RESUMO
Fragile X syndrome (FXS) is the most common genetic cause of autism spectrum disorder engendered by transcriptional silencing of the fragile X messenger ribonucleoprotein 1 (FMR1) gene. Given the early onset of behavioral and molecular changes, it is imperative to know the optimal timing for therapeutic intervention. Case reports documented benefits of metformin treatment in FXS children between 2 and 14 y old. In this study, we administered metformin from birth to Fmr1-/y mice which corrected up-regulated mitogen-2 activated protein kinase/extracellular signal-regulated kinase and mammalian/mechanistic target of rapamycin complex 1 signaling pathways and specific synaptic mRNA-binding targets of FMRP. Metformin rescued increased number of calls in ultrasonic vocalization and repetitive behavior in Fmr1-/y mice. Our findings demonstrate that in mice, early-in-life metformin intervention is effective in treating FXS pathophysiology.
Assuntos
Proteína do X Frágil da Deficiência Intelectual , Síndrome do Cromossomo X Frágil , Metformina , Metformina/farmacologia , Metformina/uso terapêutico , Síndrome do Cromossomo X Frágil/tratamento farmacológico , Síndrome do Cromossomo X Frágil/genética , Síndrome do Cromossomo X Frágil/fisiopatologia , Síndrome do Cromossomo X Frágil/metabolismo , Animais , Proteína do X Frágil da Deficiência Intelectual/genética , Proteína do X Frágil da Deficiência Intelectual/metabolismo , Camundongos , Masculino , Camundongos Knockout , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Modelos Animais de Doenças , Transdução de Sinais/efeitos dos fármacosRESUMO
Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability and is the leading known single-gene cause of autism spectrum disorder. Patients with FXS display varied behavioural deficits that include mild to severe cognitive impairments in addition to mood disorders. Currently, there is no cure for this condition; however, there is an emerging focus on therapies that inhibit mechanistic target of rapamycin (mTOR)-dependent protein synthesis owing to the clinical effectiveness of metformin for alleviating some behavioural symptoms in FXS. Adiponectin (APN) is a neurohormone that is released by adipocytes and provides an alternative means to inhibit mTOR activation in the brain. In these studies, we show that Fmr1 knockout mice, like patients with FXS, show reduced levels of circulating APN and that both long-term potentiation (LTP) and long-term depression (LTD) in the dentate gyrus (DG) are impaired. Brief (20 min) incubation of hippocampal slices in APN (50 nM) was able to rescue both LTP and LTD in the DG and increased both the surface expression and phosphorylation of GluA1 receptors. These results provide evidence for reduced APN levels in FXS playing a role in decreasing bidirectional synaptic plasticity and show that therapies which enhance APN levels may have therapeutic potential for this and related conditions.This article is part of a discussion meeting issue 'Long-term potentiation: 50 years on'.
Assuntos
Adiponectina , Giro Denteado , Modelos Animais de Doenças , Proteína do X Frágil da Deficiência Intelectual , Síndrome do Cromossomo X Frágil , Camundongos Knockout , Plasticidade Neuronal , Animais , Síndrome do Cromossomo X Frágil/fisiopatologia , Síndrome do Cromossomo X Frágil/tratamento farmacológico , Síndrome do Cromossomo X Frágil/metabolismo , Giro Denteado/metabolismo , Giro Denteado/efeitos dos fármacos , Camundongos , Plasticidade Neuronal/efeitos dos fármacos , Proteína do X Frágil da Deficiência Intelectual/metabolismo , Proteína do X Frágil da Deficiência Intelectual/genética , Adiponectina/metabolismo , Potenciação de Longa Duração/efeitos dos fármacos , Masculino , Receptores de AMPA/metabolismoRESUMO
Fragile X syndrome (FXS) is associated with disrupted cognition and sleep abnormalities. Sleep loss negatively impacts cognitive function, and one untested possibility is that disrupted cognition in FXS is exacerbated by abnormal sleep. We tested whether ML297, a hypnotic acting on G-protein-activated inward-rectifying potassium (GIRK) channels, could reverse sleep phenotypes and disrupted memory in Fmr1-/y mice. Fmr1-/y mice exhibit reduced non-rapid eye movement (NREM) sleep and fragmented NREM architecture, altered sleep electroencephalogram (EEG) oscillations, and reduced EEG coherence between cortical areas; these are partially reversed following ML297 administration. Treatment following contextual fear or spatial learning restores disrupted memory consolidation in Fmr1-/y mice. During memory recall, Fmr1-/y mice show an altered balance of activity among hippocampal principal neurons vs. parvalbumin-expressing interneurons; this is partially reversed by ML297. Because sleep disruption could impact neurophysiological phenotypes in FXS, augmenting sleep may improve disrupted cognition in this disorder.
Assuntos
Modelos Animais de Doenças , Eletroencefalografia , Proteína do X Frágil da Deficiência Intelectual , Síndrome do Cromossomo X Frágil , Transtornos da Memória , Sono , Animais , Síndrome do Cromossomo X Frágil/fisiopatologia , Síndrome do Cromossomo X Frágil/tratamento farmacológico , Síndrome do Cromossomo X Frágil/complicações , Transtornos da Memória/fisiopatologia , Transtornos da Memória/tratamento farmacológico , Camundongos , Sono/efeitos dos fármacos , Sono/fisiologia , Proteína do X Frágil da Deficiência Intelectual/metabolismo , Proteína do X Frágil da Deficiência Intelectual/genética , Masculino , Hipnóticos e Sedativos/farmacologia , Hipnóticos e Sedativos/uso terapêutico , Hipocampo/metabolismo , Hipocampo/fisiopatologia , Camundongos Endogâmicos C57BL , Medo , Consolidação da Memória/efeitos dos fármacosRESUMO
Fragile X syndrome (FXS) is a genetic disorder characterized by mutation in the FMR1 gene, leading to the absence or reduced levels of fragile X Messenger Ribonucleoprotein 1 (FMRP). This results in neurodevelopmental deficits, including autistic spectrum conditions. On the other hand, Fragile X-associated tremor/ataxia syndrome (FXTAS) is a distinct disorder caused by the premutation in the FMR1 gene. FXTAS is associated with elevated levels of FMR1 mRNA, leading to neurodegenerative manifestations such as tremors and ataxia.Mounting evidence suggests a link between both syndromes and mitochondrial dysfunction (MDF). In this minireview, we critically examine the intricate relationship between FXS, FXTAS, and MDF, focusing on potential therapeutic avenues to counteract or mitigate their adverse effects. Specifically, we explore the role of mitochondrial cofactors and antioxidants, with a particular emphasis on alpha-lipoic acid (ALA), carnitine (CARN) and Coenzyme Q10 (CoQ10). Findings from this review will contribute to a deeper understanding of these disorders and foster novel therapeutic strategies to enhance patient outcomes.
Assuntos
Síndrome do Cromossomo X Frágil , Doenças Mitocondriais , Humanos , Síndrome do Cromossomo X Frágil/tratamento farmacológico , Síndrome do Cromossomo X Frágil/genética , Tremor/tratamento farmacológico , Tremor/genética , Antioxidantes/uso terapêutico , Ataxia/tratamento farmacológico , Ataxia/genética , Proteína do X Frágil da Deficiência Intelectual/genéticaRESUMO
Cannabidiol (CBD), a non-psychotomimetic constituent of Cannabis sativa, has been recently approved for epileptic syndromes often associated with Autism spectrum disorder (ASD). However, the putative efficacy and mechanism of action of CBD in patients suffering from ASD and related comorbidities remain debated, especially because of the complex pharmacology of CBD. We used pharmacological, immunohistochemical and biochemical approaches to investigate the effects and mechanisms of action of CBD in the recently validated Fmr1-Δexon 8 rat model of ASD, that is also a model of Fragile X Syndrome (FXS), the leading monogenic cause of autism. CBD rescued the cognitive deficits displayed by juvenile Fmr1-Δexon 8 animals, without inducing tolerance after repeated administration. Blockade of CA1 hippocampal GPR55 receptors prevented the beneficial effect of both CBD and the fatty acid amide hydrolase (FAAH) inhibitor URB597 in the short-term recognition memory deficits displayed by Fmr1-Δexon 8 rats. Thus, CBD may exert its beneficial effects through CA1 hippocampal GPR55 receptors. Docking analysis further confirmed that the mechanism of action of CBD might involve competition for brain fatty acid binding proteins (FABPs) that deliver anandamide and related bioactive lipids to their catabolic enzyme FAAH. These findings demonstrate that CBD reduced cognitive deficits in a rat model of FXS and provide initial mechanistic insights into its therapeutic potential in neurodevelopmental disorders.
Assuntos
Canabidiol , Modelos Animais de Doenças , Síndrome do Cromossomo X Frágil , Hipocampo , Receptores de Canabinoides , Reconhecimento Psicológico , Animais , Síndrome do Cromossomo X Frágil/tratamento farmacológico , Síndrome do Cromossomo X Frágil/metabolismo , Canabidiol/farmacologia , Canabidiol/uso terapêutico , Receptores de Canabinoides/metabolismo , Masculino , Reconhecimento Psicológico/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Ratos , Proteína do X Frágil da Deficiência Intelectual/metabolismo , Proteína do X Frágil da Deficiência Intelectual/genética , Região CA1 Hipocampal/efeitos dos fármacos , Região CA1 Hipocampal/metabolismo , Memória/efeitos dos fármacos , Receptores Acoplados a Proteínas G/metabolismo , Simulação de Acoplamento MolecularRESUMO
Fragile X syndrome (FXS), the most common inherited cause of intellectual disability and the single-gene cause of autism, is caused by decreased expression of the fragile X messenger ribonucleoprotein protein (FMRP), a ribosomal-associated RNA-binding protein involved in translational repression. Extensive preclinical work in several FXS animal models supported the therapeutic potential of decreasing metabotropic glutamate receptor (mGluR) signaling to correct translation of proteins related to synaptic plasticity; however, multiple clinical trials failed to show conclusive evidence of efficacy. In this issue of the JCI, Berry-Kravis and colleagues conducted the FXLEARN clinical trial to address experimental design concerns from previous trials. Unfortunately, despite treatment of young children with combined pharmacological and learning interventions for a prolonged period, no efficacy of blocking mGluR activity was observed. Future systematic evaluation of potential therapeutic approaches should evaluate consistency between human and animal pathophysiological mechanisms, utilize innovative clinical trial design from FXLEARN, and incorporate translatable biomarkers.
Assuntos
Síndrome do Cromossomo X Frágil , Deficiência Intelectual , Receptores de Glutamato Metabotrópico , Animais , Criança , Humanos , Pré-Escolar , Síndrome do Cromossomo X Frágil/tratamento farmacológico , Síndrome do Cromossomo X Frágil/genética , Proteína do X Frágil da Deficiência Intelectual/genética , Proteína do X Frágil da Deficiência Intelectual/metabolismo , Proteína do X Frágil da Deficiência Intelectual/uso terapêutico , Receptores de Glutamato Metabotrópico/genética , Receptores de Glutamato Metabotrópico/metabolismo , Plasticidade NeuronalRESUMO
INTRODUCTION: Fragile X syndrome (FXS) is the most common inherited cause of Intellectual Disability. There is a broad phenotype that includes deficits in cognition and behavioral changes, alongside physical characteristics. Phenotype depends upon the level of mutation in the FMR1 (fragile X messenger ribonucleoprotein 1) gene. The molecular understanding of the impact of the FMR1 gene mutation provides an opportunity to target treatment not only at symptoms but also on a molecular level. METHODS: We conducted a systematic review to provide an up-to-date narrative summary of the current evidence for pharmacological treatment in FXS. The review was restricted to randomized, blinded, placebo-controlled trials. RESULTS: The outcomes from these studies are discussed and the level of evidence assessed against validated criteria. The initial search identified 2377 articles, of which 16 were included in the final analysis. CONCLUSION: Based on this review to date there is limited data to support any specific pharmacological treatments, although the data for cannabinoids are encouraging in those with FXS and in future developments in gene therapy may provide the answer to the search for precision medicine. Treatment must be person-centered and consider the combination of medical, genetic, cognitive, and emotional challenges.
Assuntos
Proteína do X Frágil da Deficiência Intelectual , Síndrome do Cromossomo X Frágil , Ensaios Clínicos Controlados Aleatórios como Assunto , Humanos , Canabinoides/uso terapêutico , Canabinoides/farmacologia , Proteína do X Frágil da Deficiência Intelectual/genética , Síndrome do Cromossomo X Frágil/tratamento farmacológico , Síndrome do Cromossomo X Frágil/genética , Terapia Genética/métodos , Mutação , Fenótipo , Medicina de Precisão/métodosRESUMO
Fragile X syndrome (FXS) is the leading cause of inherited autism and intellectual disabilities. Aberrant protein synthesis due to the loss of fragile X messenger ribonucleoprotein (FMRP) is the major defect in FXS, leading to a plethora of cellular and behavioral abnormalities. However, no treatments are available to date. In this study, we found that activation of metabotropic glutamate receptor 7 (mGluR7) using a positive allosteric modulator named AMN082 represses protein synthesis through ERK1/2 and eIF4E signaling in an FMRP-independent manner. We further demonstrated that treatment of AMN082 leads to a reduction in neuronal excitability, which in turn ameliorates audiogenic seizure susceptibility in Fmr1 KO mice, the FXS mouse model. When evaluating the animals' behavior, we showed that treatment of AMN082 reduces repetitive behavior and improves learning and memory in Fmr1 KO mice. This study uncovers novel functions of mGluR7 and AMN082 and suggests the activation of mGluR7 as a potential therapeutic approach for treating FXS.
Assuntos
Compostos Benzidrílicos , Síndrome do Cromossomo X Frágil , Receptores de Glutamato Metabotrópico , Camundongos , Animais , Proteína do X Frágil da Deficiência Intelectual/genética , Proteína do X Frágil da Deficiência Intelectual/metabolismo , Síndrome do Cromossomo X Frágil/tratamento farmacológico , Síndrome do Cromossomo X Frágil/genética , Receptores de Glutamato Metabotrópico/metabolismo , Modelos Animais de Doenças , Camundongos KnockoutRESUMO
Fragile X syndrome (FXS) is a neurodevelopmental disorder caused by a full mutation (> 200 CGG repeats) in the FMR1 gene. FXS is the leading cause of inherited intellectual disabilities and the most commonly known genetic cause of autism spectrum disorder. Children with FXS experience behavioral and sleep problems, anxiety, inattention, learning difficulties, and speech and language delays. There are no approved medications for FXS; however, there are several interventions and treatments aimed at managing the symptoms and improving the quality of life of individuals with FXS. A combination of non-pharmacological therapies and pharmacotherapy is currently the most effective treatment for FXS. Currently, several targeted treatments, such as metformin, sertraline, and cannabidiol, can be used by clinicians to treat FXS. Gene therapy is rapidly developing and holds potential as a prospective treatment option. Soon its efficacy and safety in patients with FXS will be demonstrated. WHAT THIS PAPER ADDS: Targeted treatment of fragile X syndrome (FXS) is the best current therapeutic approach. Gene therapy holds potential as a prospective treatment for FXS in the future.
Assuntos
Síndrome do Cromossomo X Frágil , Terapia Genética , Síndrome do Cromossomo X Frágil/terapia , Síndrome do Cromossomo X Frágil/genética , Síndrome do Cromossomo X Frágil/tratamento farmacológico , Humanos , Proteína do X Frágil da Deficiência Intelectual/genéticaRESUMO
Glutamatergic synapses encode information from extracellular inputs using dynamic protein interaction networks (PINs) that undergo widespread reorganization following synaptic activity, allowing cells to distinguish between signaling inputs and generate coordinated cellular responses. Here, we investigate how Fragile X Messenger Ribonucleoprotein (FMRP) deficiency disrupts signal transduction through a glutamatergic synapse PIN downstream of NMDA receptor or metabotropic glutamate receptor (mGluR) stimulation. In cultured cortical neurons or acute cortical slices from P7, P17 and P60 FMR1-/y mice, the unstimulated protein interaction network state resembled that of wildtype littermates stimulated with mGluR agonists, demonstrating resting state pre-activation of mGluR signaling networks. In contrast, interactions downstream of NMDAR stimulation were similar to WT. We identified the Src family kinase (SFK) Fyn as a network hub, because many interactions involving Fyn were pre-activated in FMR1-/y animals. We tested whether targeting SFKs in FMR1-/y mice could modify disease phenotypes, and found that Saracatinib (SCB), an SFK inhibitor, normalized elevated basal protein synthesis, novel object recognition memory and social behavior in FMR1-/y mice. However, SCB treatment did not normalize the PIN to a wild-type-like state in vitro or in vivo, but rather induced extensive changes to protein complexes containing Shank3, NMDARs and Fyn. We conclude that targeting abnormal nodes of a PIN can identify potential disease-modifying drugs, but behavioral rescue does not correlate with PIN normalization.
Assuntos
Benzodioxóis , Modelos Animais de Doenças , Proteína do X Frágil da Deficiência Intelectual , Síndrome do Cromossomo X Frágil , Neurônios , Proteínas Proto-Oncogênicas c-fyn , Quinases da Família src , Animais , Síndrome do Cromossomo X Frágil/metabolismo , Síndrome do Cromossomo X Frágil/tratamento farmacológico , Proteína do X Frágil da Deficiência Intelectual/metabolismo , Proteína do X Frágil da Deficiência Intelectual/genética , Camundongos , Quinases da Família src/metabolismo , Benzodioxóis/farmacologia , Proteínas Proto-Oncogênicas c-fyn/metabolismo , Neurônios/metabolismo , Neurônios/efeitos dos fármacos , Masculino , Receptores de Glutamato Metabotrópico/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fenótipo , Sinapses/metabolismo , Sinapses/efeitos dos fármacos , Mapas de Interação de Proteínas/efeitos dos fármacos , Receptores de N-Metil-D-Aspartato/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Córtex Cerebral/metabolismo , Córtex Cerebral/efeitos dos fármacos , QuinazolinasRESUMO
BACKGROUND: Many rare genetic neurodevelopmental disorders (RGNDs) are characterized by intellectual disability (ID), severe cognitive and behavioral impairments, potentially diagnosed as a comorbid autism spectrum disorder or attention-deficit hyperactivity disorder. Quality of life is often impaired due to irritability, aggression and self-injurious behavior, generally refractory to standard therapies. There are indications from previous (case) studies and patient reporting that cannabidiol (CBD) may be an effective treatment for severe behavioral manifestations in RGNDs. However, clear evidence is lacking and interventional research is challenging due to the rarity as well as the heterogeneity within and between disease groups and interindividual differences in treatment response. Our objective is to examine the effectiveness of CBD on severe behavioral manifestations in three RGNDs, including Tuberous Sclerosis Complex (TSC), mucopolysaccharidosis type III (MPS III), and Fragile X syndrome (FXS), using an innovative trial design. METHODS: We aim to conduct placebo-controlled, double-blind, block-randomized, multiple crossover N-of-1 studies with oral CBD (twice daily) in 30 patients (aged ≥ 6 years) with confirmed TSC, MPS III or FXS and severe behavioral manifestations. The treatment is oral CBD up to a maximum of 25 mg/kg/day, twice daily. The primary outcome measure is the subscale irritability of the Aberrant Behavior Checklist. Secondary outcome measures include (personalized) patient-reported outcome measures with regard to behavioral and psychiatric outcomes, disease-specific outcome measures, parental stress, seizure frequency, and adverse effects of CBD. Questionnaires will be completed and study medication will be taken at the participants' natural setting. Individual treatment effects will be determined based on summary statistics. A mixed model analysis will be applied for analyzing the effectiveness of the intervention per disorder and across disorders combining data from the individual N-of-1 trials. DISCUSSION: These N-of-1 trials address an unmet medical need and will provide information on the effectiveness of CBD for severe behavioral manifestations in RGNDs, potentially generating generalizable knowledge at an individual-, disorder- and RGND population level. TRIAL REGISTRATION: EudraCT: 2021-003250-23, registered 25 August 2022, https://www.clinicaltrialsregister.eu/ctr-search/trial/2021-003250-23/NL .
Assuntos
Transtorno do Espectro Autista , Canabidiol , Síndrome do Cromossomo X Frágil , Mucopolissacaridoses , Esclerose Tuberosa , Humanos , Canabidiol/uso terapêutico , Síndrome do Cromossomo X Frágil/complicações , Síndrome do Cromossomo X Frágil/tratamento farmacológico , Esclerose Tuberosa/complicações , Esclerose Tuberosa/tratamento farmacológico , Transtorno do Espectro Autista/tratamento farmacológico , Qualidade de Vida , Resultado do Tratamento , Mucopolissacaridoses/induzido quimicamente , Mucopolissacaridoses/tratamento farmacológico , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
El Síndrome X Frágil (SXF) es la principal causa heredada de Discapacidad intelectual (DI) y Trastorno del espectro autista (TEA). Se caracteriza por presentar un fenotipo conductual asociado a hiperactividad, déficit atencional, impulsividad, ansiedad, trastornos conductuales, espectro autista y retraso global del desarrollo. No existe actualmente un tratamiento farmacológico para el trastorno genético de base. El tratamiento farmacológico se focaliza en los síntomas que interfieren con la calidad de vida y aprendizaje, entre ellos la irritabilidad e hiperactividad. OBJETIVO: Evaluar cambios conductuales a través de la escala conductual ABC, de pacientes masculinos con diagnóstico de SXF tratados con psicoestimulantes y/o antipsicóticos en comparación a controles. MÉTODO: Se evalúa a 40 pacientes hombres con diagnóstico de SXF entre los años 2014 y 2017. Se utiliza la evaluación de la conducta mediante el puntaje en la subescala de irritabilidad e hiperactividad de la encuesta ABC-C y el registro de fármacos indicados. Se compara la sintomatología conductual en pacientes que no utilizan fármacos, aquellos que utilizan antipsicóticos, los que usan psicoestimulantes y pacientes tratados con ambos fármacos. RESULTADOS: La mediana de edad fue de 15,1 (±9,3) años. Del total de pacientes, el 42,5% reportó uso de fármacos, de éstos el 35% utilizó psicoestimulantes, 35% antipsicóticos y 30% la combinación de ambos. Se observa que solo el grupo que recibe tratamiento con psicoestimulantes y antipsicóticos en forma simultánea presenta diferencias con el subgrupo sin tratamiento farmacológico. CONCLUSIONES: En más de la mitad de nuestros pacientes se decide no utilizar tratamiento farmacológico. Sin embargo, dichos pacientes igualmente presentan sintomatología de irritabilidad e hiperactividad. Los pacientes que recibieron terapia asociada de psicoestimulantes y antipsicóticos presentan puntajes significativamente más altos en la escala de irritabilidad que aquellos que no recibieron tratamiento farmacológico. Este grupo, que constituye el 12,5% del total de la muestra, presenta un fenotipo conductual que genera mayores dificultades en la calidad de vida del paciente y su entorno.
Fragile X Syndrome (FXS) is the main inherited cause of Intellectual Disability and Autism Spectrum Disorder. It characteristically presents as a behavioral phenotype asso- ciated with hyperactivity, attention deficit, impulsivity, anxiety, behavioral disorders, autistic spectrum and global developmental delay. There is currently no pharmacological treatment for the underlying genetic disorder. Pharmacological treatment targets symptoms that interfere with quality of life and learning, including irritability and hyperactivity.OBJECTIVE: To evaluate behavioral changes through the ABC behavioral scale of male patients diagnosed with FXS treated with psychostimulants and / or antipsychotics compared to controls. METHOD: 40 male patients with a diagnosis of FXS between 2014 and 2017 were evaluated. The behavioral assessment was done by scoring the irritability and hyperactivity subscale of the ABC-C survey and by registering the prescribed drug. Behavioral symptomatology was compared in patients who do not use drugs, those who use antipsychotics, those who use psychostimulants and patients treated with both drugs. RESULTS: The median age was 15.1 (± 9.3) years. Of the total of patients, 42.5% were prescribed drugs, of these 35% used psychostimulants, 35% antipsychotics and 30% the combination of both. It was observed that the group that received treatment with both psychostimulants and antipsychotics simultaneously presented differences with the subgroup without pharmacological treatment.CONCLUSIONS: In more than half of our patients no pharmacological treatment is prescribed. However, these patients also show symptoms of irritability and hyperactivity. Patients who received associated therapy of psychostimulants and antipsychotics have significantly higher scores on the irritability scale than those who did not receive pharmacological treatment. This group, which constitutes 12.5% of the total sample, has a behavioral phenotype that generates greater difficulties in the patient's quality of life and their environment.
Assuntos
Humanos , Masculino , Criança , Adolescente , Adulto Jovem , Antipsicóticos/uso terapêutico , Síndrome do Cromossomo X Frágil/psicologia , Síndrome do Cromossomo X Frágil/tratamento farmacológico , Estimulantes do Sistema Nervoso Central/uso terapêutico , Humor Irritável , Aceitação pelo Paciente de Cuidados de Saúde , Inquéritos e Questionários , Lista de Checagem , Comportamento ProblemaRESUMO
Abstract Fragile X syndrome (FXS) is the most common cause of hereditary mental retardation, but studies on the oral health condition of these patients are rare. The aim of this study was to determine the experience of dental caries in individuals with FXS, by examining the saliva profile, oral hygiene, socioeconomic characteristics and use of controlled drugs in these patients. Dental health was estimated using the decayed, missing and filled teeth index (DMF-T) and sialometry, and the pH value and buffering capacity of the saliva, colony forming units of S. mutans (CFU/mL), visible biofilm index, and socioeconomic status were all examined. The sample, comprising 23 individuals, had an average age of 17.3 ± 5.6 years, a DMF-T index of 5.5, a diminished salivary flow (78.3%), and a low (73.9%) saliva buffering capacity. Most (52.2%) individuals presented with a high abundance (CFU/mL) of S. mutans. The experience of caries was correlated with salivary parameters, poor oral hygiene, lower socioeconomic status and an increased count of S. mutans in saliva.
Assuntos
Humanos , Masculino , Feminino , Criança , Adolescente , Adulto , Adulto Jovem , Saliva/microbiologia , Streptococcus mutans/isolamento & purificação , Cárie Dentária/microbiologia , Síndrome do Cromossomo X Frágil/complicações , Higiene Bucal/estatística & dados numéricos , Psicotrópicos/uso terapêutico , Valores de Referência , Saliva/metabolismo , Saliva/química , Salivação/efeitos dos fármacos , Taxa Secretória/efeitos dos fármacos , Fatores Socioeconômicos , Fatores de Tempo , Índice CPO , Fatores de Risco , Carga Bacteriana , Síndrome do Cromossomo X Frágil/tratamento farmacológicoRESUMO
Introdução: a síndrome do X frágil é a principal causa de retardo mental de natureza familiar. Suas características clínicas pouco marcantes fazem com que um diagnóstico de certeza a partir de testes moleculares seja imprescindível. Objetivo: descrever e avaliar as vantagens e desvantagens de uma estratégia combinada de PCR triplo metilação-específica e eletroforese capilar para o diagnóstico molecular da síndrome do X frágil, visando baixo custo, exequibilidade, reprodutibilidade e sensibilidade. Métodos: foram coletadas 43 amostras de sanguede pacientes com déficit cognitivo e de suas mães, quando indicado. Tais indivíduos possuíam exame citogenético positivo, fenótipo e/ou história familiar sugestivas de síndrome do X frágil. Após extração de DNA, foi realizada eletroforese capilar com marcadores fluorescentes,tratamento com bissulfito de sódio e três reações de PCR metilação-específicas em cada amostra. Resultados: foi possível determinar o genótipo em 29 pacientes: 23 (14 homens e nove mulheres) apresentavam alelos com tamanho normal e seis (todos do sexo masculino) possuíam alelos na faixa de mutação completa. Em outras seis amostras, todas do sexo feminino, foi possível determinar um alelo na faixa normal e outro alelo alterado, entretanto, sem diferenciação entre faixa de pré-mutação ou de mutação completa. Nas demais oito amostras(cinco homens e três mulheres), não se pôde determinar o genótipo. Conclusões: a técnica proposta faz uma triagem de pacientes, mas apresenta desvantagens, como não terem sido obtidos resultados satisfatórios com as reações para alelos metilados e a análise dos rastrosdas PCRs com três primers ter se mostrado difícil e dependente de observador.
Introduction: The fragile X syndrome is the main cause of inherited mental retardation. Its very small remarkable clinical characteristics make that a surely diagnosis from molecular tests be indispensable. Objective: To describe and assess the advantages and disadvantages of a combined strategy of methylation-specific triple polymerase chain reaction (PCR)and capillary electrophoresis for the molecular diagnosis of the fragile X syndrome, seeking low cost, feasibility, reproducibility, and sensibility. Methods: 43 blood samples were collected from patients with cognitive deficit and their mothers, when indicated. Such subjects presented a positive cytogenetic exam, phenotype and/or familiar history suggestive of the fragile X syndrome. After DNA extraction, capillary electrophoresis with fluorescent markers, treatment with sodium bisulfite, and three methylation-specific PCR reactions were performed in each sample. Results: It was possible to determine the genotype in 29 patients: 23 (14 men and 9 women) presented alleles with normal size and six (all male) had them in the complete mutation range. In other six female samples, it was possible to determine an allele in the normal range and another altered; nevertheless, without differentiation between the pre-mutation or complete mutation ranges. In the other eight samples (five men and threewomen), it was not possible to establish the genotype. Conclusions: The suggested technique does a patient?s screening, but it has some disadvantages such as non-satisfying results been seen with the reactions for methylated alleles and analysis of the PCRs tracks with three primers being difficult and dependent on the observer.
Assuntos
Humanos , Eletroforese Capilar , Patologia Molecular , Síndrome do Cromossomo X Frágil/diagnóstico , Síndrome do Cromossomo X Frágil/tratamento farmacológicoRESUMO
FXTAS (Fragile X-associated tremor and ataxia syndrome) is a late- onset neurodegenerative disorder affecting mainly men, over 50 years of age, who are carriers of the FMR1 gene premutation. The full mutation of this gene causes the fragile X syndrome (FXS), the most common cause of inherited mental retardation. Individuals affected by FXTAS generally present intention tremor and gait ataxia that might be associated to specific radiological and/or neuropathological signs. Other features commonly observed are parkinsonism, cognitive decline, peripheral neuropathy and autonomic dysfunction. Nearly a decade after its clinical characterization, FXTAS is poorly recognized in Brazil. Here we present a review of the current knowledge on the clinical, genetic and diagnostic aspects of the disease.
A FXTAS (síndrome de tremor e ataxia associada ao X frágil) é uma doença neurodegenerativa de início tardio que afeta principalmente homens acima dos 50 anos de idade, portadores de pré-mutação do gene FMR1. A mutação completa desse gene é responsável pela síndrome do cromossomo X frágil (SXF), a causa mais comum de deficiência mental herdada. Indivíduos afetados pela FXTAS geralmente apresentam tremor de intenção e ataxia de marcha que podem estar associados a sinais radiológicos ou neuropatológicos específicos. Outras características comumente observadas são parkinsonismo, declínio cognitivo, neuropatia periférica e disfunções autonômicas. Quase uma década após sua caracterização clínica, a FXTAS é mal conhecida por médicos no Brasil. Esta revisão apresenta o conhecimento atual sobre os aspectos clínicos, genéticos e diagnósticos da síndrome.