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INTRODUCTION: Fragile X syndrome (FXS) is the most common cause of hereditary genetic disorder in a single gene characterised by intellectual disability. Behavioural features such as autism, hyperactivity and anxiety disorder may be present. Biofilm development and pathogenicity of Streptococcus mutans may be altered because FXS renders the dental approach and oral hygiene more complex. OBJECTIVES: The purpose of this study was to compare the levels of transcripts for VicRK and CovR of S. mutans isolated from FXS patients with the levels of transcripts for VicRK and CovR of standard strain ATCC, using a quantitative polymerase chain reaction (qPCR). METHODS: The caries experience index was assessed by the International Caries Detection and Assessment System (ICDAS), Periodontal Condition Index (PCI) and Invasive Dental Treatment Need Index (INI). RESULTS: The clinical index findings revealed a high rate of caries cavities and bleeding on probing of FXS patients. When VicRK and CovR transcript levels were compared with the reference strain, Fragile X patients were found to have significantly higher values. CONCLUSION: The present study demonstrated that FXS patients have more adverse clinical conditions, with increased biofilm accumulation and virulence. When combined with behavioural abnormalities, these patients become even more vulnerable to dental caries.

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The FMR1 5' regulation gene region harbors a CGG trinucleotide repeat expansion (CGG-TRE) that causes Fragile X syndrome (FXS) when it expands to more than 200 repetitions. Ricaurte is a small village in southwestern Colombia, with an FXS prevalence of 1 in 38 men and 1 in 100 women (~100 times higher than the worldwide reported prevalence), defining Ricaurte as the largest FXS cluster in the world. In the present study, using next-generation sequencing of whole exome capture, we genotype 55 individuals from Ricaurte (49 with either full mutation or with premutation), four individuals from neighboring villages (with either the full mutation or with the premutation), and one unaffected woman, native of Ricaurte, who did not belong to any of the affected families. With advanced clustering and haplotype reconstruction, we modeled a common haplotype of 33 SNPs spanning 83,567,899 bp and harboring the FMR1 gene. This reconstructed haplotype was found in all the men from Ricaurte who carried the expansion, demonstrating that the genetic conglomerate of FXS in this population is due to a founder effect. The definition of this founder effect and its population outlining will allow a better prediction, follow-up, precise and personalized characterization of epidemiological parameters, better knowledge of the disease's natural history, and confident improvement of the clinical attention, life quality, and health interventions for this community.

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BACKGROUND: Fragile X syndrome (FXS) is primarily due to CGG repeat expansions in the FMR1 gene. FMR1 alleles are classified as normal (N), intermediate (I), premutation (PM), and full mutation (FM). FXS patients often carry an FM, but size mosaicism can occur. Additionally, loss of methylation boundary upstream of repeats results in de novo methylation spreading to FMR1 promoter in FXS patients. RESEARCH DESIGN AND METHODS: This pilot study investigated the methylation boundary and adjacent regions in 66 males with typical and atypical FXS aged 1 to 30 years (10.86 ± 6.48 years). AmplideX FMR1 mPCR kit was used to discriminate allele profiles and methylation levels. CpG sites were assessed by pyrosequencing. RESULTS: 40 out of 66 FXS patients (60.6%) showed an exclusive FM (n = 40), whereas the remaining (n = 26) exhibited size mosaicism [10 PM_FM (15.15%); 10 N_FM (15.15%); 2 N_PM_FM (3%)]. Four patients (6.1%) had deletions near repeats. Noteworthy, a CpG within FMR1 intron 2 displayed hypomethylation in FXS patients and hypermethylation in controls, demonstrating remarkable specificity, sensitivity, and accuracy when a methylation threshold of 69.5% was applied. CONCLUSIONS: Since intragenic methylation is pivotal in gene regulation, the intronic CpG might be a novel epigenetic biomarker for FXS diagnosis.

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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.

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Fragile X Syndrome (FXS) is a neurodevelopmental disorder and the leading monogenic cause of autism and intellectual disability. For years, several efforts have been made to develop an effective therapeutic approach to phenotypically rescue patients from the disorder, with some even advancing to late phases of clinical trials. Unfortunately, none of these attempts have completely succeeded, bringing urgency to further expand and refocus research on FXS therapeutics. FXS arises at early stages of postnatal development due to the mutation and transcriptional silencing of the Fragile X Messenger Ribonucleoprotein 1 gene (FMR1) and consequent loss of the Fragile X Messenger Ribonucleoprotein (FMRP) expression. Importantly, FMRP expression is critical for the normal adult nervous system function, particularly during specific windows of embryogenic and early postnatal development. Cellular proliferation, migration, morphology, axonal guidance, synapse formation, and in general, neuronal network establishment and maturation are abnormally regulated in FXS, underlying the cognitive and behavioral phenotypes of the disorder. In this review, we highlight the relevance of therapeutically intervening during critical time points of development, such as early postnatal periods in infants and young children and discuss past and current clinical trials in FXS and their potential to specifically target those periods. We also discuss potential benefits, limitations, and disadvantages of these pharmacological tools based on preclinical and clinical research.

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This study aimed to assess the Family Quality of Life (FQoL) of Brazilian families with male children with Fragile X syndrome (FXS). Data from 53 families were collected using forms that included sociodemographic and clinical information, as well as the Beach Center Family Quality of Life Scale, a 5-point Likert scale ranging from "very dissatisfied" (1) to "very satisfied" (5). The mean overall FQoL score was 3.56 ± 0.79; the emotional well-being domain had the lowest score (2.98 ± 1.11) and showed significant differences between the other domains: family interaction (3.81 ± 0.89; p < 0.001), parenting (3.66 ± 0.89; p < 0.001), physical and material well-being (3.48 ± 0.83; p < 0.001), and disability-related support (3.75 ± 0.98; p < 0.001). Physical and material well-being was the second-lowest domain and was statistically different from the family interaction domain (p = 0.013). Lower FQoL satisfaction ratings were found in families with children who had difficulty getting along with people of the same age (t(51) = -3.193, p = 0.002; d = 1.019) and difficulty in living together on a day-to-day basis (t(51) = -3.060, p = 0.004; d = 0.888). These results highlight the importance of proper emotional support for the family, emphasizing the need to provide assistance not only for individuals with FXS but also for other family members. Besides, we advocate for the adoption of public policies that provide financial assistance to families and the implementation of the Brazilian Policy of Comprehensive Care for People with Rare Diseases.

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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.

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Fragile X syndrome (FXS) is caused by the loss of function of Fragile X mental retardation protein (FMRP). FXS is one of the leading monogenic causes of intellectual disability (ID) and autism. Although it is caused by the failure of a single gene, FMRP that functions as an RNA binding protein affects a large number of genes secondarily. All these genes represent hundreds of potential targets and different mechanisms that account for multiple pathological features, thereby hampering the search for effective treatments. In this scenario, it seems desirable to reorient therapies toward more general approaches. Neuronal calcium sensor 1 (NCS-1), through its interaction with the guanine-exchange factor Ric8a, regulates the number of synapses and the probability of the release of a neurotransmitter, the two neuronal features that are altered in FXS and other neurodevelopmental disorders. Inhibitors of the NCS-1/Ric8a complex have been shown to be effective in restoring abnormally high synapse numbers as well as improving associative learning in FMRP mutant flies. Here, we demonstrate that phenothiazine FD44, an NCS-1/Ric8a inhibitor, has strong inhibition ability in situ and sufficient bioavailability in the mouse brain. More importantly, administration of FD44 to two different FXS mouse models restores well-known FXS phenotypes, such as hyperactivity, associative learning, aggressive behavior, stereotype, or impaired social approach. It has been suggested that dopamine (DA) may play a relevant role in the behavior and in neurodevelopmental disorders in general. We have measured DA and its metabolites in different brain regions, finding a higher metabolic rate in the limbic area, which is also restored with FD44 treatment. Therefore, in addition to confirming that the NCS-1/Ric8a complex is an excellent therapeutic target, we demonstrate the rescue effect of its inhibitor on the behavior of cognitive and autistic FXS mice and show DA metabolism as a FXS biochemical disease marker.

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BACKGROUND: Fragile X syndrome, the major cause of inherited intellectual disability among men, is due to deficiency of the synaptic functional regulator FMR1 protein (FMRP), encoded by the FMRP translational regulator 1 (FMR1) gene. FMR1 alternative splicing produces distinct transcripts that may consequently impact FMRP functional roles. In transcripts without exon 14 the translational reading frame is shifted. For deepening current knowledge of the differential expression of Fmr1 exon 14 along the rat nervous system development, we conducted a descriptive study employing quantitative RT-PCR and BLAST of RNA-Seq datasets. RESULTS: We observed in the rat forebrain progressive decline of total Fmr1 mRNA from E11 to P112 albeit an elevation on P3; and exon-14 skipping in E17-E20 with downregulation of the resulting mRNA. We tested if the reduced detection of messages without exon 14 could be explained by nonsense-mediated mRNA decay (NMD) vulnerability, but knocking down UPF1, a major component of this pathway, did not increase their quantities. Conversely, it significantly decreased FMR1 mRNA having exon 13 joined with either exon 14 or exon 15 site A. CONCLUSIONS: The forebrain in the third embryonic week of the rat development is a period with significant skipping of Fmr1 exon 14. This alternative splicing event chronologically precedes a reduction of total Fmr1 mRNA, suggesting that it may be part of combinatorial mechanisms downregulating the gene's expression in the late embryonic period. The decay of FMR1 mRNA without exon 14 should be mediated by a pathway different from NMD. Finally, we provide evidence of FMR1 mRNA stabilization by UPF1, likely depending on FMRP.

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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.

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Dendritic spines are small protrusions stemming from the dendritic shaft that constitute the primary specialization for receiving and processing excitatory neurotransmission in brain synapses. The disruption of dendritic spine function in several neurological and neuropsychiatric diseases leads to severe information-processing deficits with impairments in neuronal connectivity and plasticity. Spine dysregulation is usually accompanied by morphological alterations to spine shape, size and/or number that may occur at early pathophysiological stages and not necessarily be reflected in clinical manifestations. Autism spectrum disorder (ASD) is one such group of diseases involving changes in neuronal connectivity and abnormal morphology of dendritic spines on postsynaptic neurons. These alterations at the subcellular level correlate with molecular changes in the spine proteome, with alterations in the copy number, topography, or in severe cases in the phenotype of the molecular components, predominantly of those proteins involved in spine recognition and adhesion, reflected in abnormally short lifetimes of the synapse and compensatory increases in synaptic connections. Since cholinergic neurotransmission participates in the regulation of cognitive function (attention, memory, learning processes, cognitive flexibility, social interactions) brain acetylcholine receptors are likely to play an important role in the dysfunctional synapses in ASD, either directly or indirectly via the modulatory functions exerted on other neurotransmitter receptor proteins and spine-resident proteins.

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OBJECTIVE: Our study aimed to identify mutations in the FMR1 gene in a group of Brazilian women diagnosed with primary ovarian insufficiency (POI). METHODS: This cross-sectional study included patients aged under 40 years with confirmed POI from a convenience sample of patients seen from June 2017 to December 2018 at a University Hospital in Curitiba, Brazil. Genomic DNA was extracted and analyzed using FragilEase(tm) PCR kits (PerkinElmer), a commercially available test that enables the quantification of CGG trinucleotide repeat expansions in the FMR1 gene. RESULTS: A total of 52 patients with an average age of 35.8±3.97 years were included. Fifty (96.1%) had normal alleles with 18 to 43 CGG repeats. The most frequent CGG-repeat sizes were 28 and 30. Two patients (3.8%) presented mutations in the FMR1 gene. The first had alleles with 19/97 CGG repeats, was categorized as a premutation carrier for FXS, and had a son with cognitive impairment. The second had alleles with 21/45 CGG repeats and was described as belonging to the gray zone. CONCLUSIONS: In our study, 3.8% of the females with POI had mutations in the FMR1 gene. The most frequent allele sizes were 28 and 30 CGG repeats.

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Fragile X syndrome (FXS) has a classic phenotype, however its expression can be variable among full mutation males. This is secondary to variable methylation mosaicisms and the number of CGG triplet repeats in the non-coding region of the Fragile X Mental Retardation 1 (FMR1) gene, producing a variable expression of the Fragile X Mental Retardation Protein (FMRP). Here we report a family with several individuals affected by FXS: a boy with a hypermethylated FMR1 mutation and a classic phenotype; a man with an FMR1 gene mosaicism in the range of premutation (PM) and full mutation (FM), who has a mild phenotype due to which FXS was initially disregarded; and the cases of four women with a FM and mosaicism. This report highlights the importance of DNA molecular testing for the diagnosis of FXS in patients with developmental delay, intellectual disability and/or autism due to the variable phenotype that occurs in individuals with FMR1 mosaicisms.

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Fragile X syndrome (FXS) is the most common cause of hereditary intellectual disability and the second most common cause of intellectual disability of genetic etiology. This complex neurodevelopmental disorder is caused by an alteration in the CGG trinucleotide expansion in fragile X mental retardation gene 1 (FMR1) leading to gene silencing and the subsequent loss of its product: fragile X mental retardation protein 1 (FMRP). Molecular diagnosis is based on polymerase chain reaction (PCR) screening followed by Southern blotting (SB) or Triplet primer-PCR (TP-PCR) to determine the number of CGG repeats in the FMR1 gene. We performed, for the first time, screening in 247 Ecuadorian male individuals with clinical criteria to discard FXS. Analysis was carried out by the Genetics Service of the Hospital de Especialidades No. 1 de las Fuerzas Armadas (HE-1), Ecuador. The analysis was performed using endpoint PCR for CGG fragment expansion analysis of the FMR1 gene. Twenty-two affected males were identified as potentially carrying the full mutation in FMR1 and thus diagnosed with FXS that is 8.1% of the sample studied. The average age at diagnosis of the positive cases was 13 years of age, with most cases from the geographical area of Pichincha (63.63%). We confirmed the familial nature of the disease in four cases. The range of CGG variation in the population was 12-43 and followed a modal distribution of 27 repeats. Our results were similar to those reported in the literature; however, since it was not possible to differentiate between premutation and mutation cases, we can only establish a molecular screening approach to identify an expanded CGG repeat, which makes it necessary to generate national strategies to optimize molecular tests and establish proper protocols for the diagnosis, management, and follow-up of patients, families, and communities at risk of presenting FXS.

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Fragile X syndrome is the most common monogenetic cause of inherited intellectual disability and syndromic autism spectrum disorder. Fragile X syndrome is caused by an expansion (full mutation ≥200 CGGs repeats, normal 10-45 CGGs) of the fragile X mental retardation 1 (FMR1) gene, epigenetic silencing of the gene, which leads to reduction or lack of the gene's product: the fragile X mental retardation protein. In this cross-sectional study, we assessed general and pharmacotherapy knowledge (GK and PTK) of fragile X syndrome and satisfaction with education in neurodevelopmental disorders (NDDs) among senior medical students in Serbia (N=348), Georgia (N=112), and Colombia (N=58). A self-administered 18-item questionnaire included GK (8/18) and PTK (7/18) components and self-assessment of the participants education in NDDs (3/18). Roughly 1 in 5 respondents had correct answers on half or more facts about fragile X syndrome (GK>PTK), which ranged similarly 5-7 in Serbia, 6-8 in Georgia, and 5-8 in Colombia, respectively. No cohort had an average value greater than 9 (60%) that would represent passing score "cut-off." None of the participants answered all the questions correctly. More than two-thirds of the participants concluded that they gained inadequate knowledge of NDDs during their studies, and that their education in this field should be more intense. In conclusion, there is a major gap in knowledge regarding fragile X syndrome among senior medical students in these three developing countries. The finding could at least in part be generalized to other developing countries aimed toward increasing knowledge and awareness of NDDs and fostering an institutional collaboration between developed and developing countries.

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Objective: To evidence the need for screening fragile X syndrome (FXS) in egg donors in assisted reproduction protocols. Case report : This is the report of a boy with FXS who inherited the mutated allele from an ovule donated by the mother´s sister through an assisted reproduction protocol. Identifying premutation (PM) carriers of FXS amongst gamete donors isn't part of the obligatory genetic analysis for donors and is only considered by most of the in vitro fertility societies and guidelines as part of the extension screening tests. Conclusion: It is cost-effective to do pre-conceptional screening for the PM or full mutation (FM) of the FMR1 gene affected in FXS in every woman undergoing assisted reproductive methods, including gamete donors even without a positive family history of intellectual disabilities. This case supports the need of rethinking the guidelines on the necessary gamete donor screening tests in assisted reproduction protocols.

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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.

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The human gut microbiome is the ecosystem of microorganisms that live in the human digestive system. Several studies have related gut microbiome variants to metabolic, immune and nervous system disorders. Fragile X syndrome (FXS) is a neurodevelopmental disorder considered the most common cause of inherited intellectual disability and the leading monogenetic cause of autism. The role of the gut microbiome in FXS remains largely unexplored. Here, we report the results of a gut microbiome analysis using a FXS mouse model and 16S ribosomal RNA gene sequencing. We identified alterations in the fmr1 KO2 gut microbiome associated with different bacterial species, including those in the genera Akkermansia, Sutterella, Allobaculum, Bifidobacterium, Odoribacter, Turicibacter, Flexispira, Bacteroides, and Oscillospira. Several gut bacterial metabolic pathways were significantly altered in fmr1 KO2 mice, including menaquinone degradation, catechol degradation, vitamin B6 biosynthesis, fatty acid biosynthesis, and nucleotide metabolism. Several of these metabolic pathways, including catechol degradation, nucleotide metabolism and fatty acid biosynthesis, were previously reported to be altered in children and adults with autism. The present study reports a potential association of the gut microbiome with FXS, thereby opening new possibilities for exploring reliable treatments and non-invasive biomarkers.

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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.

RESUMO

The purpose of this article is to discuss the clinical management and behavior during periodontal treatment in two patients with fragile X syndrome (FXS) using alternative communication with pictures (ACP). Both patients had a history of previous dental care only possible under general anesthesia. The ACP was used to anticipate the activities to be carried out, promoting ambiance, improving the professional-patient communication, and decreasing the stress of the patient. It was possible to carry out outpatient care without oral sedation and containment/physical restraint in both patients, being surpassed the communicative and behavioral difficulties. These case reports allow us to re-think dental care under general anesthesia or other invasive methods for patients with FXS. Therefore, the ACP is an important mediator tool that can facilitate the insertion and the management of patients with FXS, allowing the dental care outpatient clinic to promote oral health and quality of life for these patients, improving adherence to periodontal treatment and the periodontal maintenance for oral hygiene.