Fragile X Syndrome in children

Fragile X syndrome is caused by the expansion of CGG triplets in the FMR1 gene, which generates epigenetic changes that silence its expression. The absence of the protein coded by this gene, FMRP, causes cellular dysfunction, leading to impaired brain development and functional abnormalities. The physical and neurologic manifestations of the disease appear early in life and may suggest the diagnosis. However, it must be confirmed by molecular tests. It affects multiple areas of daily living and greatly burdens the affected individuals and their families. Fragile X syndrome is the most common monogenic cause of intellectual disability and autism spectrum disorder; the diagnosis should be suspected in every patient with neurodevelopmental delay. Early interventions could improve the functional prognosis of patients with Fragile X syndrome, significantly impacting their quality of life and daily functioning. Therefore, healthcare for children with Fragile X syndrome should include a multidisciplinary approach.

El síndrome de X frágil es causado por la expansión de tripletas CGG en el gen FMR1, el cual genera cambios epigenéticos que silencian su expresión. La ausencia de la proteína codificada por este gen, la FMRP, causa disfunción celular, llevando a deficiencia en el desarrollo cerebral y anormalidades funcionales. Las manifestaciones físicas y neurológicas de la enfermedad aparecen en edades tempranas y pueden sugerir el diagnóstico. Sin embargo, este debe ser confirmado por pruebas moleculares. El síndrome afecta múltiples aspectos de la vida diaria y representa una alta carga para los individuos afectados y para sus familias. El síndrome de C frágil es la causa monogénica más común de discapacidad intelectual y trastornos del espectro autista; por ende, el diagnóstico debe sospecharse en todo paciente con retraso del neurodesarrollo. Intervenciones tempranas podrían mejorar el pronóstico funcional de pacientes con síndrome de X frágil, impactando significativamente su calidad de vida y funcionamiento. Por lo tanto, la atención en salud de niños con síndrome de X frágil debe incluir un abordaje multidisciplinario.

Síndrome metabólico en el adulto mayor vinculado a los programas de actividad física comunitaria / Metabolic Syndrome in the Elderly Adult Involved in the Community Physical Activity Programs

Introducción: El síndrome metabólico es una situación clínica compleja que se asocia a un incremento de la morbilidad y mortalidad. Los elementos que lo componen aumentan el riesgo de diabetes mellitus tipo II y enfermedad cardiovascular. Objetivo: Determinar el comportamiento del síndrome metabólico en el adulto mayor vinculado a los programas de actividad física comunitaria del proyecto Lindo Amanecer del municipio Arroyo Naranjo. Métodos: Se realizó un estudio observacional descriptivo de corte transversal. El universo de estudio lo constituyeron 120 adultos mayores, de los que se entrevistaron a 106, en el período de abril a octubre de 2018. Se siguieron los criterios del Adult Treatment Panel III para el diagnóstico de síndrome metabólico. Las variables descriptivas se expresaron en porcientos y para la comparación de variables en estudio se utilizó el método estadístico de ji al cuadrado. Resultados: Los resultados obtenidos mostraron un 41,51 por ciento de personas con síndrome metabólico, predominaron las personas de 70 y más años de edad (54,54 por ciento y el sexo femenino (93,18 por ciento). El 100 por ciento tuvieron cifras de presión arterial ≥ 130/85 mmHg. El 100 por ciento de los pacientes desconocían su enfermedad. Conclusiones: Se encontró predominio en los pacientes con síndrome metabólico del sexo femenino y del grupo de edad de 70 y más años. El diagnóstico a nivel de la Atención Primaria de Salud es deficiente. Se asocia a la hipertensión arterial, obesidad abdominal y al riesgo de enfermedad cardiovascular(AU)

Introduction: Metabolic syndrome is a complex clinical situation associated with an increase in morbidity and mortality. The elements that mark it up increase the risk of type 2 diabetes mellitus and cardiovascular disease. Objective: To determine the behavior of metabolic syndrome in elderly adults involved in the community physical activity programs of the Lindo Amanecer project in the municipality of Arroyo Naranjo. Methods: A cross-sectional descriptive observational study was carried out. The study universe was made up of 120 elderly adults, 106 of which were interviewed in the period from April to October 2018. The Adult Treatment Panel III criteria for the diagnosis of metabolic syndrome were followed. The descriptive variables were expressed in percentages and, for the comparison of variables under study, the chi-square statistical method was used. Results: The obtained results showed 41.51percent of people with metabolic syndrome, with a predominance of people aged 70 years and older (54.54percent) and the female sex (93.18percent). One hundred percent had blood pressure values over or equal to 130/85 mmHg. One hundred percent of the patients did not have any knowledge of their disease. Conclusions: In patients with metabolic syndrome, the predominance corresponded to the female sex, as well as the age group of 70 years and older. Diagnosis at the primary healthcare level is deficient. It is associated with arterial hypertension, abdominal obesity and the risk of cardiovascular disease(AU)

FMR1 alleles in women with idiopathic infertility / Alelos do gene FMR1 em mulheres com infertilidade idiopática

INTRODUCTION: The frequency of the premutation alleles of the FMR1 gene varies from 1:100 to 1:260 Israeli, Canadian, Finnish and American women, but it is unknown in Brazil. Premutation carriers may have reduced reproductive age and are at risk of transmitting the expanded allele to their offspring, and consequently fragile X syndrome. OBJECTIVE: To observe the distribution range of the FMR1 gene alleles in a population of women with idiopathic infertility, without symptoms of premature ovarian insufficiency. METHODS: The presence of premutation in FMR1 was assessed by conventional PCR, agarose, and acrylamide gel and analysis of fragments in capillary electrophoresis. Lymphocyte DNA obtained from 283 women undergoing infertility treatment was analyzed. RESULTS: 169 patients had the normal heterozygous allele (59.7%), 114 had the normal homozygous allele (40.6%) and no patient had the premutation. Premature ovarian insufficiency is seen in 20 to 30% of women with the permutated allele. Thus, the condition can be asymptomatic in a large part of the premutation carriers. Brazil has a diverse population and, therefore, the allele frequencies of many gene variants are unknown. Previous Brazilian studies have shown a low frequency of the premutation allele in different patient cohorts. Corroborating these articles, the results demonstrated that the frequency of the premutation allele is low in the infertile women population studied. CONCLUSION: Tracking the size of the FMR1 gene alleles allows the expansion of knowledge about the frequency of risk alleles associated with genetic diseases in the Brazilian population.

INTRODUÇÃO: A frequência dos alelos pré-mutados do gene FMR1 varia de 1:100 e 1:260 mulheres israelenses, canadenses, finlandesas e americanas, mas é desconhecida no Brasil. Portadoras da pré-mutação podem apresentar redução da idade reprodutiva e possuem risco de transmissão do alelo expandido para a prole, e consequentemente a Síndrome do X frágil. OBJETIVO: Observar a faixa de distribuição dos alelos do gene FMR1 em uma população de mulheres com infertilidade idiopática, sem sintomas de insuficiência ovariana prematura. MÉTODOS: A presença da pré-mutação em FMR1 foi avaliada por PCR convencional, gel de agarose e acrilamida e análise de fragmentos em eletroforese capilar. Analisou-se DNA de linfócitos obtidos de 283 mulheres em tratamento de infertilidade. RESULTADOS: Foi observado que 169 pacientes apresentam o alelo heterozigoto normal (59,7%), 114 apresentam o alelo homozigoto normal (40,6%) e nenhuma paciente apresentou a pré-mutação. A insuficiência ovariana prematura é observada em 20 a 30% das mulheres portadoras do alelo pré-mutado. Assim, a presença de um alelo pré-mutado pode ser assintomática em grande parte dos casos. O Brasil possui uma população diversificada e, portanto, as frequências alélicas de muitas variantes gênicas são desconhecidas. Estudos brasileiros anteriores mostraram uma baixa frequência do alelo pré-mutado em diferentes coortes de pacientes. Corroborando estes autores, os resultados demonstram que frequência do alelo pré-mutado é baixa na população de mulheres inférteis estudada. CONCLUSÃO: O rastreamento do tamanho dos alelos do gene FMR1 permite ampliar o conhecimento sobre a frequência dos alelos de risco para doenças genética na população brasileira.

Mecanismos epigenéticos involucrados en la génesis del autismo / Epigenetic mechanisms involved in the genesis of autism

Resumen El autismo es un trastorno del neurodesarrollo de base neurobiológica, caracterizado por alteración en la interacción social y la comunicación, intereses restringidos y conductas estereotipadas. Se relaciona con trastornos en la sinaptogénesis y a multiples etiologías. La identificación de factores epigenéticos implicados en la génesis del autismo permiten una mejor comprensión de los mecanismos moleculares invo lucrados. Nuestro objetivo fue analizar los mecanismos epigenéticos relacionados al desarrollo del autismo, puntualizando entidades específicas y sus mecanismos fisiopatológicos. Analizamos de qué manera se rela cionan los trastornos en la metilación del ADN, la modificación de las histonas, la remodelación cromosómica y la regulación mediada por el ARN no codificantes con diversos síndromes genéticos como el frágil X, Rett, Mecp2patías, Phelam McDermid, tóxicos prenatales como el alcohol, ácido valproico, cannabis y ambientales cómo el estrés materno, todos ellos asociados a una mayor prevalencia de autismo. En conclusión, el recono cimiento de estos mecanismos abre nuevas posibilidades para la prevención, y probablemente en un futuro, en las entidades genéticas, permitirá el desarrollo de tratamientos específicos con modificaciones a la medida de cada entidad.

Abstract Autism is a neurobiological developmental disorder characterized by poor social interaction and communication, narrow interests, and stereotyped behaviors. It has been associated with disorders of synaptogenesis and multiple etiologies. The iden tification of the epigenetic factors involved in the genesis of autism allows a better understanding of the molecular mechanisms involved. Our objective was to analyze the epigenetic mechanisms related to the development of autism, specifying specific entities and their pathophysiological mechanisms. We analyze how DNA methylation disorders, histone modification, remodeling and chromosomal regulation mediated by non-coding RNA are related to various genetic syndromes such as fragile X, Rett, Pathias Mecp2, Phelam McDermid, prenatal toxins such as alcohol, valproic. acid, cannabis, and environmental toxins such as maternal stress, all associated with a higher prevalence of autism. In conclusion: the recognition of these mechanisms opens up new possibilities for preven tion and it is likely that, in genetic entities, it will allow the development of specific treatments with modifications tailored to each entity.

Validation of an educational booklet: effect on the knowledge about prevention of metabolic syndrome in adolescents / Validación de un cuadernillo educativo: efecto sobre el conocimiento acerca de la prevención del síndrome metabólico entre adolescentes / Validação de cartilha educativa: efeito no conhecimento sobre prevenção da síndrome metabólica em adolescentes

ABSTRACT Objective: to validate an educational booklet for the promotion of knowledge about the prevention of Metabolic Syndrome in adolescents. Method: a time series quasi-experiment conducted in 2020 with 37 adolescents from five public schools belonging to the teaching state network of Picos, Piauí, Brazil. It was conducted in two phases: 1) development of a script of questions about the prevention of MS and its content validation by 17 experts; 2) quasi-experiment with reading of the booklet called "Síndrome Metabólica: Como me prevenir?" ("Metabolic Syndrome: How can I protect myself?", and assessment of the adolescents' knowledge through a script of questions before and after reading the booklet. To analyze content validity of the script of questions, the Content Validity Ratio was calculated (CVR>0.529). The McNemar test (p<0.05) was used to investigate the effect of the educational booklet on the adolescents' knowledge. The study was approved by the Research Ethics Committee of Universidade Federal do Piauí. Results: the script of question's overall CVR was 0.718, representing good content validation. Three assertions were removed (CVR>0.529). Regarding the adolescents' knowledge, 45.9% improved it, with no significant difference (p=0.067). Conclusion: the adolescents' knowledge was higher in almost half of the participants in the post-test, showing that reading the educational booklet favored knowledge about the prevention of Metabolic Syndrome.

RESUMEN Objetivo: validar el cuadernillo educativo para promover el conocimiento sobre la prevención del Síndrome Metabólico entre adolescentes. Método: cuasi experimento de series temporales realizado en 2020 con 37 adolescentes de cinco escuelas públicas pertenecientes a la red estatal de enseñanza de Picos, Piauí, Brasil. Se realizó en dos fases: 1) desarrollo del guion de preguntas sobre prevención del SM y su validación de contenido a cargo de 17 especialistas; 2) cuasiexperimento con lectura del cuadernillo "Síndrome Metabólica: Como me prevenir?" ("Síndrome Metabólico: ¿Cómo puedo protegerme?"), y evaluación del conocimiento de los adolescentes antes y después de la lectura a través del guion de preguntas. Para analizar la validez del contenido del guion de preguntas, se calculó la Relación de Validez de Contenido (Content Validity Ratio, CVR>0,529). Para investigar el efecto del cuadernillo educativo sobre el conocimiento de los adolescentes, se utilizó la prueba de McNemar (p<0,05). El estudio fue aprobado por el Comité de Ética e Investigación de la Universidade Federal do Piauí. Resultados: el CVR total del guion fue de 0,718, lo que representa buena validación del contenido del guion de preguntas. Se eliminaron tres afirmaciones (CVR>0,529). En relación con el conocimiento de los adolescentes, el 45,9% presentó mejoras, sin diferencias significativas (p=0,067). Conclusión: el conocimiento de los adolescentes fue superior en prácticamente la mitad de los participantes en el post-test, lo que demuestra que leer el cuadernillo educativo favoreció el conocimiento sobre la prevención del Síndrome Metabólico.

RESUMO Objetivo: validar a cartilha educativa para promoção do conhecimento sobre prevenção da Síndrome Metabólica em adolescentes. Método: quase experimento de séries temporais realizado em 2020 com 37 adolescentes de cinco escolas públicas da rede estadual de ensino de Picos-Piauí-Brasil. Foi realizado em duas fases: 1) desenvolvimento de roteiro de questões sobre prevenção da SM e sua validação de conteúdo por 17 especialistas; 2) quase-experimento com implementação de leitura da cartilha "Síndrome Metabólica: Como me prevenir?", e avaliação do conhecimento dos adolescentes pré e pós-leitura via roteiro de questões. Para análise da validade de conteúdo do roteiro de questões calculou-se a Content Validity Ratio (CVR>0,529). Para investigar o efeito da cartilha educativa no conhecimento dos adolescentes utilizou-se o teste de McNemar (p<0,05). O estudo foi aprovado pelo Comitê de Ética e Pesquisa da Universidade Federal do Piauí. Resultados: a CVR total do roteiro foi de 0,718, representando boa validação de conteúdo do roteiro de questões. Três assertivas foram eliminadas (CVR>0,529). Sobre o conhecimento dos adolescentes, 45,9% melhoraram seu conhecimento, sem diferença significativa (p=0,067). Conclusão: o conhecimento dos adolescentes foi maior em quase metade dos adolescentes no pós-teste, demonstrando que a leitura da cartilha educativa favoreceu o conhecimento sobre a prevenção da Síndrome Metabólica.

Restoration of FMRP expression in adult V1 neurons rescues visual deficits in a mouse model of fragile X syndrome

Many people affected by fragile X syndrome (FXS) and autism spectrum disorders have sensory processing deficits, such as hypersensitivity to auditory, tactile, and visual stimuli. Like FXS in humans, loss of Fmr1 in rodents also cause sensory, behavioral, and cognitive deficits. However, the neural mechanisms underlying sensory impairment, especially vision impairment, remain unclear. It remains elusive whether the visual processing deficits originate from corrupted inputs, impaired perception in the primary sensory cortex, or altered integration in the higher cortex, and there is no effective treatment. In this study, we used a genetic knockout mouse model (Fmr1KO), in vivo imaging, and behavioral measurements to show that the loss of Fmr1 impaired signal processing in the primary visual cortex (V1). Specifically, Fmr1KO mice showed enhanced responses to low-intensity stimuli but normal responses to high-intensity stimuli. This abnormality was accompanied by enhancements in local network connectivity in V1 microcircuits and increased dendritic complexity of V1 neurons. These effects were ameliorated by the acute application of GABAA receptor activators, which enhanced the activity of inhibitory neurons, or by reintroducing Fmr1 gene expression in knockout V1 neurons in both juvenile and young-adult mice. Overall, V1 plays an important role in the visual abnormalities of Fmr1KO mice and it could be possible to rescue the sensory disturbances in developed FXS and autism patients.

Tratamiento ortopédico funcional de los maxilares y ortodóntico en paciente con síndrome del cromosoma X- frágil. Reporte de caso / Functional orthopedic jaw and orthodontic treatment in a patient with fragile-X syndrome. A case report

El síndrome X frágil (SXF) es un trastorno ligado al cromosoma X, en el brazo largo Xq27.3, que provoca diversas alteraciones como problemas de conducta, deficiencia intelectual, macroorquidia, pabellones auditivos grandes y prominentes, paladar profundo y ojival, prognatismo mandibular, maloclusión y anomalías dentarias. El objetivo de este informe fue presentar el caso clínico de una paciente de 16 años con SXF, leucodermia, que se sometió a un tratamiento ortopédico funcional de los maxilares para la corrección del apiñamiento dentario. En el examen clínico se observaron timidez, ansiedad, inestabilidad emocional, trastornos conductuales esporádicos asociados a discapacidad intelectual leve, alteraciones craneofaciales y oclusales. Luego del estudio, evaluación radiográfica panorámica y trazados cefalométricos, se decidió instalar un dispositivo ortopédico funcional de maxilar, tipo Pistas Planas Indirectas, para posterior tratamiento ortodóncico correctivo. Bien al inicio del tratamiento se observó dificultad de comprensión y colaboración por parte de la paciente y su responsable (madre) y, luego de 5 meses, aún con mejoras en las funciones estomatognáticas, se inició el tratamiento ortodóntico con dispositivo fijo, el que fue concluido luego de dos años. El éxito del tratamiento de ortopedia funcional de los maxilares y/u ortodóntico, principalmente en el SXF, se basa en el abordaje comportamental y motivación en todas las etapas del tratamiento por el profesional, así como en un ambiente familiar colaborativo.

The Fragile-X Syndrome (FXS) is a disorder linked to X chromosome, on the long arm Xq27.3, causing several changes such as behavioral problems, intellectual disability, macroorchidism, large and prominent auricles, deep and ogival palate, mandibular prognathism, increased mandibular angle, malocclusion, and dental anomalies. The objective was to present a case of a 16-year-old patient with FXS, leukoderma, submitted to orthopedic functional maxillary treatment to correct dental crowding. In general, clinical examination, behavioral changes such as shyness, anxiety, emotional lability, sporadic disturbances of behavior associated with mild mental disabilities were remarkable. After panoramic radiographic evaluation and cephalometric tracings, it was decided to install the functional orthopedic appliance of the jaws, Indirect Flat Planes type, for later corrective orthodontic treatment. At beginning of treatment, there was a difficulty in understanding and collaborating, not only from the patient's side but also from the mother's. After five months, even with the improvement in stomatognathic functions, orthodontic treatment with a fixed appliance was started, which was concluded after two years. Success of functional and / or orthodontic jaw orthopedics treatment, especially in FXS, is based on behavioral approach and motivation in all stages, by the professional as well as a collaborative family environment.

Síndrome X frágil y otras patologías asociadas al gen FMR1 / Fragile X Syndrome and Other Pathologies Associated with the FMR1 Gene / Síndrome do X frágil e outras patologias associadas ao gene FMR1

Resumen: el síndrome X frágil es la causa más frecuente de retraso psicomotor vinculado al cromosoma X en niños, con una prevalencia de 1 : 5.000 en hombres y 1 : 4.000 - 8.000 en mujeres. Además, es la causa hereditaria más asociada al síndrome del espectro autista. Esta patología posee como base etiológica la expansión del triplete CGG en el extremo distal del gen FMR1, lo que causa su silenciamiento. Los pacientes afectados con este síndrome suelen padecer de problemas conductuales, neurológicos, cardíacos y ortopédicos. Este síndrome también se relaciona con la insuficiencia ovárica primaria asociada al X frágil, y el síndrome de temblor y ataxia asociado al X frágil que afectan a la madre y al abuelo materno, y que, por su reciente descripción, podrían ser desconocidos por el personal sanitario, lo que retrasa su diagnóstico y tratamiento. El objetivo de este artículo es analizar estas enfermedades, con el fin de describir el conocimiento actual sobre su etiología, las manifestaciones clínicas, el diagnóstico y el tratamiento. Esto se realizó mediante la recopilación de artículos en Pubmed, con algunas contribuciones de las bases de datos Scielo, Redalyc, Europe PMC, Science Direct, Google Académico y Genetics Home Reference. Entre las conclusiones principales se destaca que los fenotipos asociados a la premutación del gen FMR1 contemplan mecanismos fisiopatológicos diferentes al síndrome X frágil, a pesar de estar íntimamente relacionados.

Abstract: fragile X syndrome is the most common cause of X-linked psychomotor retardation in children, with a prevalence of 1 : 5.000 in males and 1 : 4.000 -8.000 in females. It is also the hereditary cause most associated with autism spectrum syndrome. The etiological basis of this pathology is the expansion of the CGG triplet at the distal end of the FMR1 gene, which causes its silencing. Patients affected with this syndrome usually suffer from behavioral, neurological, cardiac and orthopedic problems. This syndrome is also related to Fragile X-associated primary ovarian insufficiency, and Fragile X-associated tremor and ataxia syndrome affecting the mother and maternal grandfather, which, because of their recent description, may be unknown to health care providers, delaying their diagnosis and treatment. The objective of this article is to analyze these diseases, in order to describe the current knowledge about their etiology, clinical manifestations, diagnosis and treatment. This was done by collecting articles in Pubmed, with some contributions from Scielo, Redalyc, Europe PMC, Science Direct, Google Scholar and Genetics Home Reference databases. Among the main conclusions, it is highlighted that the phenotypes associated with FMR1 gene premutation involve different pathophysiological mechanisms to Fragile X syndrome, despite being closely related.

Resumo: a síndrome do X frágil é a causa mais comum de retardo psicomotor ligado ao cromossomo X em crianças, com prevalência de 1 : 5.000 em homens e 1 : 4.000 a 8.000 em mulheres. Além disso, é a causa mais hereditária associada à síndrome do espectro do autismo. Essa patologia tem como base etiológica a expansão do trigêmeo CGG na extremidade distal do gene FMR1, o que causa seu silenciamento. Pacientes com essa síndrome geralmente sofrem de problemas comportamentais, neurológicos, cardíacos e ortopédicos. Essa síndrome também está relacionada à insuficiência ovariana primária associada ao X frágil, à síndrome do tremor e à ataxia associada ao X frágil, que acometem a mãe e o avô materno, e que, devido à sua descrição recente, poderiam ser desconhecidas pelos profissionais de saúde, o que atrasa seu diagnóstico e tratamento. O objetivo deste artigo é analisar essas doenças, a fim de descrever o conhecimento atual sobre sua etiologia, manifestações clínicas, diagnóstico e tratamento. Isso foi feito através da recopilação de artigos no Pubmed, com algumas contribuições das bases de dados Scielo, Redalyc, Europe PMC, Science Direct, Google Academic e Genetics Home Reference. Dentre as principais conclusões, destaca-se que os fenotipos associados à premutação do gene FMR1 incluem outros mecanismos fisiopatológicos além da síndrome do X frágil, apesar de eles estarem intimamente relacionados.

Dysregulated CRMP Mediates Circadian Deficits in a Drosophila Model of Fragile X Syndrome / 神经科学通报·英文版

Fragile X syndrome (FXS) is the leading inherited cause of intellectual disability, resulting from the lack of functional fragile X mental retardation protein (FMRP), an mRNA binding protein mainly serving as a translational regulator. Loss of FMRP leads to dysregulation of target mRNAs. The Drosophila model of FXS show an abnormal circadian rhythm with disruption of the output pathway downstream of the clock network. Yet the FMRP targets involved in circadian regulation have not been identified. Here, we identified collapsing response mediator protein (CRMP) mRNA as a target of FMRP. Knockdown of pan-neuronal CRMP expression ameliorated the circadian defects and abnormal axonal structures of clock neurons (ventral lateral neurons) in dfmr1 mutant flies. Furthermore, specific reduction of CRMP in the downstream output insulin-producing cells attenuated the aberrant circadian behaviors. Molecular analyses revealed that FMRP binds with CRMP mRNA and negatively regulates its translation. Our results indicate that CRMP is an FMRP target and establish an essential role for CRMP in the circadian output in FXS Drosophila.

Repeat expansion and methylation-sensitive triplet-primed polymerase chain reaction for fragile X mental retardation 1 gene screening in institutionalised intellectually disabled individuals

INTRODUCTION@#Fragile X syndrome (FXS) is the most prevalent X-linked intellectual disability (ID) and a leading genetic cause of autism, characterised by cognitive and behavioural impairments. The hyperexpansion of a CGG repeat in the fragile X mental retardation 1 (FMR1) gene leads to abnormal hypermethylation, resulting in the lack or absence of its protein. Tools for establishing the diagnosis of FXS have been extensively developed, including assays based on triplet-primed polymerase chain reaction (TP-PCR) for detection and quantification of the CGG trinucleotide repeat expansion, as well as determination of the methylation status of the alleles. This study aimed to utilise a simple, quick and affordable method for high sensitivity and specificity screening and diagnosis of FXS in institutionalised individuals with ID.@*METHODS@#A total of 109 institutionalised individuals at the Center for Social Rehabilitation of Intellectual Disability Kartini, Temanggung, Central Java, Indonesia, were screened in a three-step process using FastFrax™ Identification, Sizing and Methylation Status Kits.@*RESULTS@#Two samples that were classified as indeterminate with respect to the 41-repeat control at the identification step were subsequently determined to be non-expanded by both sizing and methylation status analyses. Two samples classified as expanded at the identification step were determined to carry full mutation expansions > 200 repeats that were fully methylated using sizing and methylation status analyses, respectively, yielding a disease prevalence of 1.83%.@*CONCLUSION@#Repeat expansion and methylation-specific TP-PCR is practical, effective and inexpensive for the diagnosis of FXS, especially in high-risk populations of individuals with ID of undetermined aetiology.

Síndrome del X frágil en fecundación in vitro: reporte de caso / Fragile X syndrome in in vitro fertilization: a case report

INTRODUCCIÓN: El síndrome de X frágil (SXF) es la primera causa heredable de discapacidad intelectual y autismo. Mujeres con la premutación del gen FMR1, relacionado con SXF, suelen ser asintomáticas, pero pueden tener hijos afectados. Se reporta un caso de SXF producto de fecundación in vitro con óvulos de una donante portadora de la premutación del FMR1. DESCRIPCIÓN DEL CASO: Pareja que requirió reproducción asistida dado que la mujer tenía antecedente de hipofisectomía; se realizó fecundación in vitro con óvulo donado, lográndose un embarazo gemelar. El gemelo femenino fue diagnosticado a los 2 años de edad con mutación completa del gen FMR1 y SXF, y la donante de óvulos, quien era asintomática, fue posteriormente confirmada como portadora de la premutación del FMR1. DISCUSIÓN: El protocolo de evaluación del riesgo de heredar enfermedades genéticas para donantes de óvulos se limita al cariotipo bandas G. Esta prueba no analiza alteraciones genéticas de herencia recesiva. Mediante secuenciación de nueva generación se podrían identificar portadoras de variantes alélicas patogénicas en estado de heterocigosis. Las mujeres con premutación del FMR1, tienen un riesgo del 50% de transmitir el alelo anormal a sus descendientes en cada embarazo, y estos de ser afectados por el SXF; por tanto, la asesoría genética es requerida en estos casos. CONCLUSIÓN: Los donantes de gametos deberían ser evaluados mediante pruebas moleculares para detección de variantes alélicas que pudieran ser transmitidas a sus gametos, y que pudieran generar enfermedades genéticas en los embarazos a partir de ellos.

INTRODUCTION: Fragile X syndrome (SXF) is the lead hereditary cause of intellectual disability and autism. Women with premutation in FMR1 gene, related to SXF, are usually asymptomatic, but they could have affected children. We report a case of SXF, product of an in vitro fertilization, secondary to an egg donation from a carrier of the premutation in the FMR1 gene. DESCRIPTION OF THE CASE: A couple required assisted reproduction because the woman had antecedent of hypophysectomy. An in vitro fertilization was done using a donated egg, achieving a twin pregnancy. The female twin was diagnosed with full mutation in the FMR1 gene and SXF by her second year of age. Donor woman, who was asymptomatic, was found to be a carrier of the premutation for SXF. DISCUSSION: The protocols to evaluate the risk of inherit genetic diseases for egg donors stint to band G karyotypes, which don—t consider genetic alterations with recessive inheritance pattern. Next generation sequencing allows to identify carriers of allelic heterozygote variations related with pathology. Women with the premutation in FMR1 have a risk of 50%, in each pregnancy, to pass down an affected allele to their offspring, who would be affected by SXF. Genetic counseling is mandatory in that cases. CONCLUSION: Gamete donor candidates should be submitted to molecular tests to identify allelic variants that could be inherited to the recipient offspring and cause genetic diseases.

Identificação de alterações genéticas relacionadas à síndrome do X frágil e ao transtorno de espectro do autismo por meio de ferramentas de bioinformática / Identification of genetic changes related to fragile x syndrome and autism spectrum disorder by bioinformatic tools

Introdução: a Síndrome do X Frágil (FXS) é a forma mais prevalente de deficiência intelectual herdável, e é a principal causa monogênica para o desenvolvimento de Transtorno de Espectro do Autismo (TEA). Objetivo: o objetivo do presente estudo é identificar RNAm associados à possíveis vias neurocomportamentais na SFX como no TEA, através de ferramentas de bioinformática. Metodologia: para identificação de possíveis vias alteradas entre a SFX e pacientes com TEA, utilizamos os bancos de dados GSE65106 e GSE21348 para anotação, visualização e descoberta integrada (DAVID 6.8). O valor de p <0,05 e fold change maior que 2 vezes (FC > 2) definidos como os limiares para a identificação de genes diferencialmente expressos (DE-RNAm). Resultados: foi possível identificar cerca de 32 DE-RNAm com funções em vias de spliceossomo, apoptose, transcrição, e em vias neurológicas comportamentais expressos exclusivamente na SFX. Os genes CAPNS1, HNRNPK, HNRPM, foram identificados como hipoexpressos em indivíduos com síndrome do X Frágil. Estes genes tem importante função moduladora nas respostas do potencial de longo prazo (LTP), plasticidade neural, e em transportadores de serotonina (SERT) alterando respostas que englobam humor, cognição e comportamentos, além de interferirem no receptor de dopamina (D2R) alterando as funções motoras e circuitos de recompensa. Conclusão: os genes CAPNS1, HNRNPK, HNRNPM foram identificados como marcadores genéticos eurocomportamentais importantes para a síndrome do X-frágil com expressão diminuída na doença, indicando uma possível modulação desses genes em aspectos fenotípicos marcantes da doença.

Introduction: fragile X Syndrome (FXS) is the most prevalent form of inheritable intellectual disability, and is the leading monogenic cause for the development of Autism Spectrum Disorder (ASD). Objective: the aim of this study is to identify mRNA associated with possible neurobehavioral pathways in SFX as in ASD, using bioinformatics tools. Methodology: to identify possible altered pathways between SFX and ASD patients, we used the GSE65106 and GSE21348 databases for annotation, visualization and integrated discovery (DAVID 6.8). The p value <0.05 and fold change greater than 2 times (HR> 2) are defined as the thresholds for the identification of differentially expressed genes (DE-mRNA). Results: it was possible to identify about 32 DE-mRNA with functions in spliceosome, apoptosis, transcription, and behavioral neurological pathways expressed exclusively in SFX. CAPNS1, HNRNPK, HNRPM genes were identified as hypoexpressed in individuals with fragile X syndrome. These genes play an important modulating role in long-term potential (LTP), neural plasticity, and serotonin transporters (SERT) responses by altering mood, cognition, and behavioral responses, and by interfering with dopamine receptor (D2R) by motor functions and reward circuits. Conclusion: the CAPNS1, HNRNPK, HNRNPM genes have been identified as important neurobehavioral genetic markers for impaired X-syndrome, indicating a possible modulation of these genes into marked phenotypic aspects of the disease.

Características físicas e bucais na síndrome do X frágil: revisão de literatura / Physical and oral characteristics of fragile X syndrome: literature review

Introdução: A síndrome do cromossomo X frágil é uma síndrome genética que acomete principalmente indivíduos do sexo masculino. O nome desta síndrome ocorre como consequência de um estreitamento da extremidade distal do braço longo do cromossomo X, local chamado de sítio frágil. O presente trabalho apresenta uma revisão de literatura, apresentando etiologia, prevalência, métodos de diagnósti-co, características comportamentais, características físicas gerais e de interesse odontológico, além das considerações acerca do atendimento, realizado pelo cirurgião-dentista, em portadores da síndrome do X frágil. Revisão de literatura: As principais características comportamentais são o déficit de atenção, a dificuldade na interação social, a timidez, a ansiedade, a labilidade emocional e os movimentos este-reotipados de mãos. Os achados de interesse odontológico mais prevalentes na literatura foram palato ogival, prog-natismo mandibular, macroglossia, hipoplasia de esmalte e má oclusão. Discussão: Não foram encontrados muitos artigos voltados para a análise facial e odontológica destes pacientes. O atendimento deste público é um desafio para o cirurgião-dentista devido às características comportamentais e fisiológicas apresentadas. Conclusão: o conhecimento das características desta síndrome pelo profissional é impor-tante, pois a síndrome comumente se associa à doenças sistêmicas que podem influenciar no plano de tratamento, além de alterações orofaciais importantes.

Introduction: The fragile X syndrome is a genetic syn-drome that mainly affects males. The name of this syn-drome occurs as a consequence of a narrowing of the distal end of the long arm of the X chromosome, a site called the fragile site. This paper presents a review of the literature, presenting etiology, prevalence, diagnostic methods, behavioral characteristics, general physical characteristics and dental interest, as well as considera-tions about the care provided by the dentist in patients with fragile X syndrome. Literature review: The main behavioral characteristics are attention deficit, difficulty in social interaction, shyness, anxiety, emotional lability and stereotyped hand movements. The most prevalent findings of dental interest in the literature were the ogival palate, mandibular prognathism, macroglossia, enamel hypoplasia and malocclusion. Discussion: There were not many articles focused on facial and dental analysis of these patients. The care of this public is a challenge for the dentist due to the behavioral and physiological characteristics presented. Conclusion: professional know-ledge of the characteristics of this syndrome is important, as the syndrome is commonly associated with systemic diseases that may influence the treatment plan, as well as major orofacial changes.

Síndrome X frágil: presentación clínica, patología y tratamiento / Fragile X syndrome: clinical presentation, pathology and treatment

Resumen El síndrome X frágil es la condición monogenética que produce más casos de autismo y de discapacidad intelectual. La repetición de tripletes CGG (> 200) y su metilación conllevan el silenciamiento del gen FMR1. La proteína FMRP (producto del gen FMR1) interacciona con los ribosomas, controlando la traducción de mensajeros específicos y su pérdida produce alteraciones de la conectividad sináptica. El tamizaje de síndrome X frágil se realiza por reacción en cadena de la polimerasa. La recomendación actual de la Academia Americana de Pediatría es realizar pruebas a quienes presenten discapacidad intelectual, retraso global del desarrollo o antecedentes familiares de afección por la mutación o premutación. Países hispanos como Colombia, Chile y España reportan altas prevalencias de síndrome X frágil y han creado asociaciones o corporaciones nacionales de X frágil que buscan acercar a los pacientes a redes disponibles de diagnóstico y tratamiento.

Abstract Fragile X syndrome is the monogenetic condition that produces more cases of autism and intellectual disability. The repetition of CGG triplets (> 200) and their methylation entail the silencing of the FMR1 gene. The FMRP protein (product of the FMR1 gene) interacts with ribosomes by controlling the translation of specific messengers, and its loss causes alterations in synaptic connectivity. Screening for fragile X syndrome is performed by polymerase chain reaction. Current recommendation of the American Academy of Pediatrics is to test individuals with intellectual disability, global developmental retardation or with a family history of presence of the mutation or premutation. Hispanic countries such as Colombia, Chile and Spain report high prevalence of fragile X syndrome and have created fragile X national associations or corporations that seek to bring patients closer to available diagnostic and treatment networks.

Assessment of FMR1 triplet repeats in patients affected with mental retardation, fragile X syndrome and primary ovarian insufficiency

The CGG repeats in the FMR1 gene expand in patients with fragile X syndrome, fragile X-associated tremour/ataxia syndrome and fragile X-associated primary ovarian failure. In this study, the CGG repeats in the FMR1 gene were studied in 449 males and 207 females using traditional polymerase chain reaction and triplet repeat primed PCR methods, also 18 CVS samples (six males and 12 females) were tested for prenatal diagnosis. Further, methylation sensitive multiplexed ligation dependent probe amplification was performed on some samples to confirm the results. Regarding the male patients, 1.1% and 9.7% had premutation (PM) and full mutation (FM) alleles, respectively. Also three (0.66%) male patients were mosaic for PM and FM alleles. Among females, 1.9% were GZ carriers and 5.8% were PM carriers. Prenatal diagnosis resulted in detection of two PM and one FM males as well as one FM carrier female. Our results were in concordance with the previously published results.

Fragilidad del X y otras entidades asociadas al gen FMR1: estudio de 28 familias afectadas / Fragile X syndrome and other entities associated with the FMR1 gene: Study of 28 affected families

El síndrome de fragilidad del cromosoma X es la causa de discapacidad intelectual heredable más frecuente. Asociado a trastornos del espectro autista en un tercio de los pacientes, afecta, con mayor prevalencia, a los varones. Se debe a una expansión de trinucleótidos CGG (citosina, guanina, guanina), llamada mutación completa en el locus Xq27.3 del gen FMR1, que conduce a la hipermetilación en el promotor del gen y reduce los niveles de expresión de FMRP, una proteína implicada en la maduración y plasticidad sináptica. Una expansión menor de CGG es la causa de insuficiencia ovárica primaria y del síndrome de temblor/ataxia asociado a X frágil, caracterizado por ataxia cerebelosa progresiva, de inicio tardío, y temblor de intención. En el presente estudio de serie de casos, se analiza la segregación de mutaciones del gen FMR1 en diferentes familias y la variabilidad de expresión clínica que llevó a la consulta genética.

The fragile X syndrome occurs due to an expansion of CGG trinucleotides, called full mutation, which is found at the Xq27.3 locus of the FMR1 gene. It is the most common cause of inherited intellectual disability. Associated with autistic spectrum disorders in one third of the patients, it affects males with higher prevalence. It also leads to hypermethylation of the gene promoter, silencing it and reducing the expression levels of FMRP, a protein involved in synaptic maturation and plasticity. A lower expansion causes primary ovarian failure syndrome as well as tremor and ataxia syndrome characterized by progressive cerebellar ataxia of late onset and intention tremor. In the present case-control study we analyze the segregation of mutations of the FMR1 gene in different families and the variability of expression that led to the genetic consultation.

Evaluation of FMR1 gene mutations in Turkish women newly diagnosed with primary ovarian failure

Background: One of the known causes of ovarian dysfunction is fragile X mental retardation gene 1 (FMR1) premutation. The prevalence of FMR1 premutation in primary ovarian failure (POF) cases may differ between the studies due to some reasons including POF definition, definition of premutation, and determination of study population, ethnicity, genetic and environmental factors. In this study authors aimed to determine the prevalence of FMR1 mutations in patients who applied to present clinic and diagnosed as POF.Methods: This retrospective cohort study was conducted on 200 women who had been newly diagnosed with POF in present clinic between 2013 and 2014. The presence of cytogenetic fragility was firstly investigated in all patients by using the lymphocyte culture method, and molecular analysis of the FMR1 gene was then performed. Genomic DNA’s of cases were isolated using standard protocols, followed by polymerase chain reaction amplification with an appropriate program. Fragment analysis of the amplification products were performed by agarose gel electrophoresis.Results: Cytogenetic analysis results in 200 cases were numerically and structurally normal in all patients, and as a result of molecular genetic analysis of FMR1 gene; 1 (0.5%) patient had complete mutation and 9 (4.5%) patients had premutation carriage.Conclusions: FMR1 gene mutations are common in women with POF. These mutations should be investigated in all patients presenting with POF, particularly in cases with early onset and family history of POF, and also genetic counseling should be given to those patients.

Lifestyle and quality of life in patients with metabolic syndrome and type 2 diabetes / Estilo de vida y calidad de vida en pacientes con sindrome metabólico y diabetes tipo 2

The objective of the study was to determine the lifestyle and quality of life in type 2 diabetes mellitus and metabolic syndrome patients in the city of Popayán. A descriptive cross-sectional study was carried out with 81 patients with metabolic syndrome and type 2 diabetes mellitus diagnoses. EUROQOL questionnaires of 5 Dimensions-3 Levels were applied, as well as the IMEVID test, in order to evaluate the quality of life and lifestyle of each group of patients. Anthropometric measures were also taken, suchas Body Mass Index, Waist-Hip Ratio and skinfolds. Regarding the results, 33.33% of the participants were between 61 and 70 years of age 56.8% presented moderate pain problems/discomfort, 61.7% presented an unhealthy lifestyle and obtained variable relationships such as: waist-hip ratio -glycemia (p = 0.021, r = -0.257), body density -triglycerides (p = 0.018, r = 0.263), age and mobility EUROQOL (p = 0.001, r = 0.350). In conclusion, lifestyle changes are one of the pillars to control metabolic syndromeand type 2 diabetes mellitus. Evaluating the quality of life also makes it possible to understand how compromised patients' abilities are, in order to create relevant strategies and actions that seek their well-being.

El objetivo del estudio fue determinar el estilo de vida y calidad de vida en pacientes con diabetes mellitus tipo 2 y síndrome metabólico en la ciudad de Popayán. Se realizó un estudio descriptivo de corte transversal con 81 pacientes, a los cuales se le aplicaron los cuestionarios EUROQOL de 5 Dimensiones­3 Niveles y el test IMEVID para evaluar la calidad de vida y el estilo de vida respectivamente, también se tomaron medidas antropométricas como Índice de masa corporal, índice cintura-cadera y pliegues cutáneos. Respecto a los resultados el 33.33% de los participantes están entre los 61 y 70 años de edad, se identificó que el 56.8% presentan moderados problemas en dolor/malestar, 61.7% presentaron un regular estilo de vida y se obtuvo relación entre variables como: índice de cintura cadera ­glicemia (p=0.021; r = -0.257), densidad corporal -triglicéridos (p= 0.018; r= 0.263), edad y EUROQOL movilidad (p= 0.001; r=0.350). En conclusión, la modificación del estilo de vida es uno de los pilares en la prevención y el manejo del síndrome metabólico y la diabetes mellitus tipo 2, así como también la evaluación de la calidad de vida permite generar las estrategias y acciones pertinentes que busquen el bienestar del paciente

Prenatal diagnosis for 30 women carrying a FMR1 mutation / 中华医学遗传学杂志

Objective@#To determine the CGG repeat number and methylation status of FMR1 gene for fetuses whose mothers have carried a FMR1 mutation.@*Methods@#For 30 pregnant women, the fetal CGG repeat number was determined with a GC-rich PCR system by using chorionic villus, amniotic fluid or umbilical blood samples. The methylation status of the FMR1 gene was confirmed with Southern blotting.@*Results@#In total 30 prenatal diagnoses were performed for 29 carriers of FMR1 gene mutations and 1 with FMR1 gene deletion mosaicism. Three fetuses were found to carry premutations, 9 were with full mutations and 1 with mosaicism of premutation and full mutations. Eighteen fetuses were normal.@*Conclusion@#Considering the genetic complexity of Fragile X syndrome (FXS), single method may not suffice accurate determination of their genetic status. The pitfalls and technical limitations of protocols requires adoption of personalized strategy for its prenatal diagnosis.

Persistent metabolic syndrome and risk of cardiovascular disease in children and adolescents / Síndrome metabólico infantojuvenil persistente y relación con el riesgo de enfermedad cardiovascular / Síndrome metabólica infanto-juvenil persistente e relação com o risco de doença cardiovascular

ABSTRACT Objective: to verify persistence of metabolic syndrome (MetS) and components in overweight children and adolescents, as well as its relation to socioeconomic and demographic characteristics and to the Pathobiological Determinants of Atherosclerosis in Youth (PDAY) score. Method: a two-point longitudinal study: at enrollment and after a 24-month interval, with 133 individuals ages from two to 18 years. The demographic anthropomorphic and blood variables were evaluated. Analysis was carried out by simple and paired association tests, as well as multiple logistic regression. Results: persistent MetS was observed in 38.3% of the sample, associated cardiovascular risk (ACR) in 79.7%, reduction in arterial pressure and do HDL-c. After adjusting for age and sex, excess weight (ExpB: 0.182; CI: 0.059-0.561), low HDL-c (ExpB: 9.247; CI: 1.157-73.930) and high LDL-c (ExpB:1.915; CI: 0.921-3.979) were associated with persistent MetS. Conclusion: persistent MetS was associated with obesity, HDL-c and LDL-c, but not with the PDAY score.

RESUMEN Objetivo: Verificar persistencia del síndrome metabólico (SM) y componentes en niños y adolescentes con exceso de peso, además de su relación con características socioeconómicas, demográficas y con el puntaje de Pathobiological Determinants of Atherosclerosis in Youth (PDAY). Método: Estudio longitudinal con dos ítems: reclutamiento y 24 meses con 133 individuos de entre 2 y 18 años. Evaluadas variables socioeconómicas, demográficas, antropométricas y sanguíneas. Realizado análisis mediante tests de asociación simple y pareada, además de regresión logística múltiple. Resultados: Se verificó persistencia de SM en 38,3% de muestra, riesgo cardiovascular asociado (RCV) en 79,7%, reducción de presión arterial y HDL-c. Ajustados por edad y sexo, el exceso de peso (ExpB: 0,182; IC: 0,059-0,561), el bajo HDL-c (ExpB:9,247; IC:1,157-73,930) y el elevado LDL-c (ExpB:1,915; IC: 0,921-3,979) se mostraron asociados a la SM persistente. Conclusión: El SM persistente estuvo asociado al exceso de peso, HDL-c y LDL-c, pero no con el puntaje PDAY.

RESUMO Objetivo: verificar a persistência da síndrome metabólica (SM) e componentes em crianças e adolescentes com excesso de peso, além de sua relação com características socioeconômicas, demográficas e com o escore Pathobiological Determinants of Atherosclerosis in Youth (PDAY). Método: estudo longitudinal com dois pontos: recrutamento e 24 meses com 133 indivíduos entre dois e 18 anos. Foram avaliadas variáveis socioeconômicas, demográficas, antropométricas e sanguíneas. Realizou-se análise através de testes de associação simples e pareado, além de regressão logística múltipla. Resultados: verificou-se persistência de SM em 38,3% da amostra, risco cardiovascular associado (RCV) em 79,7%, redução da pressão arterial e do HDL-c. Ajustados por idade e sexo, o excesso de peso (ExpB: 0,182; IC: 0,059-0,561), o baixo HDL-c (ExpB: 9,247; IC: 1,157-73,930) e o elevado LDL-c (ExpB:1,915; IC: 0,921-3,979) mostraram-se associados à SM persistente. Conclusão: a SM persistente teve associação com o excesso de peso, HDL-c e LDL-c, mas não com o escore PDAY.