RESUMO
In this study, 103 unrelated South-American patients with mucopolysaccharidosis type II (MPS II) were investigated aiming at the identification of iduronate-2-sulfatase (IDS) disease causing mutations and the possibility of some insights on the genotype-phenotype correlation The strategy used for genotyping involved the identification of the previously reported inversion/disruption of the IDS gene by PCR and screening for other mutations by PCR/SSCP. The exons with altered mobility on SSCP were sequenced, as well as all the exons of patients with no SSCP alteration. By using this strategy, we were able to find the pathogenic mutation in all patients. Alterations such as inversion/disruption and partial/total deletions of the IDS gene were found in 20/103 (19%) patients. Small insertions/deletions/indels (<22 bp) and point mutations were identified in 83/103 (88%) patients, including 30 novel mutations; except for a higher frequency of small duplications in relation to small deletions, the frequencies of major and minor alterations found in our sample are in accordance with those described in the literature.
Assuntos
Éxons , Iduronato Sulfatase/genética , Mucopolissacaridose II/genética , Mutação , Adulto , Feminino , Estudos de Associação Genética , Técnicas de Genotipagem , Humanos , Mucopolissacaridose II/diagnóstico , Mucopolissacaridose II/patologia , Análise de Sequência de DNA , Índice de Gravidade de Doença , América do SulRESUMO
The aim of the study was to characterize clinically and biochemically mucopolysaccharidosis type II (MPS II) heterozygotes. Fifty-two women at risk to be a carrier, with a mean age of 34.1 years (range 16-57 years), were evaluated through pedigree analysis, medical history, physical examination, measurement of iduronate sulfatase (IDS) activities in plasma and in leukocytes, quantification of glycosaminoglycans (GAGs) in urine, and analysis of the IDS gene. Eligibility criteria for the study also included being 16 years of age or older and being enrolled in a genetic counselling programme. The pedigree and DNA analyses allowed the identification of 40/52 carriers and 12/52 non-carriers. All women evaluated were clinically healthy, and their levels of urinary GAGs were within normal limits. Median plasma and leukocyte IDS activities found among carriers were significantly lower than the values found for non-carriers; there was, however, an overlap between carriers' and non-carriers' values. Our data suggests that MPS II carriers show lower plasma and leukocyte IDS activities but that this reduction is generally associated neither with changes in levels of urinary GAGs nor with the occurrence of clinical manifestations.
Assuntos
Heterozigoto , Mucopolissacaridose II/genética , Adolescente , Adulto , Biomarcadores/análise , Biomarcadores/urina , Estudos de Casos e Controles , Análise Mutacional de DNA , Família , Saúde da Família , Feminino , Glicoproteínas/análise , Glicoproteínas/genética , Glicosaminoglicanos/análise , Glicosaminoglicanos/urina , Humanos , Pessoa de Meia-Idade , Mucopolissacaridose II/diagnóstico , Mucopolissacaridose II/urina , Linhagem , Exame Físico , Adulto JovemRESUMO
This paper presents data collected by a Brazilian center in a multinational multicenter observational study of patients with mucopolysaccharidosis type VI (MPS VI), aiming at determining the epidemiological, clinical, and biochemical profile of these patients. Twenty-eight south-American patients with MPS VI were evaluated through medical interview, physical exam, echocardiogram, electrocardiogram, ophthalmologic evaluation, quantification of glycosaminoglycans (GAGs) in urine, and measurement of the activity of N-acetylgalactosamine-4-sulfatase (ARSB) in leukocytes. 92.9% of patients were Brazilian. Mean age at diagnosis and at evaluation was 48.4 months and 97.1 months, respectively. 88% of patients had onset of symptomatology before the age of 36 months. Consanguinity was reported by 27% of the families. Mean weight and height at birth were 3.481 kg and 51.3 cm, respectively. The most frequently reported clinical manifestations were short stature, corneal clouding, coarse facial features, joint contractures, and claw hands. All patients presented with echocardiogram changes as well as corneal clouding. Mean ARSB activity in leukocytes was 5.4 nmoles/h/mg protein (reference values: 72-174), and urinary excretion of GAGs was on average 7.9 times higher than normal. The number of clinical manifestations did not show a significant correlation with the levels of urinary GAGs nor with the ARSB activity. Also, no significant correlation was found between the levels of urinary GAGs and the ARSB activity. It was concluded that MPS VI has high morbidity and that, when compared with data published in the literature, patients in our study were diagnosed later and presented with a higher frequency of cardiological findings.
Assuntos
Mucopolissacaridose VI/epidemiologia , Mucopolissacaridose VI/patologia , Fenótipo , Brasil/epidemiologia , Pré-Escolar , Chile/epidemiologia , Ecocardiografia , Eletrocardiografia , Glicosaminoglicanos/urina , Humanos , Entrevistas como Assunto , N-Acetilgalactosamina-4-Sulfatase/metabolismoRESUMO
Fragile X syndrome is the most common form of inherited mental retardation in men. The molecular mechanism underlying the disease is an amplification of a polymorphic trinucleotide repeat (CGG)n located at 5' end of FMR1 which promotes transcriptional silencing of the gene. Four different classes of alleles could be distinguished in the population based on the size of the repeat, however only large amplifications over 200 CGG are associated with the disease. In the past decade several authors have associated premutated alleles, which harbor expansions from 61 to 200 repeats, with the occurrence of premature ovarian failure (POF). In this work we describe a large Brazilian family in which a POF/premutated woman has transmitted to five out of seven daughters a FMR1 premutated allele. From these five women with premutations, three have experienced premature ovarian failure. Our data clearly indicate a co-segregation pattern of inheritance between POF and fragile X premutation.
Assuntos
Segregação de Cromossomos , Cromossomos Humanos X/genética , Proteínas do Tecido Nervoso/genética , Insuficiência Ovariana Primária/genética , Proteínas de Ligação a RNA , Adulto , Alelos , Brasil , Feminino , Proteína do X Frágil da Deficiência Intelectual , Inativação Gênica , Humanos , Masculino , Linhagem , Repetições de TrinucleotídeosRESUMO
The fragile X syndrome (FRAXA) is the most common cause of inherited mental retardation. However, it has been frequently underdiagnosed in pediatric population. The characterization of the most significant pre and post-puberal clinical features observed among patients that are positive for the FMR-1 mutation, is useful as a screening tool for ordering the DNA test. Therefore, a screening program for FRAXA has been conducted in a sample of 104 mentally retarded individuals (92 males and 12 females), comprehending familial history and physical examination in order to determine the clinical characteristics. The molecular test for the disease was performed in all individuals. Seventeen patients (14 males) were positive for the FMR-1 mutation. Familial mental retardation and poor eye contact were the most common clinical findings with statistical significance (p<0.05) in FRAXA pre and post-puberal patients. The post-puberal patients presented, as opposed to the control group, large ears, broad forehead and macroorchidism.
Assuntos
Síndrome do Cromossomo X Frágil/genética , Deficiência Intelectual/genética , Adolescente , Adulto , Estudos de Casos e Controles , Criança , Pré-Escolar , Feminino , Síndrome do Cromossomo X Frágil/diagnóstico , Humanos , Masculino , Mutação , LinhagemRESUMO
PURPOSE: To evaluate three methods for digoxin dose adjustment in aged patients. METHODS: We determined the plasma digoxin levels that would be attained in 47 consecutive old patients with doses adjusted to the creatinin clearance (Clc) by means of three mathematical functions. RESULTS: Age: 79.1 +/- 6.1 years of age; Clc: 0.77 +/- 0.24 mL/kg of lean body weight and minute. Once the dose has been fitted to the digoxin pharmacokinetic parameters described in the bibliography, the drug levels would oscillate between 0.8 and 2.0 ng/mL in 85.1% of the patients, with a 95% confidence interval (95% CI) from 72.3% to 92.6%; in 0.0% of the patients the levels would be greater than 2 ng/mL (95% IC: 0.0% to 7.6%). The precision and the bias would be 0.40 ng/mL (95% IC: 0.33 to 0.46 ng/mL) and--0.08 ng/m (95% IC: -0.19 to 0.04 ng/mL), respectively. The drug level would not be associated with the Clc (coefficient of Clc in the regression line: -0.0003; P > 0.9). The results would be worse with the others two mathematical functions. CONCLUSION: The first of the above adjustment methods would lead to good results if digoxin has not been prescriped in order to control the cardiac frequency in the setting of auricular fibrillation.
Assuntos
Digoxina/administração & dosagem , Digoxina/sangue , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Monitorização Fisiológica , Valor Preditivo dos Testes , Estudos RetrospectivosRESUMO
Huntington disease (HD) is associated with expansions of a CAG trinucleotide repeat in the HD gene. Accurate measurement of a specific CAG repeat sequence in the HD gene in 92 Brazilian controls without HD, 44 Brazilian subjects with clinical findings suggestive of HD and 40 individuals from 6 putative HD families, showed a range from 7 to 33 repeats in normal subjects and 39 to 88 repeats in affected subjects. A trend between early age at onset of first symptoms and increasing number of repeats was seen. Major increase of repeat size through paternal inheritance than through maternal inheritance was observed. Data generated from this study may have significant implications for the etiology, knowledge of the incidence, diagnosis, prognosis, genetic counseling and treatment of HD Brazilian patients.
Assuntos
Doença de Huntington/genética , Expansão das Repetições de Trinucleotídeos/genética , Adolescente , Adulto , Idade de Início , Brasil/etnologia , Estudos de Casos e Controles , Criança , Análise Mutacional de DNA , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da PolimeraseRESUMO
Neste estudo investigamos a organizaçäo cromossômica de pacientes com retardo mental e/ou malformaçöes congênitas, visando a avaliaçäo de causas genéticas associadas a estes distúrbios. Os padröes de bandas GTG e CBG foram estudados a partir da cultura de linfócitos de sangue periférico, estimulados por fitohemaglutinina M. Dentre os 98 indivíduos portadores de retardo mental e/ou malformaçöes congênitas analisados, diagnosticamos as seguintes síndromes: 12 casos de Down, dois de Edwards, um de Patau, cinco de Turner, dois de Klinefelter, um de "cri-du-chat", e um caso de translocaçäo balanceada entre os cromossomos 13 e 14, um caso de cromossomo derivado e um outro de cromossomo marcador. Encontramos anomalias cromossômicas em 26 por cento dos pacientes, das quais 82 por cento eram alteraçöes numéricas e o restante (18 por cento) representou rearranjos estruturais. Este percentual significativo enfatiza o uso da cariotipagem de rotina em pacientes com retardo mental e/ou malformaçöes congênitas.
Assuntos
Humanos , Masculino , Feminino , Recém-Nascido , Lactente , Pré-Escolar , Criança , Adolescente , Adulto , Aberrações Cromossômicas , Aconselhamento Genético , Deficiência Intelectual , CariotipagemRESUMO
O retardo mental é uma característica comum aos pacientes que buscam o Serviço de Genética Médica, apresentando heterogeneidade clínica e etiológica. Neste trabalho, estudos cromossômicos foram realizados em 30 indivíduos portadores de retardo mental e atraso psicomotor. Verificamos que 40 por cento dos indivíduos investigados apresentaram anomalias cromossômicas. Nos demais casos (60 por cento) o cariótipo foi normal. Este estudo reforça a importância da investigaçåo citogenética em indivíduos portadores de retardo mental e atraso psicomotor rastreando aberraçöes cromosssômicas numéricas ou estruturais e auxiliando no diagnóstico, prognóstico e aconselhamento gewnético das famílias
Assuntos
Humanos , Masculino , Feminino , Lactente , Pré-Escolar , Criança , Adolescente , Adulto , Aberrações Cromossômicas , Aconselhamento Genético , Deficiência Intelectual , Transtornos PsicomotoresRESUMO
O retardo mental e uma caracteristica comum aos pacientes que buscam o Servico de Genetica Medica, apresentando heterogeneidade clinica e etiologica. Neste trabalho, estudos cromossomicos foram realizados em 30 individuos portadores de retardo mental e atraso psicomotor: Verificamos que 40 por cento dos individuos investigados apresentaram anomalias cromossomicas. Nos demais casos (60 por cento) o cariotipo foi normal. Este estudo reforca a importancia da investigacao citogenetica em individuos portadores de retardo mental e atraso psicomotor rastreando aberracoes cromossomicas numericas ou estruturais e auxiliando no diagnostico e Aconselhamento Genetico das familias.