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.

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.

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.

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.

Evaluación del uso de fármacos y conducta en pacientes con síndrome X frágil / Asessment of pharmacological freatment and behavioral changes in patients with fragile X syndrome

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.

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.

Envejecimiento en personas con trastorno del espectro autista / Aging in people with autism spectrum disorder

El trastorno del espectro autista se caracteriza por una alteración cualitativa en la interacción social y la comunicación, asociada a intereses restringidos y conductas estereotipadas. Esta condición acompañará a las personas a lo largo de toda la vida, con variaciones en su evolución. Nuestros objetivos fueron conocer las características evolutivas de las personas con trastorno del espectro autista, analizando aspectos cognitivos, conductuales, salud, mortalidad y sus necesidades en la etapa de envejecimiento, que permitan orientar la planificación de recursos específicos de apoyo. Se analizaron estudios relacionados con la evolución en la vida adulta en personas con este trastorno, con o sin entidades identificadas, y las condiciones sociosanitarias que deben ser consideradas en los procesos de envejecimiento. El conocimiento sobre el envejecimiento en personas con autismo es aún escaso y resulta difícil definir un patrón específico pues este dependerá, entre otros factores, de la etiología, el grado, la presencia de discapacidad intelectual y/o epilepsia, y el ámbito en el que viven, los cuales pueden incluso condicionar la expectativa de vida. El envejecimiento se ha asociado a trastornos del humor, depresión, deterioro en funciones ejecutivas y memoria episódica, aunque resulta difícil diferenciarlo del envejecimiento natural en personas con desarrollo típico. La identificación de una entidad específica permitirá conocer la posible evolución y prevenir complicaciones en síndromes que pueden estar asociados con autismo: X frágil, Down, Angelman, Rett y Williams, por ello jerarquizamos la consulta genética y neurológica.

Autism spectrum disorder is characterized by a qualitative alteration in social interaction and communication associated with restricted interests and stereotyped behaviors. This condition will accompany people throughout their lives, with variations in their evolution. Our objectives were to know the evolutionary characteristics of people with autistic spectrum disorder, analyzing cognitive, behavioral, health, mortality and their needs in the aging stage, which will guide the planning of specific support resources. We analyze studies related to the evolution in adult life in people with this disorder, with or without identified entities, and socio-health conditions that should be considered in the aging process. The knowledge about aging in people with autism is still scarce and it is difficult to define a specific pattern because this will depend, among other factors, on the etiology, the degree, the presence of intellectual disability and/or epilepsy, and the scope in where live, which can even condition the life expectancy. Aging has been associated with mood disorders, depression, deterioration in executive functions and episodic memory, although it is difficult to differentiate it from natural aging in people with typical development. The identification of a specific entity will allow to know the possible evolution and prevent complications in syndromes that may be associated with autism: fragile X, Down, Angelman, Rett and Williams, for that reason we rank the genetic and neurological consultation.

Fragile X Syndrome in a Colombian Family / Sindrome X frágil en una Familia Colombiana

RESUMEN Se realizó un estudio descriptivo a una familia de Cali, Colombia, en el cual se evaluaron nueve pacientes, tres de los cuales presentaban discapacidad intelectual sin diagnóstico etiológico anterior. El caso índice fue diagnosticado con el síndrome X frágil mediante pruebas moleculares de ADN. Se realizaron pruebas en cascada a todos los miembros de la familia disponibles, identificando dos individuos adicionales con la mutación completa y cuatro portadores del alelo con pre mutación. Con este informe pretendemos contribuir a la epidemiología colombiana del síndrome y destacamos la importancia del diagnóstico etiológico de la discapacidad intelectual y proporcionar un tratamiento integral y específico a las personas afectadas. Además se busca identificar a los portadores de la pre mutación o mujeres con mutación completa sin fenotipo clásico para el asesoramiento genético y la educación sobre posibles patologías asociadas.

SUMMARY A study was performed on a family from Cali, Colombia in which nine patients were evaluated, three of which presented with intellectual disability with no previous etiological diagnosis. The proband was diagnosed with Fragile X syndrome by DNA molecular testing and, cascade testing, performed on all available family members, identifying two additional individuals with the full mutation and four carriers of a premutation allele. With this report we seek to contribute to Colombian epidemiology of the syndrome and emphasize the importance of diagnosis to provide a comprehensive and specific treatment to those affected. Further we seek to identify premutation carriers in their families or women with a full mutation without the classic phenotype for genetic counseling and education about potential associated pathologies.

Tremor-Ataxia syndrome and primary ovarian insufficiency in an FMR1 premutation carrier / Síndrome de Tremor Ataxia y falla ovárica prematura en portadora de la premutación del gen FMR1

Abstract Introduction: The FMR1 gene has four allelic variants according to the number of repeats of the CGG triplet. Premutation carriers with between 55 and 200 repeats are susceptible to developing pathologies such as tremor and ataxia syndrome (FXTAS) and fragile X-associated primary ovarian insufficiency (FXPOI) syndrome. Case description: The patient was a 53-year-old female farmer with severe tremor in the upper limbs at rest that worsens with movement, tremor in the jaw and tongue, and generalized cerebral atrophy. She is a carrier of the FMR1 premutation diagnosed by PCR and Southern Blot, complying with the clinical and radiological criteria of FXTAS, and in addition, has a history of vagal symptoms suggestive of ovarian failure and menstrual cycle disorders that led to hysterectomy at age 33 and was subsequently diagnosed with FXPOI. Conclusion: An unusual case of FXTAS and FXPOI complying with clinical and radiological criteria is reported in a premutation carrier of the FMR1 gene.

Resumen Introducción: el gen FMR1 tiene cuatro variantes alélicas según el número de repeticiones de la tripleta CGG. Los portadores de la premutación con un número entre 55 y 200 repeticiones son susceptibles de desarrollar patologías como el síndrome de temblor y ataxia (FXTAS) y síndrome de falla ovárica prematura (FXPOI) asociados al X frágil. Descripción del caso: Mujer de 53 años, agricultora, con temblor severo en miembros superiores en reposo que empeora con el movimiento, temblor en mandíbula y lengua, atrofia cerebral generalizada, portadora de la premutación del gen FMR1 diagnosticada por PCR y Southern Blot, cumpliendo con criterios clínicos y radiológicos de FXTAS; ademas, historia de síntomas vagales sugestivos de falla ovárica y trastornos del ciclo menstrual que llevaron a histerectomía a los 33 años, haciendose diagnóstico FXPOI. Conclusión: Se reporta un caso inusual en portadoras de la premutación del gen FMR1, con criterios clínicos y radiológicos de FXTAS y FXPOI.

A Síndrome do X Frágil e o estabelecimento de fenótipos cognitivo-comportamentais: uma revisão sistemática de literatura / The Fragile X Syndrome and the development of cognitive-behavioral phenotypes: a literature systematic review

Este artigo consiste em uma revisão sistemática de literatura que tem como objetivo fazer um panorama do conteúdo das publicações sobre cognição, comportamento e Síndrome do X Frágil. Realizou-se o levantamento bibliográfico nas bases de dados Pubmed, Science Direct, SciELO e LILACS, por meio dos descritores pré-estabelecidos cognition, behavior e Fragile X Syndrome. Foram selecionados 9 trabalhos para uma análise mais cuidadosa. Todos eram relevantes em relação às características fenotípicas cognitivo-comportamentais de crianças com a Síndrome do X Frágil, relatavam pesquisas experimentais transversais e descreviam aspectos comportamentais e/ou relacionados às funções executivas. As características cognitivas mais frequentemente apontadas pela revisão realizada foram: baixo coeficiente de inteligência, prejuízos na atenção, linguagem deficitária e motricidade. Já os aspectos comportamentais destacados estavam relacionados ao transtorno do espectro autista, à ansiedade e às dificuldades na socialização. Notou-se a presença de poucos estudos disponíveis na literatura e a necessidade de maiores investimentos nessa área de pesquisa. Mais estudos auxiliarão na maior compreensão da Síndrome do X Frágil e ampliarão as possibilidades de intervenção.

This article consists of a systematic literature review that aims to make an overview of the content of publications on cognition, behavior and Fragile X syndrome. It was conducted the literature review in Pubmed, Science Direct, SciELO and LILACS, usingthe pre-established descriptors cognition, behavior and Fragile X Syndrome. Nine papers were selected for closer examination. All were relevant in relation to cognitive behavioral phenotypic characteristics of children with Fragile X Syndrome, reported cross experimental research and described behavioral aspects and/or related to executive functions. Cognitive characteristics most often highlighted by the review were conducted: low intelligence quotient, impairments in attention, poor motor skills and language. Behavioral aspects were related to autism spectrum disorder, anxiety and difficulties in socialization. The presence of few studies available in the literature and the need for further investments in this area of research it was noted. More studies will assist in better understanding of Fragile X Syndrome and expand the possibilities of intervention.

Report of a patient with fragile X syndrome unexpectedly identified by karyotype analysis / Relato de um paciente com a síndrome do X frágil identificada de forma inesperada por meio do cariótipo

ABSTRACT Fragile X syndrome is considered the main known cause of inherited learning disabilities and it is characterized by mutations in the FMR1 gene. Our aim was to report an unexpected detection of a patient with fragile X syndrome by GTG-Banding karyotype analysis (G-bands after trypsin and Giemsa). The karyotype analysis identified Xq27.3 fragility in 17% of the metaphases analyzed and in 54% when using TC 199, consistent with the cytogenetic diagnosis of the syndrome. This case was the sole one to present the fra(X) tests in the high-resolution karyotype analysis in our care service, contributing to future diagnoses of patients with history of developmental delay.

RESUMO A síndrome do X frágil é a principal causa conhecida de deficiência de aprendizagem herdada, caracterizada por mutações no gene FMR1. Relatamos a detecção inesperada de um paciente com síndrome do X frágil por meio de cariótipo de sangue periférico com bandamento GTG (bandamento G após tripsina e Giemsa). A análise cariotípica identificou fragilidade Xq27.3 em 17% das metáfases analisadas e em 54% quando utilizado TC 199, consistente com o diagnóstico citogenético da síndrome. Este caso foi o único a apresentar as provas de fra(X) no cariótipo de alta resolução em nosso serviço de atendimento, contribuindo para futuros diagnósticos de pacientes com história de atraso no desenvolvimento.

Primeras manifestaciones clínicas de un síndrome de X frágil en la comunidad / First clinical manifestations of a case of fragile X syndrome in the community

Fundamento: el síndrome del X frágil es el más común de los trastornos de retraso mental ligados al cromosoma X. Objetivo: presentar las primeras manifestaciones clínicas de un caso de síndrome de X frágil que no comenzó con retardo del desarrollo psicomotor. Caso clínico: paciente que es remitido a consulta de genética por presentar macrocráneo y orejas displásicas en forma de copa. Al año y seis meses presentó retardo del desarrollo psicomotor. El examen físico, los exámenes complementarios dieron el diagnóstico de un síndrome del X Frágil. Se le puso tratamiento en consulta de estimulación temprana y el paciente mejoró el desarrollo psicomotor. Conclusiones: la aparición de macrocefalia y el retardo del desarrollo psicomotor contribuyeron a realizar el diagnóstico oportuno de esta enfermedad. La estimulación temprana permitió avances en el desarrollo psicomotor del paciente.

Background: fragile X Syndrome is the most common mental retardations disorders linked to X chromosome. Objective: to show the first clinical manifestations of a case of Fragile X Syndrome case that did not began with psychomotor development retardation. Clinical case: a patient who is transferred to genetic consult for presenting macrocranium, dysplastic ears in form of cup. Aged one year and six month old, he had psychomotor development retardation. Physical examinations and complementary test confirmed Fragile X Syndrome diagnosis. The patient was treated in early stimulation consult which improved the psychomotor development retardation. Conclusions: the presence of macrocephaly and later psychomotor development retardation helped to make the appropriate diagnosis of that disorder. Early stimulation permitted advances in psychomotor development in this patient.

Manejo hemodinámico mediante monitor no invasivo de gasto cardiaco para craneotomía urgente en el síndrome X frágil: reporte de caso / Haemodynamic management using non-invasive cardiac output monitoring for urgent craniotomy in fragile X syndrome: Case report

Fragile X syndrome is an inherited form of mental retardation with a connective tissue component involving mitral valve prolapse. The most frequent manifestations of fragile X syndrome are learning disability, orofacial morphological alterations and macroorchidism. The usefulness of advanced haemodynamic monitoring for goal-directed therapy is increasingly high during neurosurgical procedures. Non-invasive cardiac output monitoring may be considered as a new alternative for emergency neurosurgical procedures. Our aim was to detect haemodynamic changes in a syndromic fragile X patient, given the usual concomitant presentation of cardiovascular disease, such as mitral valve prolapse and dilated aortic root, in an attempt at obtaining the best intraoperative and postoperative neurological outcomes without worsening cardiovascular function, by means of individualized intra-operative goal directed therapy. This type of non-invasive monitoring allows surgery to proceed without delay and provides excellent information of the haemodynamic status. This syndrome is relevant due to its anaesthetic implications and the paucity of cases published to date.

El síndrome X frágil es una forma hereditaria de retraso mental con una afectación de tejido conectivo que produce prolapso de la válvula mitral. Las manifestaciones más frecuentes del síndrome X frágil son la dificultad en el aprendizaje, alteraciones morfológicas orofaciales y macroorquidismo. La utilidad de la monitorización hemodinámica avanzada para terapia dirigida por objetivos es cada vez mayor durante los procedimientos neuroquirúrgicos. La monitorización no invasiva de gasto cardiaco puede considerarse una nueva alternativa en los procedimientos neuroquirúrgicos emergentes. Nuestro objetivo fue detectar los cambios hemodinámicos en un paciente sindrómico X frágil que suelen presentar patología cardiovascular, como prolapso mitral y dilatación de la raíz aórtica, intentando obtener los mejores resultados neurológicos intraoperatorios y posoperatorios sin deteriorar la función cardiovascular individualizada por una terapia guiada por objetivos. Este tipo de monitorización no invasiva permite desarrollar la intervención quirúrgica sin demora, aportando gran información del estado hemodinámico. Este síndrome es relevante debido a sus implicaciones anestésicas y los pocos casos publicados hasta la fecha.

Aspectos estomatológicos en el síndrome del X frágil: Revisión de la literatura y presentación de un caso clínico / Stomatological aspects in fragile X syndrome cases: Literature review and clinical case presentation

El síndrome del X frágil (SXF) es una anomalía genética causada por la replicación excesiva en la secuencia del nucleótido CGG que ocasiona anomalías físicas y psicológicas importantes, las cuales repercuten en el desarrollo intelectual del niño, además de que es la segunda causa genética más importante de retraso mental después del síndrome de Down; en ocasiones, y debido a la transición epidemiológica los trastornos de déficit de atención así como la hiperactividad, son confusos en el diagnóstico clínico y puede ser que el SXF sea subdiagnosticado. En la práctica estomatológica los trastornos del comportamiento son de suma importancia, ya que la piedra angular en el manejo de la conducta es la comunicación. Este trabajo está destinado a estimular al clínico para que busque más en los pacientes con retraso mental, trastorno por déficit de atención (TDA) e hiperactividad para encontrar el SXF, ya que el subdiagnóstico complica el tratamiento, el cual es específico y el consejo genético es importante en estos pacientes.

Fragile X syndrome (FXS) is a genetic anomaly caused by excessive replication in the CGG nucleotide sequence which elicits severe physiological and physical anomalies which impair the child's intellectual development. Moreover, FXS constitutes, after Down's syndrome, the second most frequent genetic cause for mental retardation. Due to epidemiological transition, attention deficit disorders as well as hyperactivity are confused in the clinical diagnosis; this might lead to a situation where FXS might be under-diagnosed. In the realm of stomatological practice, behavior disorders are most important since communication can be considered the cornerstone of behavior management. The present study purports the aim of encouraging the clinician to look further into patients afflicted with mental retardation, TDA and hyperactivity to find FXS since under-diagnosis impairs treatment, is specific and genetic counseling for these patients is of the utmost importance.

Fragile X Syndrome / Síndrome de X Frágil

Fragile X Syndrome (FXS) is a genetic disease due to a CGG trinucleotide expansion, named full mutation (greater than 200 CGG repeats), in the FMR1 gene locus Xq27.3; which leads to an hypermethylated region in the gene promoter therefore silencing it and lowering the expression levels of FMRP, a protein involved in synaptic plasticity and maturation. Individuals with FXS present with intellectual disability, autism, hyperactivity, long face, large or prominent ears and macroorchidism at puberty and thereafter. Most of the young children with FXS will present with language delay, sensory hyper arousal and anxiety. Girls are less affected than boys, only 25% have intellectual disability. Given the genomic features of the syndrome, there are patients with a number of triplet repeats between 55 and 200, known as premutation (PM) carriers. Most carriers have a normal IQ but some have developmental problems. The diagnosis of FXS has evolved from karyotype with special culture medium, to molecular techniques that are more sensitive and specific including PCR and Southern Blot. During the last decade, the advances in the knowledge of FXS, has led to the development of investigations on pharmaceutical management or targeted treatments for FXS. Minocycline and sertraline have shown efficacy in children.

El Síndrome de X Frágil (SXF), es una enfermedad genética debida a una expansión del trinucleótido CGG, nombrada mutación completa (más de 200 repeticiones de CGG) en el gen FMR1, locus Xq27.3; la cual lleva a una hipermetilación de la región promotora del gen, silenciándolo y disminuyendo los niveles de expresión de la proteína FMRP relacionada con la plasticidad y maduración neuronal. Los individuos con SXF presentan retardo mental, autismo, hiperactividad, cara alargada, orejas grandes o prominentes y macroorquidismo desde la pubertad. La mayoría de niños con SXF presentan retraso en el lenguaje, hiperactivación sensorial y ansiedad. Las niñas se afectan menos que los varones, solo el 25% presenta retardo mental. Dadas las características genómicas del síndrome, existen pacientes con un número de repetición de la tripleta entre 55 y 200 que se denominan portadores de la premutación. La mayoría de los portadores tienen un coeficiente intelectual normal, pero presentan problemas en el desarrollo. El diagnóstico en SXF ha evolucionado del cariotipo con medio especial de cultivo, a pruebas moleculares más sensibles y específicas incluyendo PCR y Southern blot. Durante la última década, los avances en el conocimiento sobre el SXF han permitido el desarrollo de investigaciones sobre el manejo farmacológico o tratamientos específicos para el SXF. La minociclina y la sertralina han demostrado eficacia en niños.

Fragile X Syndrome and Epilepsy: case report / Síndrome do X Frágil e Epilepsia: relato de caso

Introduction: Learning disabilities is defined by intelligence quotient of less than or equal to 70 associated with limited learning functions such as cognition, language, motor function and social skills activities. Epilepsy is more common in individuals with learning disabilities and its frequency increases progressively considering severe intellectual impairment. Fragile X syndrome is the most common genetic cause of learning disability and 10-20% of these children have epilepsy. Methods: We describe a patient with fragile X syndrome, who had febrile seizures leading to temporal lobe epilepsy. Results: Male patient, 36 years old. He had several episodes of febrile seizures from one to seven years old and at the age of 27 he started with spontaneous dyscognitive seizures with possible temporal lobe origin. His brother, who also has the diagnosis of fragile X syndrome, presented a single afebrile seizure as a child. Patient's MRI showed left hippocampal atrophy. Conclusion: The relationship between febrile seizure and temporal lobe epilepsy in the context of fragile X syndrome is discussed in this article. Fragile X syndrome turns patients morevulnerable to have any kind of seizures. Therefore, we have to prevent febrile seizures in these patients...

Introdução: O déficit de aprendizagem é definido por quociente de inteligência inferior ou igual a 70 associado às funções limitadas de aprendizagem, tais como a cognição, a linguagem, a função motora e as habilidades sociais. Epilepsia é mais comum em indivíduos com dificuldades de aprendizagem e sua incidência aumenta progressivamente em pacientes com deficiência intelectual grave. Síndrome do X Fragil é a causa genética mais comum de deficiência de aprendizado e 10-20% destas crianças têm epilepsia. Métodos: Nós descrevemos um paciente com síndrome do X frágil, que teve convulsões febris e evoluiu com epilepsia do lobo temporal. Resultados: O paciente apresentou dois episódios de convulsão febril durante a infância e, com 27 anos, iniciou crises discognitivas típicas de lobo temporal. Seu irmão, que também tem síndrome do X frágil, apresentou crise afebril única na infância. A RM do paciente mostrou atrofia hipocampal à esquerda. Conclusão: A relação entre a convulsão febril e epilepsia do lobo temporal no contexto da síndrome do X frágil é discutida neste artigo. Pacientes com síndrome do X frágil são mais suscetíveis a ter qualquer tipo de crise epiléptica. Portanto, temos que tentar evitar crise febril prolongada nestes pacientes...

Cognitive and behavioral heterogeneity in genetic syndromes / Heterogeneidade cognitiva e comportamental em síndromes genéticas

OBJECTIVE: this study aimed to investigate the cognitive and behavioral profiles, as well as the psychiatric symptoms and disorders in children with three different genetic syndromes with similar sociocultural and socioeconomic backgrounds. METHODS: thirty-four children aged 6 to 16 years, with Williams-Beuren syndrome (n = 10), Prader-Willi syndrome (n = 11), and Fragile X syndrome (n = 13) from the outpatient clinics of Child Psychiatry and Medical Genetics Department were cognitively assessed through the Wechsler Intelligence Scale for Children (WISC-III). Afterwards, a full-scale intelligence quotient (IQ), verbal IQ, performance IQ, standard subtest scores, as well as frequency of psychiatric symptoms and disorders were compared among the three syndromes. RESULTS: significant differences were found among the syndromes concerning verbal IQ and verbal and performance subtests. Post-hoc analysis demonstrated that vocabulary and comprehension subtest scores were significantly higher in Williams-Beuren syndrome in comparison with Prader-Willi and Fragile X syndromes, and block design and object assembly scores were significantly higher in Prader-Willi syndrome compared with Williams-Beuren and Fragile X syndromes. Additionally, there were significant differences between the syndromes concerning behavioral features and psychiatric symptoms. The Prader-Willi syndrome group presented a higher frequency of hyperphagia and self-injurious behaviors. The Fragile X syndrome group showed a higher frequency of social interaction deficits; such difference nearly reached statistical significance. CONCLUSION: the three genetic syndromes exhibited distinctive cognitive, behavioral, and psychiatric patterns. .

OBJETIVO: investigar o perfil cognitivo e comportamental, sintomas e transtornos psiquiátricos em crianças com três diferentes síndromes genéticas, com antecedentes socioculturais e socioeconômicos semelhantes. MÉTODOS: trinta e quatro crianças, entre 6 e 16 anos, com as síndromes de Williams-Beuren (n = 10), de Prader-Willi (n = 11) e do X-Frágil (n = 13), dos ambulatórios de Psiquiatria Infantil e Genética Médica, foram avaliadas cognitivamente pela Escala Wechsler de Inteligência para Crianças (WISC-III). Posteriormente, o QI total, o QI Verbal, o QI de Execução, os escores ponderados dos subtestes e a frequência de sintomas e transtornos psiquiátricos foram comparados entre as síndromes. RESULTADOS: diferenças significativas foram encontradas entre as síndromes quanto ao QI Verbal e os subtestes verbais e de execução. A análise Post-hoc demonstrou que os escores dos subtestes vocabulário e compreensão foram significativamente superiores na síndrome de Williams-Beuren em relação às síndromes de Prader-Willi e do X-Frágil, e os escores dos subtestes cubos e armar objetos foram significativamente superiores na síndrome de Prader-Willi em relação às síndromes de Williams-Beuren e do X-Frágil. Além disso, houve diferença significativa entre as síndromes quanto às características comportamentais e os sintomas psiquiátricos. O grupo com síndrome de Prader-Willi apresentou maior frequência de hiperfagia e comportamentos autolesivos. Já o grupo com síndrome do X-Frágil apresentou maior frequência do déficit da interação social. Esta diferença quase alcançou a significância estatística. CONCLUSÃO: as três síndromes genéticas ...