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The Brazilian Unified National Health System (SUS) has incorporated newborn screening for cystic fibrosis since 2001. The protocol involves two samples of immunoreactive trypsinogen (IRT1/IRT2). This study aims to analyze fixed and floating values at the first and second IRT (IRT1/IRT2) cutoff points and assess the accuracy of the IRT/IRT methodology in a population from Northeastern Brazil. Descriptive, individual-level data from the newborn screening reference service data system (2013-2017) were used in this observational population study. The sensitivity, specificity, and positive predictive values (PPV) for the protocol were calculated. The best cutoff point was determined using the Youden's index. The previous year's cut-off values for the IRT1 and IRT2 99.4-, 99.5-, 99.6-, and 99.7-percentiles were utilized for the floating cutoff. During the studied period, 840,832 newborns underwent screening for cystic fibrosis, obtaining 49 cystic fibrosis diagnoses: 39 by newborn screening (79.6%) and 10 (20.4%) by clinical suspicion (false negative). The sensitivity, specificity, and PPV of the protocol totaled 79.6%, 99.9%, and 6.1%, respectively. No proposed cutoff for IRT1 performed better than the current one. IRT2 performed similarly to the current protocol at a cutoff point of 90ng/mL, showing the appropriate sensitivity and specificity while reducing the frequency of false positives. The protocol to screen newborns for cystic fibrosis had low sensitivity, a predictive positive value, and a high number of false positives and negatives. A floating cut point for IRT1 or IRT2 seems to constitute no viable option. However, changing the IRT2 cut point from 70ng/mL to 90ng/mL seems to have advantages and should undergo consideration.
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Fibrose Cística , Triagem Neonatal , Sensibilidade e Especificidade , Tripsinogênio , Humanos , Fibrose Cística/diagnóstico , Triagem Neonatal/métodos , Triagem Neonatal/normas , Recém-Nascido , Brasil , Tripsinogênio/sangue , Tripsinogênio/análise , Feminino , Valor Preditivo dos Testes , Masculino , Valores de ReferênciaRESUMO
Objective: To characterize adherence to Phenylketonuria (PKU) management practices among PKU patients treated at reference sites around Argentina, Brazil, and Mexico. Methods: This is a retrospective, observational, multicenter, and multinational survey-based study using aggregate data. From an initial list of 40 sites, 22 clinicians expressed interest in completing the survey, with 20 clinicians from 20 unique sites fulfilling all the study criteria. The Survey contained 28 questions, including respondent's clinic characteristics, clinic PKU treatment recommendations, and patient adherence to clinic recommendations. Survey was available in local languages, and the respondents were asked to consult their clinic records to complete their responses. Adherence was assessed by target blood phenylalanine (Phe), target blood testing frequency, and clinic visits. Results: A total of 1077 (out of 1377) actively managed PKU patients (seen in the clinic in the last 3 years) from 13 clinics in Brazil, six in Argentina, and one in Mexico were analyzed. Upper blood Phe target was set over 360 µMol/L in 70% of the clinics for adult patients. Around 40% of the patients >30 years old had Phe blood tests done twice a year or less, with 60% of the clinics recommending semestral visits for adults <30 years old. Twice a month was the most common frequency of visits for <1 year old. The COVID-19 pandemic was a disruptor for frequency of visits and exams. Conclusions: These results show that there is still room for improvement in terms of adherence, namely in adults and older children. More efforts must be made to educate patients and healthcare professionals about the importance of treatment adherence, accompanied by public policies that expand access to pharmacological and dietary treatment with diversity and quality to improve adherence to adequate blood Phe levels.
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BACKGROUND: Lysosomal diseases (LDs) are progressive life-threatening disorders that are usually asymptomatic at birth. Specific treatments are available for several LDs, and early intervention improves patient's outcomes. Thus, these diseases benefit from newborn screening (NBS). We have performed a pilot study for six LDs in Brazil by tandem mass spectrometry. METHODS: Dried blood spot (DBS) samples of unselected newborns were analyzed by the Neo-LSD™ kit (Perkin-Elmer) by MS/MS. Samples with low enzyme activity were submitted to the evaluation of specific biomarkers by ultra-performance liquid chromatography tandem-mass spectrometry as the second-tier, and were analyzed by a next-generation sequencing (NGS) multi-gene panel as the third-tier. All tests were performed in the same DBS sample. RESULTS: In 20,066 newborns analyzed, 15 samples showed activity of one enzyme below the cutoff. Two newborns had biochemical and molecular results compatible with Fabry disease, and five newborns had biochemical results and pathogenic variants or variants of unknown significance (VUS) in GAA. CONCLUSIONS: This study indicates that the use of enzyme assay as the first-tier test gives an acceptably low number of positive results that requires second/third tier testing. The possibility to run all tests in a DBS sample makes this protocol applicable to large-scale NBS programs.
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Doença de Fabry , Triagem Neonatal , Humanos , Recém-Nascido , Triagem Neonatal/métodos , Projetos Piloto , Espectrometria de Massas em Tandem/métodos , Brasil/epidemiologia , Doença de Fabry/diagnósticoRESUMO
Abstract Objective: To analyze the performance of the cystic fibrosis (CF) newborn screening (NBS) program over its first five years in a Brazilian northeastern state. Methods: A population-based study using a screening algorithm based on immunoreactive trypsinogen (IRT)/IRT. Data were retrieved from the state referral screening center registry. The program performance was evaluated using descriptive indicators such as the results of an active search, coverage, newborn's age at the time of blood sampling, the time between sample collection and its arrival at the laboratory, and the child's age at diagnosis of disease. Results: The public CF screening program covered 82.6% of the 1,017,576 births that occurred, with an accumulated five-year incidence of 1:20,767 live births. The median (25th-75th) age at diagnosis was 3.5 (2.3-7.3) months. The sampling before 7 days of life for the first IRT (IRT1) increased between 2013 and 2017 from 42.2 to 48.3%. Around 5% of IRT1 samples and 30% of the second samples were collected after 30 days of life. In the first and second stages of screening, 23.6% and 19.9% of the infants, respectively, were lost to follow-up. In both stages of screening, the samples were retained at the health units for a median (25th-75th) of 9.0 (7.0-13.0) days. Conclusions: The coverage by the CF-NBS program was satisfactory as compared to other Brazilian state rates and the percentage of IRT1 samples collected within the first week of life increased progressively. However, time of samples retention at the health units, inappropriate sampling, inherent methodological problems, and loss of follow-up need to improve.
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OBJECTIVE: To analyze the performance of the cystic fibrosis (CF) newborn screening (NBS) program over its first five years in a Brazilian northeastern state. METHOD: A population-based study using a screening algorithm based on immunoreactive trypsinogen (IRT)/IRT. Data were retrieved from the state referral screening center registry. The program performance was evaluated using descriptive indicators such as the results of an active search, coverage, newborn's age at the time of blood sampling, the time between sample collection and its arrival at the laboratory, and the child's age at diagnosis of disease. RESULTS: The public CF screening program covered 82.6% of the 1,017,576 births that occurred, with an accumulated five-year incidence of 1:20,767 live births. The median (25th-75th) age at diagnosis was 3.5 (2.3-7.3) months. The sampling before 7 days of life for the first IRT (IRT1) increased between 2013 and 2017 from 42.2 to 48.3%. Around 5% of IRT1 samples and 30% of the second samples were collected after 30 days of life. In the first and second stages of screening, 23.6% and 19.9% of the infants, respectively, were lost to follow-up. In both stages of screening, the samples were retained at the health units for a median (25th-75th) of 9.0 (7.0-13.0) days. CONCLUSIONS: The coverage by the CF-NBS program was satisfactory as compared to other Brazilian state rates and the percentage of IRT1 samples collected within the first week of life increased progressively. However, time of samples retention at the health units, inappropriate sampling, inherent methodological problems, and loss of follow-up need to improve.
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Fibrose Cística , Testes Genéticos , Humanos , Lactente , Recém-Nascido , Brasil/epidemiologia , Fibrose Cística/diagnóstico , Fibrose Cística/genética , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Testes Genéticos/métodos , Triagem Neonatal/métodos , TripsinogênioRESUMO
INTRODUCTION: Congenital adrenal hyperplasia (CAH), a genetic disease characterized by defective cortisol synthesis and excessive levels of sex hormones, can cause precocious puberty in both sexes in untreated individuals and virilization in female patients with a 46, XX karyotype. The female paraurethral (Skene's) gland has been reported as prostate analogous. Growth of prostate tissue is associated with androgen production; therefore, prostate-specific antigen (PSA) levels may represent a marker of virilization in 46, XX patients with CAH. OBJECTIVES: To describe PSA levels in 46, XX patients and evaluate whether higher PSA levels are associated with androgenization and the severity of the disease. STUDY DESIGN: Sixty-six patients with CAH and a 46, XX karyotype were included, irrespective of age. Serum PSA, testosterone, 17-hydroxyprogesterone (17-OHP) and androstenedione levels were measured. Patients' age, age at diagnosis, forms of the disease, Prader classification, bone age assessment, sex of rearing, surgery, and the presence of clinical complications were obtained from their medical records. RESULTS: The mean age of patients was 11.45 ± 10.74 years. Forty-three patients (65%) were diagnosed neonatally at a median of 0.08 years (mean 1.47 ± 2.34 years), with registers of 17-OHP measurements (Guthrie test) being available in 51%. Testosterone, 17-OHP and androstenedione were significantly high. PSA was detectable in 25% of cases (levels >0.01 ng/ml), with a mean of 0.03 ± 0.09 ng/ml, and only in patients over five years of age. A correlation was found between PSA and age (p < 0.001), age at diagnosis (p = 0.002), testosterone (p = 0.001) and androstenedione (p = 0.023). There was no correlation between PSA and the forms of CAH or Prader classification. A sub-analysis of the patients over five years of age in whom PSA was detectable also showed that there was a correlation between PSA (p < 0.05) and age at analysis, age at diagnosis, testosterone and androstenedione levels. DISCUSSION: Limitations of this study include the small sample size due to the rareness of the disease, its retrospective nature, the absence of a control group, the fact that the sample was selected at two referral centers, which could have resulted in a selection bias, and the use of different reference values in the different laboratories conducting the PSA tests. CONCLUSIONS: PSA is detectable in 25% of 46, XX patients with CAH, only after five years of age. PSA level increases significantly with age, age at diagnosis, and testosterone and androstenedione levels, confirming a correlation between PSA levels and elevated androgen levels.
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Hiperplasia Suprarrenal Congênita , Antígeno Prostático Específico , 17-alfa-Hidroxiprogesterona , Adolescente , Hiperplasia Suprarrenal Congênita/diagnóstico , Androgênios , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Estudos Retrospectivos , Adulto JovemRESUMO
OBJECTIVE: To characterize metabolic control and verify whether it has any relation with socioeconomic, demographic, and body composition variables in children and adolescents with phenylketonuria (PKU) diagnosed in the neonatal period. METHODS: This cohort study collected retrospective data of 53 phenylketonuric children and adolescents. Data on family income, housing, and mother's age and schooling level were collected, and anthropometric measures of body composition and distribution were taken. All dosages of phenylalanine (Phe) from the last five years (2015-2019) were evaluated and classified regarding their adequacy (cutoffs: 0-12 years: 2-6 mg/dL; 12-19 years: 2-10 mg/dL). Adequate metabolic control was considered if ≥7%) of the dosages were within desired ranges. RESULTS: The mean (±standard deviation) age in the last year was 10.1±4.6 years. Most of them were under 12 years old (33/53; 62.3%) and had the classic form of the disease (39/53; 73.6%). Better metabolic control was observed among adolescents (68.4 versus 51.4%; p=0.019). Overweight was found in 9/53 (17%) and higher serum Phe levels (p<0.001) were found in this group of patients. Metabolic control with 70% or more Phe level adequacy decreased along with the arm muscle area (AMA) (ptendency=0.042), being 70.0% among those with low reserve (low AMA), and 18.5% among those with excessive reserve (high AMA). CONCLUSIONS: Adequate metabolic control was observed in most patients. The findings suggest that, in this sample, the levels of phenylalanine may be related to changes in body composition.
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Composição Corporal/fisiologia , Erros Inatos do Metabolismo/diagnóstico , Fenilalanina/sangue , Fenilcetonúrias/diagnóstico , Fenilcetonúrias/metabolismo , Adolescente , Antropometria/métodos , Estudos de Casos e Controles , Criança , Pré-Escolar , Estudos de Coortes , Demografia , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Erros Inatos do Metabolismo/sangue , Erros Inatos do Metabolismo/epidemiologia , Estado Nutricional , Sobrepeso/epidemiologia , Fenilcetonúrias/epidemiologia , Estudos Retrospectivos , Fatores SocioeconômicosRESUMO
ABSTRACT Objective: To characterize metabolic control and verify whether it has any relation with socioeconomic, demographic, and body composition variables in children and adolescents with phenylketonuria (PKU) diagnosed in the neonatal period. Methods: This cohort study collected retrospective data of 53 phenylketonuric children and adolescents. Data on family income, housing, and mother's age and schooling level were collected, and anthropometric measures of body composition and distribution were taken. All dosages of phenylalanine (Phe) from the last five years (2015-2019) were evaluated and classified regarding their adequacy (cutoffs: 0-12 years: 2-6 mg/dL; 12-19 years: 2-10 mg/dL). Adequate metabolic control was considered if ≥7%) of the dosages were within desired ranges. Results: The mean (±standard deviation) age in the last year was 10.1±4.6 years. Most of them were under 12 years old (33/53; 62.3%) and had the classic form of the disease (39/53; 73.6%). Better metabolic control was observed among adolescents (68.4 versus 51.4%; p=0.019). Overweight was found in 9/53 (17%) and higher serum Phe levels (p<0.001) were found in this group of patients. Metabolic control with 70% or more Phe level adequacy decreased along with the arm muscle area (AMA) (ptendency=0.042), being 70.0% among those with low reserve (low AMA), and 18.5% among those with excessive reserve (high AMA). Conclusions: Adequate metabolic control was observed in most patients. The findings suggest that, in this sample, the levels of phenylalanine may be related to changes in body composition.
RESUMO Objetivo: Caracterizar o controle metabólico e verificar se existe relação entre ele, variáveis socioeconômicas, demográficas e composição corporal de crianças e adolescentes com fenilcetonúria (FNC) diagnosticada no período neonatal. Métodos: Coorte com coleta retrospectiva de dados de 53 crianças e adolescentes fenilcetonúricos. Foram coletados dados de renda familiar, moradia, idade e escolaridade materna e realizaram-se medidas antropométricas de composição e distribuição corporal. Todas as dosagens de fenilalanina (Fal) dos últimos cinco anos (2015-2019) foram avaliadas e classificadas quanto à adequação (cortes: 0-12 anos: 2-6 mg/dL; 12-19 anos: 2-10 mg/dL). A proporção de dosagens adequadas ≥70% foi considerada como controle metabólico adequado. Resultados: A média (±desvio padrão) de idade, no último ano, foi de 10,1±4,6 anos. A maioria tinha menos de 12 anos (33/53; 62,3%) e apresentava a forma clássica da doença (39/53; 73,6%). Observou-se melhor controle metabólico entre os adolescentes (68,4 vs. 51,4%; p=0,019). Excesso de peso foi encontrado em 9/53 (17%) e maiores níveis séricos de Fal foram descritos nesse grupo (p<0,001). O percentual de controle metabólico com 70% ou mais de adequação dos níveis de Fal foi decrescente de acordo com a área muscular do braço (AMB; ptendência=0,042), sendo de 70% entre os de baixa reserva (AMB reduzida) e de 18,5% entre os com excesso (AMB elevada). Conclusões: Observou-se controle metabólico adequado na maioria dos avaliados e os achados sugerem que, nesta amostra, os níveis de fenilalanina podem estar relacionados com alterações da composição corporal.
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Humanos , Masculino , Feminino , Recém-Nascido , Lactente , Pré-Escolar , Criança , Adolescente , Fenilalanina/sangue , Fenilcetonúrias/diagnóstico , Fenilcetonúrias/metabolismo , Composição Corporal/fisiologia , Erros Inatos do Metabolismo/diagnóstico , Fenilcetonúrias/epidemiologia , Fatores Socioeconômicos , Estudos de Casos e Controles , Antropometria/métodos , Demografia , Estado Nutricional , Estudos Retrospectivos , Estudos de Coortes , Sobrepeso/epidemiologia , Erros Inatos do Metabolismo/sangue , Erros Inatos do Metabolismo/epidemiologiaRESUMO
Newborn screening enables the diagnosis of treatable disorders at the early stages, and because of its countless benefits, conditions have been continuously added to screening panels, allowing early intervention, aiming for the prevention of irreversible manifestations and even premature death. Mucopolysaccharidoses (MPS) are lysosomal storage disorders than can benefit from an early diagnosis, and thus are being recommended for newborn screening. They are multisystemic progressive disorders, with treatment options already available for several MPS types. MPS I was the first MPS disorder enrolled in the newborn screening (NBS) panel in the USA and a few other countries, and other MPS types are expected to be added. Very few studies about NBS for MPS in Latin America have been published so far. In this review, we report the results of pilot studies performed in Mexico and Brazil using different methodologies: tandem mass spectrometry, molecular analysis, digital microfluidics, and fluorimetry. These experiences are important to report and discuss, as we expect to have several MPS types added to NBS panels shortly. This addition will enable timely diagnosis of MPS, avoiding the long diagnostic odyssey that is part of the current natural history of this group of diseases, and leading to a better outcome for the affected patients.
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BACKGROUND: Maple syrup urine disease (MSUD) is an autosomal recessive inherited metabolic disease caused by deficient activity of the branched-chain α-keto acid dehydrogenase (BCKD) enzymatic complex. BCKD is a mitochondrial complex encoded by BCKDHA, BCKDHB, DBT, and DLD genes. MSUD is predominantly caused by Variants in BCKDHA, BCKDHB, and DBT genes encoding the E1α, E1ß, and E2 subunits of BCKD complex, respectively. The aim of this study was to characterize the genetic basis of MSUD by identifying the point variants in BCKDHA, BCKDHB, and DBT genes in a cohort of Brazilian MSUD patients and to describe their phenotypic heterogeneity. It is a descriptive cross-sectional study with 21 MSUD patients involving molecular genotyping by Sanger sequencing. RESULTS: Eight new variants predicted as pathogenic were found between 30 variants (damaging and non-damaging) identified in the 21 patients analyzed: one in the BCKDHA gene (p.Tyr120Ter); five in the BCKDHB gene (p.Gly131Val, p.Glu146Glnfs * 13, p.Phe149Cysfs * 9, p.Cys207Phe, and p.Lys211Asn); and two in the DBT gene (p.Glu148Ter and p.Glu417Val). Seventeen pathogenic variants were previously described and five variants showed no pathogenicity according to in silico analysis. CONCLUSION: Given that most of the patients received late diagnoses, the study results do not allow us to state that the molecular features of MSUD variant phenotypes are predictive of clinical severity.
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Doença da Urina de Xarope de Bordo , 3-Metil-2-Oxobutanoato Desidrogenase (Lipoamida)/genética , Brasil , Estudos Transversais , Humanos , Doença da Urina de Xarope de Bordo/genética , FenótipoRESUMO
Rare genetic disorders are currently in the spotlight due to the elevated number of different conditions and significant total number of affected patients. The study of these disorders is extremely helpful for the elucidation of physiological processes related with complex disorders. Isolated populations are instrumental for the study of genetic disorders, considering their homogeneity and high proportion of affected patients in a small geographic area. These favorable conditions lead to the creation of a new discipline, known as "population medical genetics", which integrates medical genetics, population genetics, epidemiological genetics and community genetics. In order to develop practical activities in this new discipline, the National Institute of Population Medical Genetics (INaGeMP) was created in 2008 in Brazil. INaGeMP has developed several tools and funded numerous research activities. In this review, we highlight three successful projects developed in the first 10 years of INaGeMP activities (2008-2018): a newborn screening pilot study for MPS VI in Northeast Brazil, the study of Machado-Joseph disease in Brazilian families with Azorian ancestry, and the high twinning rate in a small town in southern Brazil. The results of these projects in terms of scientific output and contributions to the affected communities highlight the success and importance of INaGeMP.
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BACKGROUND: Carriers of the sickle cell trait (HbAS) usually remain asymptomatic. However, under conditions of low tissue oxygenation, red blood cell sickling and vascular obstruction may develop. Chronic kidney disease (CKD) can arise from conditions promoting low-oxygen in kidney tissue, which may be aggravated by the presence of the sickle cell trait. In addition, CKD can arise from other genetic traits. AIM: To compare the frequency of HbAS among hemodialysis patients and the general newborn population of Salvador (Bahia-Brazil), as well as to investigate the frequencies of apolipoprotein L1 risk variants in patients undergoing hemodialysis. METHODS: A cross-sectional study included 306 patients with ESRD (End Stage Renal Disease) on hemodialysis for no more than three years. Hemoglobin profiles were characterized by high-performance liquid chromatography. To estimate the sickle cell trait frequency in the general population of Salvador, we analyzed data collected by a local neonatal screening program between 2011 and 2016. To exclude the potential contributing effect of the apolipoprotein L1 (APOL1) gene variants, we performed genotyping by PCR and DNA sequencing of 45 patients. RESULTS: The frequency of HbAS was significantly higher in hemodialysis patients (9.8%) than in the general population (4.6%): Odds Ratio = 2.32 (95% CI = 1.59-3.38). No differences in demographic, clinical or laboratory data were found among patients with or without the sickle cell trait. The frequency of patients with none, one or two APOL1 risk haplotypes (G1 and G2) for CKD were 80%, 18% and 2%, respectively. CONCLUSIONS: The frequency of the sickle cell trait is higher in patients with ESRD on hemodialysis compared to the general population. APOL1 haplotypes do not seem to be the determinant of ESRD in these patients.
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Falência Renal Crônica/complicações , Traço Falciforme/complicações , Traço Falciforme/epidemiologia , Apolipoproteína L1/genética , Brasil/epidemiologia , Feminino , Humanos , Recém-Nascido , Falência Renal Crônica/terapia , Masculino , Pessoa de Meia-Idade , Diálise Renal , Traço Falciforme/genéticaRESUMO
OBJECTIVE: To evaluate the candidate genes PAX-8, NKX2-5, TSH-R and HES-1 in 63 confirmed cases of thyroid dysgenesis. SUBJECTS AND METHODS: Characterization of patients with congenital hypothyroidism into specific subtypes of thyroid dysgenesis with hormone levels (TT4 and TSH), thyroid ultrasound and scintigraphy. DNA was extracted from peripheral blood leukocytes and the genetic analysis was realized by investigating the presence of mutations in the transcription factor genes involved in thyroid development. RESULTS: No mutations were detected in any of the candidate genes. In situ thyroid gland represented 71.1% of all cases of permanent primary congenital hypothyroidism, followed by hypoplasia (9.6%), ectopia (78%), hemiagenesis (6.0%) and agenesis (5.5%). The highest neonatal screening TSH levels were in the agenesis group (p < 0.001). CONCLUSIONS: Thyroid dysgenesis is possibly a polygenic disorder and epigenetic factors could to be implicated in these pathogeneses.
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Proteína Homeobox Nkx-2.5/genética , Mutação/genética , Fator de Transcrição PAX8/genética , Receptores da Tireotropina/genética , Disgenesia da Tireoide/genética , Brasil , Pré-Escolar , Estudos de Coortes , Hipotireoidismo Congênito/diagnóstico por imagem , Hipotireoidismo Congênito/etiologia , Hipotireoidismo Congênito/genética , Análise Mutacional de DNA , Feminino , Testes Genéticos , Humanos , Lactente , Recém-Nascido , Masculino , Triagem Neonatal , Disgenesia da Tireoide/complicações , Disgenesia da Tireoide/diagnóstico por imagem , Tireotropina/sangue , Tiroxina/sangue , Fatores de Transcrição HES-1/genética , UltrassonografiaRESUMO
ABSTRACT Objective: To evaluate the candidate genes PAX-8, NKX2-5, TSH-R and HES-1 in 63 confirmed cases of thyroid dysgenesis. Subjects and methods: Characterization of patients with congenital hypothyroidism into specific subtypes of thyroid dysgenesis with hormone levels (TT4 and TSH), thyroid ultrasound and scintigraphy. DNA was extracted from peripheral blood leukocytes and the genetic analysis was realized by investigating the presence of mutations in the transcription factor genes involved in thyroid development. Results: No mutations were detected in any of the candidate genes. In situ thyroid gland represented 71.1% of all cases of permanent primary congenital hypothyroidism, followed by hypoplasia (9.6%), ectopia (78%), hemiagenesis (6.0%) and agenesis (5.5%). The highest neonatal screening TSH levels were in the agenesis group (p < 0.001). Conclusions: Thyroid dysgenesis is possibly a polygenic disorder and epigenetic factors could to be implicated in these pathogeneses.
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Humanos , Masculino , Feminino , Recém-Nascido , Lactente , Pré-Escolar , Receptores da Tireotropina/genética , Proteína Homeobox Nkx-2.5/genética , Fator de Transcrição PAX8/genética , Mutação/genética , Brasil , Análise Mutacional de DNA , Testes Genéticos , Estudos de Coortes , Ultrassonografia , Hipotireoidismo Congênito/etiologia , Hipotireoidismo Congênito/genética , Hipotireoidismo Congênito/diagnóstico por imagem , Disgenesia da Tireoide/genéticaRESUMO
Maple syrup urine disease (MSUD) is an autosomal recessive inherited disorder that affects branched-chain amino acid (BCAA) catabolism and is associated with acute and chronic brain dysfunction. Recent studies have shown that inflammation may be involved in the neuropathology of MSUD. However, these studies have mainly focused on single or small subsets of proteins or molecules. Here we performed a case-control study, including 12 treated-MSUD patients, in order to investigate the plasmatic biomarkers of inflammation, to help to establish a possible relationship between these biomarkers and the disease. Our results showed that MSUD patients in treatment with restricted protein diets have high levels of pro-inflammatory cytokines [IFN-γ, TNF-α, IL-1ß and IL-6] and cell adhesion molecules [sICAM-1 and sVCAM-1] compared to the control group. However, no significant alterations were found in the levels of IL-2, IL-4, IL-5, IL-7, IL-8, and IL-10 between healthy controls and MSUD patients. Moreover, we found a positive correlation between number of metabolic crisis and IL-1ß levels and sICAM-1 in MSUD patients. In conclusion, our findings in plasma of patients with MSUD suggest that inflammation may play an important role in the pathogenesis of MSUD, although this process is not directly associated with BCAA blood levels. Overall, data reported here are consistent with the working hypothesis that inflammation may be involved in the pathophysiological mechanism underlying the brain damage observed in MSUD patients.
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Objective To search for genetic alteration in NKX2.5 gene in patients presenting both congenital heart disease (CHD) and TD. Subjects and methods Individual phenotypes were carefully analyzed in 86 children with thyroid dysgenesis (TD) using thyroid function tests, scintigraphy, ultrasound and echocardiography. DNA was extracted and NKX2.5 gene coding region was amplified by polymerase chain reaction (PCR) and sequenced. Results CHD were found in 8.1% of patients with TD. The mutation screening revealed two known polymorphisms in patients with isolated TD or TD associated with CHD. None of them are predicted to result in codon change in conserved domain. The c.63A>G polymorphism was detected in 54/86 patients (49 with isolated TD and 5 with TD combined with CHD). There was a significant association of c.63A>G polymorphism with hypoplasia (p < 0.036). The c.541G>A polymorphism was observed in only one patient with isolated thyroid hypoplasia. Conclusion NKX2.5 mutations were not found. The c.63A>G polymorphism might be associated with thyroid hypoplasia.
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Feminino , Humanos , Recém-Nascido , Masculino , Proteínas de Homeodomínio/genética , Polimorfismo Genético , Disgenesia da Tireoide/genética , Glândula Tireoide/anormalidades , Fatores de Transcrição/genética , Estudos de Associação Genética , Linhagem , Testes de Função TireóideaRESUMO
OBJECTIVE: To search for genetic alteration in NKX2.5 gene in patients presenting both congenital heart disease (CHD) and TD. SUBJECTS AND METHODS: Individual phenotypes were carefully analyzed in 86 children with thyroid dysgenesis (TD) using thyroid function tests, scintigraphy, ultrasound and echocardiography. DNA was extracted and NKX2.5 gene coding region was amplified by polymerase chain reaction (PCR) and sequenced. RESULTS: CHD were found in 8.1% of patients with TD. The mutation screening revealed two known polymorphisms in patients with isolated TD or TD associated with CHD. None of them are predicted to result in codon change in conserved domain. The c.63A>G polymorphism was detected in 54/86 patients (49 with isolated TD and 5 with TD combined with CHD). There was a significant association of c.63A>G polymorphism with hypoplasia (p < 0.036). The c.541G>A polymorphism was observed in only one patient with isolated thyroid hypoplasia. CONCLUSION: NKX2.5 mutations were not found. The c.63A>G polymorphism might be associated with thyroid hypoplasia.
Assuntos
Proteínas de Homeodomínio/genética , Polimorfismo Genético , Disgenesia da Tireoide/genética , Glândula Tireoide/anormalidades , Fatores de Transcrição/genética , Feminino , Estudos de Associação Genética , Proteína Homeobox Nkx-2.5 , Humanos , Recém-Nascido , Masculino , Linhagem , Testes de Função TireóideaRESUMO
BACKGROUND: In sickle cell disease, the quantification of Hb A2 is important for the differential diagnosis between sickle cell anemia (Hb SS) and Hb S/ß0-thalassemia.OBJECTIVE: To determine Hb A2 levels as quantified by high performance liquid chromatography in patients with sickle cell anemia (Hb SS) and with the SC hemoglobinopathy, with or without concomitant alpha thalassemia.METHODS: This is a retrospective study of 242 children aged between two and six years with diagnoses of Hb SS or Hb SC. The hemoglobin was evaluated using high performance liquid chromatography and alpha thalassemia [3.7 kb deletion (-a3.7)] was detected by polymerase chain reaction. Patients were classified as homozygous (-a3.7/-a3.7), heterozygous (-a3.7/a), or homozygous wild-type. Analysis of variance was used to compare the mean Hb A2 values between the alpha thalassemia groups.RESULTS: The mean (± standard deviation) Hb A2 concentrations in the Hb SS group (n = 135) was 3.68 ± 0.65%. The mean values for individuals with Hb SS and heterozygous (n = 28) or homozygous for alpha thalassemia (n = 3) were 3.98 ± 0.64% and 4.73 ± 0.25%, respectively. The mean Hb A2 of all the Hb SC patients (n = 107) was 4.01 ± 0.507 with 4.29 ± 0.41% and 4.91 ± 0.22% in individuals heterozygous (n = 23) and homozygous for alpha thalassemia (n = 7), respectively. All patients homozygous for alpha thalassemia had Hb A2 levels above 3.5%. However, Hb A2 values above 5.2% were seen in patients with Hb SS and Hb SC, independently of alpha thalassemia.CONCLUSION: Hb A2 levels are elevated in patients with Hb S or Hb C, and are directly influenced by the alpha thalassemia genotypes.
Assuntos
Hemoglobina A2 , Cromatografia Líquida de Alta Pressão , Talassemia beta , Talassemia alfa , Anemia FalciformeRESUMO
BACKGROUND: In sickle cell disease, the quantification of Hb A2 is important for the differential diagnosis between sickle cell anemia (Hb SS) and Hb S/ß(0)-thalassemia. OBJECTIVE: To determine Hb A2 levels as quantified by high performance liquid chromatography in patients with sickle cell anemia (Hb SS) and with the SC hemoglobinopathy, with or without concomitant alpha thalassemia. METHODS: This is a retrospective study of 242 children aged between two and six years with diagnoses of Hb SS or Hb SC. The hemoglobin was evaluated using high performance liquid chromatography and alpha thalassemia [3.7kb deletion (-α(3.7))] was detected by polymerase chain reaction. Patients were classified as homozygous (-α(3.7)/-α(3.7)), heterozygous (-α(3.7)/α), or homozygous wild-type. Analysis of variance was used to compare the mean Hb A2 values between the alpha thalassemia groups. RESULTS: The mean (±standard deviation) Hb A2 concentrations in the Hb SS group (n=135) was 3.68±0.65%. The mean values for individuals with Hb SS and heterozygous (n=28) or homozygous for alpha thalassemia (n=3) were 3.98±0.64% and 4.73±0.25%, respectively. The mean Hb A2 of all the Hb SC patients (n=107) was 4.01±0.507 with 4.29±0.41% and 4.91±0.22% in individuals heterozygous (n=23) and homozygous for alpha thalassemia (n=7), respectively. All patients homozygous for alpha thalassemia had Hb A2 levels above 3.5%. However, Hb A2 values above 5.2% were seen in patients with Hb SS and Hb SC, independently of alpha thalassemia. CONCLUSION: Hb A2 levels are elevated in patients with Hb S or Hb C, and are directly influenced by the alpha thalassemia genotypes.