ABSTRACT
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.
Subject(s)
Fragile X Syndrome , Male , Humans , Fragile X Syndrome/diagnosis , Fragile X Syndrome/genetics , Pilot Projects , Fragile X Mental Retardation Protein/genetics , Fragile X Mental Retardation Protein/metabolism , DNA Methylation , Mutation , Epigenesis, GeneticABSTRACT
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.
Subject(s)
Autism Spectrum Disorder , Fragile X Syndrome , Intellectual Disability , Humans , Child , Fragile X Syndrome/diagnosis , Fragile X Syndrome/genetics , Autism Spectrum Disorder/etiology , Autism Spectrum Disorder/genetics , Quality of Life , Fragile X Mental Retardation Protein/geneticsABSTRACT
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.
Subject(s)
Fragile X Syndrome , Intellectual Disability , Female , Fragile X Mental Retardation Protein/genetics , Fragile X Mental Retardation Protein/metabolism , Fragile X Syndrome/complications , Fragile X Syndrome/diagnosis , Fragile X Syndrome/genetics , Humans , Intellectual Disability/complications , Intellectual Disability/genetics , Male , Mosaicism , Mutation , PhenotypeABSTRACT
BACKGROUND: Fragile X syndrome (FXS) is the most common cause of inherited intellectual disability and autism spectrum disorder (ASD). In Colombia, there are no screening or testing protocols established for the diagnosis of FXS. In this study, we aimed to describe the diagnostic trends of FXS in Colombia. METHODS: Data were included on 1322 individuals obtained based on data from the only 2 databases available. Sociodemographic information and data related to the diagnostic process were obtained and included in this study. RESULTS: The average age at the time of diagnosis for individuals with the full mutation (FM) was of 26.9 ± 2.57 years and was strongly dependent on sex and socioeconomic status. Most individuals with a molecular diagnosis were from the main cities. CONCLUSION: The overall age of diagnosis of FXS is later in life than reports from other countries. Restricted access to molecular testing through the national health system might explain this discrepancy in Colombia.
Subject(s)
Autism Spectrum Disorder , Fragile X Syndrome , Intellectual Disability , Alleles , Colombia/epidemiology , Fragile X Mental Retardation Protein/genetics , Fragile X Syndrome/diagnosis , Fragile X Syndrome/epidemiology , Fragile X Syndrome/genetics , Humans , Intellectual Disability/diagnosis , Intellectual Disability/epidemiology , Intellectual Disability/geneticsABSTRACT
INTRODUCCIÓN: El síndrome de X frágil (SXF) es la primera causa heredable de discapacidad intelectual y autismo. Mujeres con la premutación del gen FMR1, relacionado con SXF, suelen ser asintomáticas, pero pueden tener hijos afectados. Se reporta un caso de SXF producto de fecundación in vitro con óvulos de una donante portadora de la premutación del FMR1. DESCRIPCIÓN DEL CASO: Pareja que requirió reproducción asistida dado que la mujer tenía antecedente de hipofisectomía; se realizó fecundación in vitro con óvulo donado, lográndose un embarazo gemelar. El gemelo femenino fue diagnosticado a los 2 años de edad con mutación completa del gen FMR1 y SXF, y la donante de óvulos, quien era asintomática, fue posteriormente confirmada como portadora de la premutación del FMR1. DISCUSIÓN: El protocolo de evaluación del riesgo de heredar enfermedades genéticas para donantes de óvulos se limita al cariotipo bandas G. Esta prueba no analiza alteraciones genéticas de herencia recesiva. Mediante secuenciación de nueva generación se podrían identificar portadoras de variantes alélicas patogénicas en estado de heterocigosis. Las mujeres con premutación del FMR1, tienen un riesgo del 50% de transmitir el alelo anormal a sus descendientes en cada embarazo, y estos de ser afectados por el SXF; por tanto, la asesoría genética es requerida en estos casos. CONCLUSIÓN: Los donantes de gametos deberían ser evaluados mediante pruebas moleculares para detección de variantes alélicas que pudieran ser transmitidas a sus gametos, y que pudieran generar enfermedades genéticas en los embarazos a partir de ellos.
INTRODUCTION: Fragile X syndrome (SXF) is the lead hereditary cause of intellectual disability and autism. Women with premutation in FMR1 gene, related to SXF, are usually asymptomatic, but they could have affected children. We report a case of SXF, product of an in vitro fertilization, secondary to an egg donation from a carrier of the premutation in the FMR1 gene. DESCRIPTION OF THE CASE: A couple required assisted reproduction because the woman had antecedent of hypophysectomy. An in vitro fertilization was done using a donated egg, achieving a twin pregnancy. The female twin was diagnosed with full mutation in the FMR1 gene and SXF by her second year of age. Donor woman, who was asymptomatic, was found to be a carrier of the premutation for SXF. DISCUSSION: The protocols to evaluate the risk of inherit genetic diseases for egg donors stint to band G karyotypes, which don—t consider genetic alterations with recessive inheritance pattern. Next generation sequencing allows to identify carriers of allelic heterozygote variations related with pathology. Women with the premutation in FMR1 have a risk of 50%, in each pregnancy, to pass down an affected allele to their offspring, who would be affected by SXF. Genetic counseling is mandatory in that cases. CONCLUSION: Gamete donor candidates should be submitted to molecular tests to identify allelic variants that could be inherited to the recipient offspring and cause genetic diseases.
Subject(s)
Humans , Male , Pregnancy , Adult , Tissue Donors , Fertilization in Vitro , Fragile X Syndrome/diagnosis , Genetic Testing , Pregnancy, TwinABSTRACT
Aims: Fragile-X syndrome (FXS) is the most common inherited form of intellectual disability; it is caused by an abnormal CGG-repeat expansion at the FMR1 gene. However, a few cases of girls with mutations in the FMR1 gene have been reported in the literature. In this study, we describe the clinical and genetic assessment of a family who exhibits the unusual coexistence of FXS, an 8p23.1 deletion, and balanced translocation t(7;10)(p10;q24) in multiple members, including a symptomatic girl with FXS. Materials and Methods: All of the family members underwent comprehensive clinical and neurological examinations. All members of the family were also molecularly diagnosed using a combination of fluorescent-polymerase chain reaction (PCR), Triplet Repeat Primed-PCR, capillary electrophoresis, and karyotyping. Results: We identified a male proband and a female patient that presented with the craniofacial characteristics of FXS, neuropsychomotor developmental delay, speech delay, intellectual deficit, and a positive molecular diagnosis of FXS. Interestingly, the female patient presented with a severe phenotype also associated with the presence of 8p23.1 deletion, while the proband patient presented a balanced translocation t(7;10)(p10;q24). Moreover, we detected multiple carriers of the FXS premutation in the family. Conclusions: To our knowledge, we describe for the first time the simultaneous occurrence of FXS and an 8p23.1 deletion and their possible synergistic effects on the phenotype of a female patient. Moreover, we describe the coexistence of FXS, an 8p23.1 deletion, and a balanced translocation t(7;10)(p10;q24) in the same family.
Subject(s)
Fragile X Syndrome/diagnosis , Fragile X Syndrome/genetics , Adolescent , Adult , Child , Child, Preschool , Chromosome Deletion , Chromosomes, Human, Pair 8/genetics , Chromosomes, Human, Pair 8/metabolism , Family , Female , Fragile X Mental Retardation Protein/genetics , Fragile X Syndrome/epidemiology , Genetic Testing/methods , Heterozygote , Humans , Intellectual Disability/genetics , Male , Mexico , Middle Aged , Mutation , Pedigree , Phenotype , Translocation, Genetic/geneticsABSTRACT
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.
Subject(s)
Dental Care , Fragile X Syndrome/diagnosis , Fragile X Syndrome/etiology , Fragile X Syndrome/epidemiologyABSTRACT
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.
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.
Subject(s)
Autistic Disorder/genetics , Fragile X Mental Retardation Protein/genetics , Fragile X Syndrome/genetics , Intellectual Disability/genetics , Attention Deficit Disorder with Hyperactivity/genetics , Checklist , Child, Preschool , Female , Fragile X Mental Retardation Protein/metabolism , Fragile X Syndrome/complications , Fragile X Syndrome/diagnosis , Fragile X Syndrome/therapy , Gene Silencing , Genetic Testing , Humans , Male , Mutation , Pedigree , Phenotype , Ribosomes/metabolism , Sex Factors , Synaptic TransmissionABSTRACT
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.
Subject(s)
Humans , Male , Child, Preschool , Autistic Disorder/genetics , Fragile X Mental Retardation Protein/genetics , Fragile X Syndrome/genetics , Intellectual Disability/genetics , Pedigree , Phenotype , Ribosomes/metabolism , Attention Deficit Disorder with Hyperactivity/genetics , Sex Factors , Genetic Testing , Synaptic Transmission , Gene Silencing , Fragile X Mental Retardation Protein/metabolism , Checklist , Fragile X Syndrome/complications , Fragile X Syndrome/diagnosis , Fragile X Syndrome/therapy , MutationABSTRACT
Fragile X syndrome (FXS) is the most common cause of inherited intellectual disabilities and autism spectrum disorders, and it is an X-linked disorder in which there is a deficiency of the fragile X mental retardation 1 protein. This protein is crucial in regulating translation of mRNAs related to dendritic maturation and cognitive development. The phenotype of FXS is characterized by neurobehavioral alterations, social deficits, communication difficulties, and findings which suggest an alteration of connective tissue, especially in the ligaments and muscles, cardiovascular system and genitourinary system. Connective tissue connects and supports all other tissues of the body and is composed of cells and extracellular matrix (ECM). Several proteins have been involved in the connective tissue abnormalities associated with the FXS, such as matrix metalloproteinase 9, which plays an important role in the homeostasis of the ECM, being a potential therapeutic target for certain tetracycline antibiotics that have shown beneficial effects in FXS. Here, we review connective tissue problems described in FXS.
Subject(s)
Connective Tissue/metabolism , Fragile X Mental Retardation Protein/genetics , Fragile X Syndrome/diagnosis , Fragile X Syndrome/etiology , Genetic Association Studies , Genetic Predisposition to Disease , Animals , Connective Tissue/physiopathology , Extracellular Matrix Proteins/genetics , Extracellular Matrix Proteins/metabolism , Fragile X Mental Retardation Protein/metabolism , Humans , Organ Specificity/genetics , Organogenesis/genetics , PhenotypeABSTRACT
OBJECTIVE: To evaluate the diagnostic process in children ultimately diagnosed with fragile X syndrome (FXS), with an emphasis on the time lag between initial presentation and on diagnosis in female vs male children. STUDY DESIGN: Interviews were conducted with 89 families of children with a final diagnosis of FXS and assessment of time intervals between initial presentation and confirmed molecular diagnosis. RESULTS: Screening of 117 patients (25 female patients) from the 89 families revealed that less than 20% of patients obtained a diagnosis within the first year of seeking medical attention. Mean age at the time of initial presentation was 12.3 months in male patients and 23 months in female patients, while definitive diagnosis of FXS was made at a mean of 4 and 9 years, respectively. Presenting symptoms of developmental delays were recognized by 72% of parents, and 84% had another child with FXS before the index case diagnosis. Average age of diagnosis for children with FXS born since 2007 was significantly lower at 31.9 months, compared with 69.5 months for children born before 2007. CONCLUSIONS: Although FXS is a significant and prevalent cause of disability in children, it is underdiagnosed and diagnosed late, especially in female patients. In every male and female patient presenting with developmental delay or autism, FXS should be considered. Dysmorphic physical features may not be present in infancy, and the absence of those features cannot exclude a diagnosis of FXS.
Subject(s)
Delayed Diagnosis/statistics & numerical data , Fragile X Syndrome/diagnosis , Adolescent , Adult , Child , Child, Preschool , Cohort Studies , Female , Humans , Infant , Male , Middle Aged , Retrospective Studies , Time Factors , Young AdultABSTRACT
OBJECTIVE: Inborn errors of metabolism (IEM) are genetic conditions that are sometimes associated with intellectual developmental disorders (IDD). The aim of this study is to contribute to the metabolic characterization of IDD of unknown etiology in Mexico. MATERIALS AND METHODS: Metabolic screening using tandem mass spectrometry and fluorometry will be performed to rule out IEM. In addition, target metabolomic analysis will be done to characterize the metabolomic profile of patients with IDD. CONCLUSION: Identification of new metabolomic profiles associated with IDD of unknown etiology and comorbidities will contribute to the development of novel diagnostic and therapeutic schemes for the prevention and treatment of IDD in Mexico.
Subject(s)
Intellectual Disability/epidemiology , Intellectual Disability/etiology , Metabolism, Inborn Errors/diagnosis , Metabolomics/methods , Adolescent , Child , Female , Fragile X Syndrome/diagnosis , Fragile X Syndrome/epidemiology , Health Surveys , Humans , Male , Mass Screening , Metabolism, Inborn Errors/epidemiology , Metabolism, Inborn Errors/metabolism , Mexico/epidemiology , Tandem Mass Spectrometry , Young AdultABSTRACT
Abstract: Objective: Inborn errors of metabolism (IEM) are genetic conditions that are sometimes associated with intellectual developmental disorders (IDD). The aim of this study is to contribute to the metabolic characterization of IDD of unknown etiology in Mexico. Materials and methods: Metabolic screening using tandem mass spectrometry and fluorometry will be performed to rule out IEM. In addition, target metabolomic analysis will be done to characterize the metabolomic profile of patients with IDD. Conclusion: Identification of new metabolomic profiles associated with IDD of unknown etiology and comorbidities will contribute to the development of novel diagnostic and therapeutic schemes for the prevention and treatment of IDD in Mexico.
Resumen: Objetivo: Los errores innatos del metabolismo (EIM) son condiciones genéticas que pueden asociarse con trastornos del desarrollo intelectual (TDI). El objetivo de este estudio es contribuir a la caracterización metabólica de los pacientes con TDI de etiología desconocida. Material y métodos: Se realizará un tamiz metabólico mediante espectrometría de masas-tándem y fluorometría para descartar EIM; además, se analizará el perfil metabolómico de los pacientes con TDI. Conclusión: La identificación de perfiles metabolómicos asociados con los TDI de etiología desconocida contribuirá al desarrollo de nuevos esquemas diagnósticos y terapéuticos para la prevención y tratamiento de los TDI en México.
Subject(s)
Humans , Male , Female , Child , Adolescent , Young Adult , Metabolomics/methods , Intellectual Disability/etiology , Intellectual Disability/epidemiology , Metabolism, Inborn Errors/diagnosis , Mass Screening , Health Surveys , Tandem Mass Spectrometry , Fragile X Syndrome/diagnosis , Fragile X Syndrome/epidemiology , Mexico/epidemiologyABSTRACT
BACKGROUND: Fragile X syndrome, the most common inherited cause of intellectual disability, is associated with a broad spectrum of disorders across different generations of a single family. This study reviews the clinical manifestations of fragile X-associated disorders as well as the spectrum of mutations of the fragile X mental retardation 1 gene (FMR1) and the neurobiology of the fragile X mental retardation protein (FMRP), and also provides an overview of the potential therapeutic targets and genetic counselling. DEVELOPMENT: This disorder is caused by expansion of the CGG repeat (>200 repeats) in the 5 prime untranslated region of FMR1, resulting in a deficit or absence of FMRP. FMRP is an RNA-binding protein that regulates the translation of several genes that are important in synaptic plasticity and dendritic maturation. It is believed that CGG repeat expansions in the premutation range (55 to 200 repeats) elicit an increase in mRNA levels of FMR1, which may cause neuronal toxicity. These changes manifest clinically as developmental problems such as autism and learning disabilities as well as neurodegenerative diseases including fragile X-associated tremor/ataxia syndrome (FXTAS). CONCLUSIONS: Advances in identifying the molecular basis of fragile X syndrome may help us understand the causes of neuropsychiatric disorders, and they will probably contribute to development of new and specific treatments.
Subject(s)
Ataxia/genetics , Fragile X Mental Retardation Protein/genetics , Fragile X Mental Retardation Protein/pharmacology , Fragile X Syndrome/genetics , Tremor/genetics , Ataxia/diagnosis , Autistic Disorder , Fragile X Syndrome/diagnosis , Humans , Intellectual Disability , Mutation/genetics , RNA, Messenger , Tremor/diagnosisABSTRACT
The aim of this study was to validate the molecular genetic diagnosis of patients suspected of Fragile X Syndrome (FXS) in the Laboratory of Human Cytogenetics and Molecular Genetics (LaGene) of the Department of Health of the State of Goiás, using polymerase chain reaction (PCR). Thirty-five patients referred by public health doctors to LaGene, indicating clinical diagnosis of FXS, were selected for this study. Two PCR analyses were performed using different primers, one for screening (PCR-T) and one for the detection of the pre-mutation (PCR-P). The products of both PCRs were subjected to polyacrylamide gel electrophoresis and then coloring. The visualization of amplicons was performed with the aid of an ultraviolet transilluminator. The diagnosis was confirmed in 88% of patients with PCR-T and 100% with PCR-P. The primer used in PCR-P was found to be more sensitive and specific, allowing to identify the mutation in the samples, generating a more conclusive case for FXS, noting that the PCR-T is also required for the pre-classification of patients. Generally, the PCR technique is cheaper and easier to handle; therefore, we suggest the implementation of PCR in the genetics laboratory of the State of Goiás (LaGene) for the diagnosis of FXS.
Subject(s)
Fragile X Mental Retardation Protein/genetics , Fragile X Syndrome/diagnosis , Fragile X Syndrome/genetics , Pathology, Molecular/methods , Alleles , Electrophoresis, Polyacrylamide Gel , Female , Fragile X Syndrome/pathology , Humans , Male , Mutation , Polymerase Chain Reaction/methods , Trinucleotide Repeat Expansion/geneticsABSTRACT
The objective of this study was to perform a study of fragile X syndrome (FXS) in São Luís, Maranhão, in males residing in five specialized institutions. Two hundred thirty-eight males with intel-lectual disability of unknown etiology participated in this study. Blood samples were processed and stored until DNA extraction. Screening for FMR1 gene mutations was performed using non-isotopic polymerase chain reaction amplification and DNA sequencing using an ABI Prism 3130 automated sequencer. Two individuals (0.84%) were positive for FMR1 mutations. One had a mutation due to expansion of the CGG repeat beyond normal levels and the other had a deletion in exon 1 of the FMR1 gene, which was confirmed by sequencing. Both probands were over 18 years old, which demonstrates the late diagnosis of the condition in these individuals and reinforces the need to implement ef-fective programs for early diagnosis of FXS in the state of Maranhão. We found that FXS might be transmitted in the families of the two indi-viduals bearing the mutation, and that it is important to understand the mutation dynamics to provide better counseling to the family members of these two individuals.
Subject(s)
DNA/genetics , Fragile X Mental Retardation Protein/genetics , Fragile X Syndrome/genetics , Genetic Testing , Mutation , Adolescent , Adult , Brazil , Child , Child, Preschool , DNA/isolation & purification , Fragile X Syndrome/diagnosis , Fragile X Syndrome/pathology , Genetic Counseling , Humans , Institutionalization , Male , Middle Aged , Pedigree , Polymerase Chain Reaction , Sequence Analysis, DNAABSTRACT
Surface treatment of dentin before the bleaching procedure may affect its permeability and influence the bond strength of restorative materials. This study evaluated the influence of surface treatment before the bleaching on shear bond strength (SBT) of restorative materials to intracoronal dentin. Dentin slabs were subjected to surface treatment: no bleaching (control - CON), no surface treatment + bleaching (HP), 37% phosphoric acid + bleaching (PA) and Er:YAG laser + bleaching (L). After the bleaching procedure, specimens (n=10) were restored with: microhybrid composite resin (MH), flowable composite resin (F), and resin-modified glass-ionomer cement (RMGIC). The shear test was carried out. ANOVA and Tukey's test (α=0.05) showed significant difference for surface treatment and restorative materials (p<0.05). CON presented higher STB and was statistically different from HP (p<0.05). PA and L showed intermediate values and were statistically similar to CON and HP (p>0.05). STB for MH and F were higher than RMGIC (p<0.05), and did not differ from each other (p>0.05). The surface treatments with phosphoric acid and Er:YAG laser before the bleaching procedure provided shear bond strength at the same level of unbleached dentin and the composite resins presented superior bond strength to the intracoronal dentin.
O tratamento superficial da dentina previamente ao clareamento pode afetar a sua permeabilidade e influenciar a resistência de união de materiais restaurados. Este estudo avaliou a influência do tratamento superficial antes do clareamento na resistência ao cisalhamento (RC) de materiais restauradores à dentina intracoronária. Fragmentos de dentina foram submetidos ao tratamento de superfície: não clareadas (controle - CON), sem tratamento de superfície + clareamento (HP), ácido fosfórico 37% + clareamento (AF), e laser Er:YAG + clareamento (L). Após o procedimento clareador, os espécimes foram restaurados com (n=10): resina composta micro-híbrida (MH), resina composta fluida (F), e cimento de ionômero de vidro modificado por resina (CIVMR). O teste de cisalhamento foi realizado. ANOVA e teste de Tukey (α=0,05) mostraram diferença significante para tratamento superficial e material restaurador (p<0,05). O grupo controle apresentou maior resistência de união e foi estatisticamente diferente de HP (p<0,05). AF e L mostraram valores intermediários e foram similares ao CON e HP (p>0,05). A resistência de união para MH e F foi maior que CIVMR (p<0,05), e não diferiram entre si (p>0,05). O tratamento da superfície dentinária com ácido fosfórico e laser Er:YAG previamente ao clareamento promoveu resistência de união ao nível da dentina não clareada e a adesão à dentina intracoronária foi superior com as resinas compostas.