis is upregulated in FXS. Similar to the findings in lymphocytes, we observed increased phosphorylation of S6K1 in brain tissue from patients with FXS (n = 4) compared to normal age-matched controls (n = 4). Finally, we detected increased expression of the cytoplasmic FMR1-interacting protein 2 (CYFIP2), a known FMRP interactor. This data verify and extend previous findings using lymphocytes for studies of neuropsychiatric disorders and provide evidence that misregulation of mTOR signaling observed in the FXS mouse model also occurs in human FXS and may provide useful biomarkers for designing targeted treatments in FXS.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/biossíntese , Síndrome do Cromossomo X Frágil/metabolismo , Transdução de Sinais/fisiologia , Serina-Treonina Quinases TOR/antagonistas & inibidores , Regulação para Cima/fisiologia , Proteínas Adaptadoras de Transdução de Sinal/genética , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Feminino , Proteína do X Frágil da Deficiência Intelectual/genética , Proteína do X Frágil da Deficiência Intelectual/metabolismo , Síndrome do Cromossomo X Frágil/genética , Regulação da Expressão Gênica/fisiologia , Humanos , Masculino , Pessoa de Meia-Idade , Cultura Primária de Células , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/fisiologia , Adulto JovemRESUMO
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.