RESUMO
PURPOSE: To identify genes involved in idiopathic absence epilepsies by analyzing gene expression using a monozygotic (MZ) twin design. METHODS: Genome-wide gene expression in lymphoblastoid cell lines (LCLs) was determined using microarrays derived from five discordant and four concordant MZ twin pairs with idiopathic absence epilepsies and five unaffected MZ twin pairs. Gene expression was analyzed using three strategies: discordant MZ twins were compared as matched pairs, MZ twins concordant for epilepsy were compared to control MZ twins, and a singleton design of affected versus unaffected MZ twin individuals was used irrespective of twin pairing. An overlapping gene list was generated from these analyses. Dysregulation of genes recognized from the microarray experiment was validated using quantitative real time PCR (qRT-PCR) in the twin sample and in an independent sample of 18 sporadic absence cases and 24 healthy controls. RESULTS: Sixty-five probe sets were identified from the three combined microarray analysis strategies. Sixteen genes were chosen for validation and nine of these genes confirmed by qRT-PCR in the twin sample. Differential expression for EGR1 (an immediate early gene) and RCN2 (coding for the calcium-binding protein Reticulocalbin 2) were reconfirmed by qRT-PCR in the independent sample. DISCUSSION: Using a unique sample of discordant MZ twins, our study identified genes with altered expression, which suggests novel mechanisms in idiopathic absence epilepsy. Dysregulation of EGR1 and RCN2 is implicated in idiopathic absence epilepsy.
Assuntos
Proteínas de Ligação ao Cálcio/genética , Proteína 1 de Resposta de Crescimento Precoce/genética , Epilepsia Tipo Ausência/diagnóstico , Epilepsia Tipo Ausência/genética , Expressão Gênica/genética , Gêmeos Monozigóticos/genética , Adulto , Anticonvulsivantes/uso terapêutico , Linhagem Celular Tumoral/patologia , Epilepsia Tipo Ausência/tratamento farmacológico , Feminino , Humanos , Masculino , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Ácido Valproico/uso terapêuticoRESUMO
The t(8;14)(q11.2;q32) is emerging as an uncommon, though recurrent cytogenetic finding. As of yet, too few cases of acute lymphoblastic leukemia (ALL) characterized by this translocation have been studied to determine its prognostic significance with confidence. We therefore report three new patients (two male children and one adult female) and present their hematologic, immunophenotypic, and clinical data. The clinical and laboratory characteristics of 26 other patients with t(8;14)(q11.2;q32) are summarized. The total number of patients now reported in the literature is 29 with a mean age of 14 years. Early relapse, that is, relapse within 6 months, does not appear to be a common feature of this group. The gender distribution is 19 males: 9 females (gender not reported in one case). Twenty-three t(8;14) patients show a pre-B immunophenotype and 24 of 24, on whom information is available, achieved complete remission after induction chemotherapy for B-ALL. Approximately one third of patients with t(8;14) have Down syndrome, 19 of 27 have additional acquired cytogenetic abnormalities, 5 of these have the t(9;22), and 4 show duplication of the abnormal chromosome 14, which is derived from the t(8;14). Hemoglobin and platelet counts are low at presentation in 10 of 10 and 8 of 9 patients, respectively, and the average white blood count is 38.9 x 10(9)/L. Of the 7 patients for whom IgH status has been determined, all show rearrangement of the IgH locus. Two of the present three patients are included in this group; their IgH rearrangement was demonstrated by fluorescence in situ hybridization with IgH break-apart probes.
Assuntos
Cromossomos Humanos Par 14/genética , Cromossomos Humanos Par 8/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Translocação Genética/genética , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Genes de Imunoglobulinas/genética , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
We present six cases of 47,+i(5p)/46 mosaicism diagnosed at chorionic villus sampling (CVS), this being the first prospective series to be reported. The clinical indication in each was advanced maternal age. Further prenatal studies in four (amniocentesis, plus fetal blood sampling in one) did not show the isochromosome. In one case, subsequent amniocentesis showed 1/48 in situ colonies with the isochromosome, but fetal blood was karyotypically normal. These five pregnancies resulted in phenotypically normal livebirths; further normal follow-up reports (from age 4 months through 4 years) are noted in four of these. Analysis of placental tissue in one case confirmed the presence of the i(5p) mosaicism. In the remaining case, in which 100% of CVS cultured cells had the i(5p), the pregnancy was terminated. Fetal skin fibroblasts did not show the i(5p). Thus, in none of these six cases was true fetal mosaicism detected, nor an abnormal phenotype noted. We suggest that a 47,+i(5p)/46 karyotype, detected at CVS, may frequently reflect confined placental mosaicism. In addition, we report a case of the primary diagnosis of 47,+i(5p)/46 mosaicism at amniocentesis. The infant appeared normal at birth, but a brain malformation was subsequently identified.