RESUMO
Objective This study aimed to analyze the frequency of GSTP1-Alw26I polymorphism and to estimate its association with toxic substances in Parkinson's disease (PD). Methods A study group with 154 patients - subdivided into familial and sporadic PD groups - and 158 elderly individuals without the disease (control group) were evaluated. GSTP1-Alw26I polymorphism was analyzed by polymerase chain reaction/restriction fragment length polymorphism (PCR-RFLP). Results Patients were significantly more exposed to pesticides compared with the control group (p=0.0004), and the heterozygote genotype associated to exposure to pesticides also prevailed in patients (p=0.0001). Wild homozygote genotype was related to tobacco use (p=0.043) and alcoholism (p=0.033) in familial PD patients. Conclusion Exposure to pesticides is associated to PD, whose effect can be enhanced when combined with the heterozygote genotype of GSTP1-Alw26I. Also, large genetic and environmental studies considering tobacco use, alcoholism, GSTP1 and PD are necessary to confirm our findings. .
Objetivo Analisar a frequência do polimorfismo GSTP1-Alw26I, assim como estimar sua associação com substâncias tóxicas na doença de Parkinson (DP). Métodos A casuística avaliada foi composta por um grupo de estudo, com 154 pacientes, subdivididos em DP familial e esporádica, e outro com 158 idosos sem a doença (grupo controle). O polimorfismo GSTP1-Alw26I foi analisado por reação em cadeia da polimerase/polimorfismo de comprimento do fragmento de restrição (PCR/RFLP). Resultados Os pacientes foram significativamente mais expostos a pesticidas, comparados com o grupo controle (p=0,0004), e o genótipo heterozigoto associado a exposição a pesticidas também prevaleceu nos pacientes (p=0,0001). O genótipo homozigoto selvagem apresentou relação com tabagismo (p=0,043) e etilismo (p=0,033) em pacientes com DP familial. Desse modo, a exposição a pesticidas está associada à DP, cujo efeito pode ser potencializado quando combinado ao genótipo heterozigoto de GSTP1-Alw26I. Estudos genético-ambientais envolvendo tabagismo, etilismo, GSTP1 e DP devem ser realizados em casuísticas numerosas, confirmando essa associação. .
Assuntos
Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , DNA-Citosina Metilases/genética , Glutationa S-Transferase pi/genética , Doença de Parkinson Secundária/induzido quimicamente , Doença de Parkinson Secundária/genética , Praguicidas/toxicidade , Polimorfismo Genético/genética , DNA Metiltransferases Sítio Específica (Adenina-Específica)/genética , Estudos de Casos e Controles , Frequência do Gene , Heterozigoto , Reação em Cadeia da Polimerase , Fatores de Risco , Fatores SexuaisRESUMO
Maturity-onset diabetes of the young (MODY) is characterized by an autosomal dominant mode of inheritance, early onset of hyperglycemia, and defects of insulin secretion. MODY subtypes described present genetic, metabolic, and clinical differences. MODY 2 is characterized by mild asymptomatic fasting hyperglycemia, and rarely requires pharmacological treatment. Hence, precise diagnosis of MODY is important for determining management and prognosis. We report two heterozygous GCK mutations identified during the investigation of short stature. Case 1: a prepubertal 14-year-old boy was evaluated for constitutional delay of growth and puberty. During follow-up, he showed abnormal fasting glucose (113 mg/dL), increased level of HbA1c (6.6%), and negative β-cell antibodies. His father and two siblings also had slightly elevated blood glucose levels. The mother had normal glycemia. A GCK heterozygous missense mutation, p.Arg191Trp, was identified in the proband. Eighteen family members were screened for this mutation, and 11 had the mutation in heterozygous state. Case 2: a 4-year-old boy investigated for short stature revealed no other laboratorial alterations than elevated glycemia (118 mg/dL); β-cell antibodies were negative. His father, a paternal aunt, and the paternal grandmother also had slightly elevated glycemia, whereas his mother had normal glycemia. A GCK heterozygous missense mutation, p.Glu221Lys, was identified in the index patient and in four family members. All affected patients had mild elevated glycemia. Individuals with normal glycemia did not harbor mutations. GCK mutation screening should be considered in patients with chronic mild early-onset hyperglycemia, family history of impaired glycemia, and negative β-cell antibodies. Arq Bras Endocrinol Metab. 2012;56(8):519-24.
O diabetes do tipo MODY (maturity-onset diabetes of the young) caracteriza-se por herança autossômica dominante, início precoce da hiperglicemia e defeitos na secreção de insulina. Os subtipos de MODY apresentam diferenças genéticas, metabólicas e clínicas. O MODY 2 é caracterizado por hiperglicemia leve assintomática e raramente requer tratamento farmacológico. O diagnóstico preciso de MODY é importante para se determinar o tratamento e o prognóstico. Relatamos duas mutações no gene GCK em heterozigose identificadas durante investigação de baixa estatura. Caso 1: paciente do sexo masculino, com 14 anos, pré-púbere, avaliado por atraso constitucional do crescimento e da puberdade. Durante o acompanhamento, apresentou glicemia de jejum alterada (113 mg/dL), aumento de HbA1c (6,6%) e anticorpos anticélulas β negativos. Seu pai e dois irmãos também apresentavam glicemia levemente elevada. A mãe tinha glicemia normal. Foi identificada no gene GCK uma mutação missense em heterozigose, p.Arg191Trp. Dezoito membros da família foram rastreados e 11 apresentavam essa mutação. Caso 2: paciente do sexo masculino, com 4 anos, em avaliação por baixa estatura. Não apresentou alterações laboratoriais, exceto por glicemia elevada (118 mg/dL). Anticorpos anticélulas β foram negativos. Seu pai, uma tia paterna e a avó paterna também apresentavam glicemia discretamente elevada, e a mãe, glicemia normal. A mutação missense em heterozigose, p.Glu221Lys, foi identificada no paciente-índice e em 4 membros da família. Todos os pacientes afetados apresentavam hiperglicemia leve. Essas mutações não foram identificadas nos indivíduos com glicemia normal. O rastreamento de mutações no gene GCK deve ser considerado em pacientes com hiperglicemia crônica leve e de início precoce, história familiar de glicemia elevada e anticorpos anticélulas β negativos. Arq Bras Endocrinol Metab. 2012;56(8):519-24.
Assuntos
Adolescente , Pré-Escolar , Humanos , Masculino , /genética , Glucoquinase/genética , Heterozigoto , Hiperglicemia/genética , Doença Crônica , /enzimologia , Hiperglicemia/enzimologiaRESUMO
Hemoglobin City of Hope (HbCH) (HBB: c.208G>A, beta 69 (E13)Gly>Ser) is a rare, anomalous change. Seven independent carriers reported so far, had not displayed any hematological manifestations. The ethnic origin of the known instances is presumably heterogeneous, although they are mainly Mediterraneans or equatorial West Africans. We describe the case of a compound heterozygote in trans for Hb S (Glu6Val) and Hb City of Hope (Gly69Ser) in an anemic two year-old boy with a severe immune-deficient phenotype and fatal chronic parvovirus B19 infection. Haplotype with the Hb S was Bantu; while it was a mixed atypical Benin/Cameroon for Hb CH. Remote ancestral origin of the City of Hope mutation in this family seems to be SubSaharan African. The compound heterozygosis in trans for hemoglobins S and City of Hope, jointly with an unfavorable HBB control region background and a viral chronic infection, seemed the cause of the fatal outcome in the patient. When accompanied by other Hb deleterious mutations in trans, Hb CH should not be considered any longer as an innocuous or functionally silent variant.
La hemoglobina City of Hope (HbCH) (HBB: c.208G>A, beta 69 (E13)Gly>Ser) es una variante infrecuente, considerada como anómala. Ninguno de los siete heterocigotos simples, genéticamente no relacionados, reportados hasta ahora, ha mostrado hemopatología. El origen étnico de esos casos es presuntamente heterogéneo, pero la mayoría parece mediterráneo o africano-ecuatorial occidental. Se describe el caso de un niño de dos años de edad con fenotipo hipoplásico mieloeritroideo severo e infección crónica por parvovirus B19, heterocigoto compuesto en trans para las hemoglobinas S (Glu6Val) y City of Hope (Gly69Ser ). El haplotipo en fase con la Hb S fue Bantú, mientras que el de la Hb CH fue un combinado atípico Benin/Camerún. El origen ancestral remoto de la mutación City of Hope (y de la Hb S) en esta familia es africano subsahariano. La heterocigosis compuesta en trans para las hemoglobinas S y City of Hope y una secuencia génica predisponente en la región de control de HBB, conjuntamente con la infección por parvovirus B19 pueden ser la causa del curso fatal del paciente. En presencia de otras mutaciones de hemoglobina deletéreas, la Hb City of Hope no debiera ser considerada una variante inocua o funcionalmente silenciosa.
Assuntos
Humanos , Masculino , Pré-Escolar , Anemia Falciforme , Heterozigoto , Haplótipos/genética , Hemoglobina Falciforme/genética , Medula Óssea/lesõesRESUMO
AIM: To present phenotypic variability of WT1-related disorders. METHODS: Description of clinical and genetic features of five 46,XY patients with WT1 anomalies. RESULTS: Patient 1: newborn with genital ambiguity; he developed Wilms tumor (WT) and chronic renal disease and died at the age of 10 months; the heterozygous 1186G>A mutation compatible with Denys-Drash syndrome was detected in this child. Patients 2 and 3: adolescents with chronic renal disease, primary amenorrhea and hypergonadotrophic hypogonadism; patient 2 had a gonadoblastoma. The heterozygous IVS9+4, C>T mutation, compatible with Frasier syndrome was detected. Patient 4: 9-year-old boy with aniridia, genital ambiguity, dysmorphisms and mental deficiency; a heterozygous 11p deletion, compatible with WAGR syndrome was detected. Patient 5: 2 months old, same diagnosis of patient 4; he developed WT at the age of 8 months. CONCLUSIONS: Constitutional abnormalities of WT1 cause gonadal and renal anomalies and predisposition to neoplasia and must be investigated in patients with ambiguous genitalia, chronic renal disease and(or) Wilms tumors; primary amenorrhea with chronic renal disease; and aniridia, genital ambiguity and dysmorphisms.
OBJETIVO: Descrever a variabilidade fenotípica das anomalias relacionadas ao WT1. MÉTODOS: Descrição das características clínicas e genéticas de cinco pacientes 46,XY com anomalias no WT1. RESULTADOS: Paciente 1: Recém-nascido com ambigüidade genital desenvolveu tumor de Wilms (TW) e insuficiência renal crônica (IRC), com óbito aos 10 meses. Detectada a mutação 1186G>A em heterozigose, compatível com síndrome de Denys-Drash. Pacientes 2 e 3: Adolescentes com IRC, amenorréia primária e hipogonadismo hipergonadotrófico; a paciente 2 apresentava gonadoblastoma. Ambas apresentavam mutação IVS9+4, C>T em heterozigose, característica da síndrome de Frasier. Paciente 4: Idade 9 anos, aniridia, ambigüidade genital, dismorfismos e deficiência mental; deleção 11p, compatível com síndrome WAGR foi encontrada em heterozigose. Paciente 5: Dois meses, mesmo diagnóstico do paciente 4, desenvolveu TW aos 8 meses. CONCLUSÕES: Alterações constitucionais do WT1 determinam anomalias gonadais, renais e predisposição a neoplasias; devem ser pesquisadas em casos de ambigüidade genital associada a IRC e(ou) TW; de amenorréia primária com IRC; e aniridia, ambigüidade genital e dismorfismos.
Assuntos
Adolescente , Criança , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Síndrome de Frasier , Genes do Tumor de Wilms , Neoplasias Renais , Proteínas WT1/genética , Amenorreia/diagnóstico , Evolução Fatal , Síndrome de Frasier/diagnóstico , Síndrome de Frasier/genética , Genitália/anormalidades , Genitália/patologia , Heterozigoto , Neoplasias Renais/diagnóstico , Neoplasias Renais/genética , Fenótipo , Insuficiência Renal Crônica/diagnósticoRESUMO
The multisteps of tumorigenesis involve the classic chromosomal instability and the mutator phenotype pathways featured by a predisposition to acquire mutations in tumor suppressor genes and oncogenes. Expansion and contraction of microsatellite sequences due to a deficient mismatch repair system are a marker of the mutator phenotype. Controversial results regarding the extent of microsatellite instability (MSI) have been reported in the development and progression of myeloid malignancies. Here, we investigated MSI and loss of heterozygosity (LOH) frequencies at the microsatellite loci BAT-26, D7S486, D8S135, ANK1, IFNA, TP53 and bcr of 19 Brazilian patients with acute (AML) and chronic myeloid leukemia (CML). One AML patient and one CML patient were categorized as having a high degree of microsatellite instability (MSI-H), corresponding to 10.5 percent (2/19) of all patients. LOH at loci BAT-26 and TP53 was present in 30 percent of the patients with AML alone. Despite the small sample size, our results suggest that the mutator phenotype, as verified by MSI frequency, could play a role in the leukemogenesis of a small subset of patients with myeloid leukemia.
Assuntos
Humanos , Adulto , Pessoa de Meia-Idade , Leucemia Mielogênica Crônica BCR-ABL Positiva , Mutação , Reação em Cadeia da Polimerase , Doença Aguda , Genética Populacional , Heterozigoto , Repetições de MicrossatélitesRESUMO
Homocysteine is a risk factor for cardiovascular disease. Mutations in a key enzyme in homocysteine metabolism, methylenetetrahydrofolate reductase, may contribute to hyperhomocysteinemia and alter folate and cobalamin levels. After starting hemodialysis, 10 mg oral folate daily and 500 micrograms intravenous methylcobalamin once weekly were prescribed to 27 hemodialysis patients (time on hemodialysis > or = 12 months) and two groups were defined: Group A normal; Group B heterozygous. Initial, third and twelfth month measurements of homocysteine, serum folate and vitamin B12 levels were collected and analyzed. Heterozygous state of methylenetetrahydrofolate reductase prevalence was 48
. Hyperhomocysteinemia was present in both groups. Cobalamin final levels were significantly lower in Group B compared to Group A. Homocysteine, serum folate and cobalamin levels at third and twelfth month were significantly different from baseline levels but non-different between them in both groups. In Group B, vitamin B12 at third month was significantly higher than initial, but final measurements were not different from baseline determinations. In conclusion, the heterozygous prevalence of the enzyme in hemodialysis patients is similar to that reported in the general population; hyperhomocysteinemia is frequent in hemodialysis patients and final levels in heterozygous patients are significantly higher than in normal patients. Cobalamin levels are lower in the heterozygous group. After one year of treatment, homocysteine tends to increase, suggesting a secondary resistance phenomenon to vitamin supplementation in heterozygous patients.
Assuntos
Humanos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Vitamina B 12/análogos & derivados , Vitamina B 12/sangue , Ácido Fólico/sangue , Oxirredutases atuantes sobre Doadores de Grupo CH-NH/genética , Homocisteína/sangue , Falência Renal Crônica/enzimologia , Vitamina B 12/uso terapêutico , Distribuição de Qui-Quadrado , Diálise Renal , Mutação Puntual/genética , Estatísticas não Paramétricas , Hiper-Homocisteinemia/prevenção & controle , Metilenotetra-Hidrofolato Redutase (NADPH2) , Ácido Fólico/uso terapêutico , Heterozigoto , Homocisteína/genética , Falência Renal Crônica/sangue , Falência Renal Crônica/terapiaRESUMO
La heterocigosidad para la talasemia ß (talasemia menor) por sí misma no conduce a sobrecarga de hierro; sin embargo, cuando coexiste con un estado homocigoto para alguna de las multiciones (H63d o C282Y) del gene de la hemocromatosis hereditaria (gen HFE), puede presentarse spbrecarga de hierro. Se describe una familia en la que el propositus, siendo doble heterocigoto para talasemia ß y para la mutación H63D del gene HFE, desarrolló sobrecarga de hierro grave y, en consecuencia, insuficiencia hepatocelular crónica con hipertensión portal. Otros miembros de la familia, con sólo talasemia o la mutación H63D no han desarrollado sobrecarga de hierro. Se discuten brevemente algunos aspectos sobre la interacción entre la talasemia ß y la hemocromatosis hereditaria y se hacen especulaciones sobre la posibilidad de que otras mutaciones genéticas que conducen a sobrecarga de hierro familiar haya sido las responsables de la sobrecarga de hierro en esta familia.
Assuntos
Humanos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Talassemia beta , Família , Hemocromatose , Heterozigoto , Genes , MutaçãoRESUMO
The efficiency and viability of a hemoglobinopathy program was investigated. The program was offered on a voluntary basis to a Brazilian community (Araras, SP) and started with the blood analyses of pregnant women. A total of 2209 pregnant women were screened in the first 39 months and 80 heterozygotes were diagnosed (52 AS, 19 AT and 9 AC). Another 1003 persons related to these heterozygotes were examined and a total of 432 heterozygotes were diagnosed (241 AS, 140 AT and 51 AC), added to 13 patients with chronic hemolytic anemia (8 SS, 3 SC, 1 TT and 1 CC) and 16 risk couples, made up of two heterozygotes. The examination percentages of pregnant women (100 per cent), newly born children (75 per cent), other children (97 per cent), husbands (56 per cent ) and other relatives (64 per cent) showed the high rate of acceptance of the program in the community. Genetic counselling was accepted by 60 per cent of the heterozygotes over 15 years of age.