Varela Monica Castro, Kok Fernando, Otto Paulo Alberto, Koiffmann Celia Priszkulnik
Centro de Estudos do Genoma Humano, Department of Biology, Institute of Biosciences, University of São Paulo, São Paulo, SP, Brazil.
Eur J Hum Genet. 2004 Dec;12(12):987-92. doi: 10.1038/sj.ejhg.5201264.
Angelman syndrome (AS) can result from either a 15q11-q13 deletion (del), paternal uniparental disomy (UPD), imprinting, or UBE3A mutations. Here, we describe the phenotypic and behavioral variability detected in 49 patients with different classes of deletions and nine patients with UPD. Diagnosis was made by methylation pattern analysis of exon 1 of the SNRPN-SNURF gene and by microsatellite profiling of loci within and outside the 15q11-q13 region. There were no major phenotypic differences between the two main classes (BP1-BP3; BP2-BP3) of AS deletion patients, except for the absence of vocalization, more prevalent in patients with BP1-BP3 deletions, and for the age of sitting without support, which was lower in patients with BP2-BP3 deletions. Our data suggest that gene deletions (NIPA1, NIPA2, CYF1P1, GCP5) mapped to the region between breakpoints BP1 and BP2 may be involved in the severity of speech impairment, since all BP1-BP3 deletion patients showed complete absence of vocalization, while 38.1% of the BP2-BP3 deletion patients were able to pronounce syllabic sounds, with doubtful meaning. Compared to UPD patients, deletion patients presented a higher incidence of swallowing disorders (73.9% del x 22.2% UPD) and hypotonia (73.3% del x 28.57% UPD). In addition, children with UPD showed better physical growth, fewer or no seizures, a lower incidence of microcephaly, less ataxia and higher cognitive skills. As a consequence of their milder or less typical phenotype, AS may remain undiagnosed, leading to an overall underdiagnosis of the disease.
天使综合征（AS）可由15q11 - q13缺失（del）、父源单亲二倍体（UPD）、印记异常或UBE3A突变引起。在此，我们描述了49例不同类型缺失患者和9例UPD患者的表型和行为变异性。通过对SNRPN - SNURF基因外显子1的甲基化模式分析以及对15q11 - q13区域内外位点的微卫星分析进行诊断。除了发声缺失（在BP1 - BP3缺失患者中更常见）以及无支撑坐立年龄（在BP2 - BP3缺失患者中较低）外，AS缺失患者的两个主要类别（BP1 - BP3；BP2 - BP3）之间没有主要的表型差异。我们的数据表明，定位于断点BP1和BP2之间区域的基因缺失（NIPA1、NIPA2、CYF1P1、GCP5）可能与言语障碍的严重程度有关，因为所有BP1 - BP3缺失患者均完全无发声，而38.1%的BP2 - BP3缺失患者能够发出有可疑意义的音节。与UPD患者相比，缺失患者吞咽障碍（73.9% del vs 22.2% UPD）和肌张力低下（73.3% del vs 28.57% UPD）的发生率更高。此外，UPD患儿身体生长更好，癫痫发作更少或无癫痫发作，小头畸形发生率更低，共济失调更少且认知技能更高。由于其表型较轻或不太典型，AS可能仍未被诊断出来，导致该疾病总体诊断不足。
