RESUMO
OBJECTIVE: To search for mutations in melanocortin pathway elements, that is, the melanocortin-4 receptor (MC4R ), agouti-related protein (AGRP ), and (alpha-melanocyte-stimulating hormone (alpha MSH ) genes in children with severe obesity. STUDY DESIGN: Direct sequencing of the MC4R encoding sequence and single-strand polymorphism conformation analysis of AGRP and alpha MSH genes were performed in 63 severely obese children. Polymerase chain reaction (PCR) assays of restriction fragment length polymorphism were used to assess the frequency of each newly discovered mutation in 283 non-obese control subjects. RESULTS: Four dominantly inherited, heterozygous, missense MC4R mutations (Val50Met, Ser58Cys, Ile102Ser, and Ile170Val) were identified in 4 unrelated children and none of the control subjects. Expression of the obese phenotype was variable in mutation-positive family members. Clinical and laboratory features were similar in the obese children with and without an MC4R mutation. Two polymorphisms were detected in the AGRP -encoding sequence (a silent mutation in exon 1 and Ala67Thr in exon 2), with similar frequencies in the obese and control groups. No mutations were found in the alpha MSH gene. CONCLUSIONS: MC4R mutations may be a non-negligible cause of severe obesity in children with variable expression and penetrance. Mutations in AGRP and alpha MSH genes were not among the causes of obesity in our population.
Assuntos
Análise Mutacional de DNA , Hormônios Estimuladores de Melanócitos/genética , Obesidade/genética , Proteínas/genética , Receptores de Peptídeos/genética , Adolescente , Proteína Relacionada com Agouti , Índice de Massa Corporal , Estudos de Casos e Controles , Criança , Pré-Escolar , Feminino , Humanos , Peptídeos e Proteínas de Sinalização Intercelular , Masculino , Linhagem , Reação em Cadeia da Polimerase , Polimorfismo Genético , Polimorfismo de Fragmento de Restrição , Receptor Tipo 4 de MelanocortinaRESUMO
The conventional treatment of autoimmune hepatitis (AIH) with prednisone and azathioprine induces remission in most cases but is often associated with poorly tolerated side effects. We carried out a retrospective study to evaluate the efficacy of and the tolerance to cyclosporin treatment in 15 children and adolescents with type 2 AIH. Eight children received cyclosporin as primary immunosuppression because of risk factors for poor tolerance of steroids. Five other patients with relapsing AIH refused to resume treatment with steroids and were treated with cyclosporin. In both groups alanine aminotransferase activity returned to normal within 6 months. Side effects were minimal and well tolerated. No relapse occurred in 10 patients after 1 to 6 years. Cyclosporin was withdrawn in 3 patients after 1, 2, and 3 years and replaced by low doses of prednisone in combination with azathioprine. In 2 other children with acute liver failure, which progressed despite treatment with steroids and azathioprine, the addition of cyclosporin was followed by normalization of prothrombin time.