RESUMO
Prader-Willi syndrome (PWS) is a multisystemic disorder caused by the loss of expression of paternally transcribed genes within chromosome 15q11-q13. Most cases are due to paternal deletion of this region; the remaining cases result from maternal uniparental disomy (UPD) and imprinting defects. To better understand the phenotypic variability of PWS, a genotype-phenotype correlation study was performed in 91 children with PWS. Patients were diagnosed by Southern Blot Methylation assay and genetic subtypes were established using FISH and microsatellite analyses. Fifty-nine subjects with deletion (31/28 males/females; mean age 3.86 years), 30 with UPD (14/16 males/females; mean age 3.89 years) and 2 girls with a presumed imprinting defect (mean age 0.43 yrs) were identified. For correlation purposes patients were grouped as "deleted" and "non-deleted." An increased maternal age was found in the UPD group. Four of Holm's criteria were more frequently present in the deleted group: need for special feeding techniques, sleep disturbance, hypopigmentation, and speech articulation defects. Concerning cognitive assessments, only 9.52% of subjects with deletion had Full-Scale IQ (FSIQ) > or =70, while 61.53% of subjects without deletion had FSIQ > or =70. Similar results were found in behavioral measures. Sleep disorders and carbohydrate metabolism were systematically assessed. Polysomnoghaphic studies revealed a higher frequency of central events with desaturations > or =10% in the deleted group (P = 0.020). In summary, the phenotype was significantly different between both groups in certain parameters related to the CNS. These results might be related to the differences in brain gene expression of the genetic subtypes.
Assuntos
Fenótipo , Síndrome de Prader-Willi/etiologia , Adolescente , Pesos e Medidas Corporais , Metabolismo dos Carboidratos , Criança , Comportamento Infantil , Pré-Escolar , Deleção Cromossômica , Cromossomos Humanos Par 15 , Feminino , Intolerância à Glucose/etiologia , Humanos , Lactente , Recém-Nascido , Resistência à Insulina , Masculino , Síndrome de Prader-Willi/genética , Síndrome de Prader-Willi/metabolismo , Síndrome de Prader-Willi/fisiopatologia , Pesquisa , Transtornos do Sono-Vigília/etiologiaRESUMO
Prader-Willi syndrome (PWS) is a multisystemic disorder caused by the loss of expression of paternally transcribed genes in the PWS critical region of chromosome 15. Various molecular mechanisms are known to lead to PWS: deletion 15q11-q13 (75% of cases), maternal uniparental disomy (matUPD15) (23%) and imprinting defects (2%). FISH and microsatellite analysis are required to establish the molecular etiology, which is essential for appropriate genetic counseling and care management. We characterized an Argentinean population, using five microsatellite markers (D15S1035, D15S11, D15S113, GABRB3, D15S211) chosen to develop an appropriate cost-effective method to establish the parental origin of chromosome 15 in nondeleted PWS patients. The range of heterozygosity for these five microsatellites was 0.59 to 0.94. The average heterozygosity obtained for joint loci was 0.81. The parental origin of chromosome 15 was established by microsatellite analysis in 19 of 21 non-deleted PWS children. We also examined the origin of the matUPD15; as expected, most of disomies were due to a maternal meiosis I error. The molecular characterization of this set of five microsatellites with high heterozygosity and polymorphism information content improves the diagnostic algorithm of Argentinean PWS children, contributing significantly to adequate genetic counseling of such families.
Assuntos
Cromossomos Humanos Par 15/genética , Repetições de Microssatélites/genética , Síndrome de Prader-Willi/etiologia , Argentina , Estudos de Casos e Controles , Feminino , Triagem de Portadores Genéticos/métodos , Marcadores Genéticos/genética , Humanos , Masculino , Reação em Cadeia da Polimerase , Síndrome de Prader-Willi/genética , Sequências de Repetição em Tandem/genéticaRESUMO
Prader-Willi syndrome (PWS) is a multisystemic disorder caused by the loss of expression of paternally transcribed genes in the PWS critical region of chromosome 15. Various molecular mechanisms are known to lead to PWS: deletion 15q11-q13 (75% of cases), maternal uniparental disomy (matUPD15) (23%) and imprinting defects (2%). FISH and microsatellite analysis are required to establish the molecular etiology, which is essential for appropriate genetic counseling and care management. We characterized an Argentinean population, using five microsatellite markers (D15S1035, D15S11, D15S113, GABRB3, D15S211) chosen to develop an appropriate cost-effective method to establish the parental origin of chromosome 15 in nondeleted PWS patients. The range of heterozygosity for these five microsatellites was 0.59 to 0.94. The average heterozygosity obtained for joint loci was 0.81. The parental origin of chromosome 15 was established by microsatellite analysis in 19 of 21 non-deleted PWS children. We also examined the origin of the matUPD15; as expected, most of disomies were due to a maternal meiosis I error. The molecular characterization of this set of five microsatellites with high heterozygosity and polymorphism information content improves the diagnostic algorithm of Argentinean PWS children, contributing significantly to adequate genetic counseling of such families.
Assuntos
Humanos , Masculino , Feminino , /genética , Repetições de Microssatélites/genética , Síndrome de Prader-Willi/etiologia , Argentina , Triagem de Portadores Genéticos/métodos , Estudos de Casos e Controles , Marcadores Genéticos/genética , Reação em Cadeia da Polimerase , Sequências de Repetição em Tandem/genética , Síndrome de Prader-Willi/genéticaRESUMO
A Síndrome de Prader-Willi (SPW) e a Síndrome de Angelman (SA) säo doenças neurogenéticas consideradas como exemplos do fenômeno de impressäo genômica, em seres humano, estando relacionadas com alteraçöes envolvendo a regiäo cromossômica 15q11-13. As alteraçöes genéticas predominantes, na SPW, säo deleçöes na regiäo 15q11-13, de origem paterna e dissomia uniparental materna e, na SA, encontram-se deleçöes na regiäo 15q11-13 materna e dissomia uniparental paterna. Estudamos 5 pacientes com suspeita clínica de SPW e 4 pacientes com suspeita clínica de SA, atendidos no Setor de Genética Médica do Hospital das Clínicas da FMRP-USP, com o objetivo de estabelecer o diagnóstico clínico e etiológico nessa amostra. Para isso, utilizamos citogenética convencional, estudo de metilaçäo por Southern blotting com a sonda KB17 (ilha CpG do gene SNRPN), após digestäo com as enzimas de restriçäo Xba I e Not I, e análise de polimorfismos de repetiçäo (CA)n por PCR, usando os primers 196 e IR4-3R. Dos 9 pacientes avaliados, todos tiveram avaliaçäo citogenética convencional normal. Foram confirmados molecularmente 1 caso de SPW por deleçäo nova, 1 caso de SPW por dissomia uniparenteal materna e 1 caso de SPW em que a causa genética näo pode ser esclarecida pela análise de polimorfismo com os primers usados. Foram confirmados, molecularmente, 2 casos de SA, ambos por deleçäo nova na regiäo 15q11-13 e, 1 caso de SA, cuja clínica é extremamente sugestiva, teve resultado molecular normal, podendo-se sugerir uma mutaçäo de ponto no gene responsável pela SA.
Assuntos
Humanos , Masculino , Feminino , Pré-Escolar , Criança , Adolescente , Adulto , Síndrome de Angelman/genética , Síndrome de Prader-Willi/genética , Southern Blotting , Deleção Cromossômica , Cromossomos Humanos Par 15/genética , Reação em Cadeia da Polimerase , Síndrome de Angelman/diagnóstico , Síndrome de Angelman/etiologia , Síndrome de Prader-Willi/diagnóstico , Síndrome de Prader-Willi/etiologiaRESUMO
A Síndrome de Prader-Willi é uma doença rara, congênita, que acomete 1 a cada 15 mil nascimentos, caracterizada por hipogonadismo, hiperfagia com obesidade mórbida, baixa estatura, retardo mental, fácies dismórfica, sendo originada de uma anormalidade no braço longo do cromossomo 15 no locus 15q 11-13 de origem paterna. Relata-se caso de Síndrome de Prader-Willi, com revisäo da literatura, apresentando características clínicas, genéticas, dietéticas, metabólicas e tratamento