Clinical and genetic spectrum of Sanfilippo type c (MPS IIIC) disease in the Netherlands
Clinical and genetic spectrum of Sanfilippo type c (MPS IIIC) disease in the Netherlands
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DOI：
10.1016/j.ymgme.2007.09.011
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发表时间：
2008-02-01
影响因子：
3.8
通讯作者：
Wijburg, F. A.
中科院分区：
文献类型：
--
作者：
Ruijter, G. J. G.;Valstar, M. J.;Wijburg, F. A.
粘多糖样沉积症IIIC（MPS IIIC，Sanfilippo C综合征）是一种由溶酶体酶乙酰辅酶A：α-氨基葡萄糖苷N-乙酰转移酶（HGSNAT）缺乏引起的溶酶体贮积症。我们对29名荷兰MPS IIIC患者进行了临床研究，并确定了最近发现的HGSNAT基因的致病突变。据报道，所有患者在生命的第一年内精神发育均正常。第一个临床症状通常在1至6岁（平均3.5岁）之间出现，包括延迟的精神发育和行为问题。其他症状包括睡眠和听力问题、反复感染、腹泻和癫痫。两个姐妹篇的病情减轻，直到第三个十年才出现症状。平均死亡年龄为34岁（范围25-48岁）。分子分析显示，除了一名患者外，所有患者的两种等位基因都发生了突变。共发现14种不同的突变：两个剪接位点突变，一个移码突变由于插入，三个无义突变和八个错义突变。两个突变，p.R344C和p.S518F，在荷兰血统的先证者中频繁发生，分别占突变等位基因的22.0%和29.3%。这项研究表明，MPS IIIC的病程比以前报道的要轻，严重程度和临床病程即使在同胞之间也高度可变，使个体患者临床表型的预测复杂化。一个明确的表型-基因型相关性无法建立，除了突变p.G262R和p.S539C只发现在两个姐妹篇晚发型疾病，并推测传达一个温和的表型。(C)2007爱思唯尔公司All rights reserved.
Mucopolysaccharidosis IIIC (MPS IIIC, Sanfilippo C syndrome) is a lysosomal storage disorder caused by deficiency of the lysosomal enzyme acetyl-CoA:alpha-glucosaminide N-acetyltransferase (HGSNAT). We performed a clinical study on 29 Dutch MPS IIIC patients and determined causative mutations in the recently identified HGSNAT gene.Psychomotor development was reported to be normal in all patients during the first year of life. First clinical signs were usually noted between I and 6 years (mean 3.5 years), and consisted of delayed psychomotor development and behavioral problems. Other symptoms included sleeping and hearing problems, recurrent infections, diarrhoea and epilepsy. Two sisters had attenuated disease and did not have symptoms until the third decade. Mean age of death was 34 years (range 25-48). Molecular analysis revealed mutations in both alletes for all patients except one. Altogether 14 different mutations were found: two splice site mutations, one frame shift mutation due to an insertion, three nonsense mutations and eight missense mutations. Two mutations, p.R344C and p.S518F, were frequent among probands of Dutch origin representing 22.0% and 29.3%, respectively, of the mutant alleles.This study demonstrates that MPS IIIC has a milder course than previously reported and that both severity and clinical course are highly variable even between sibs, complicating prediction of the clinical phenotype for individual patients. A clear phenotype-genotype correlation could not be established, except that the mutations p.G262R and p.S539C were only found in two sisters with late-onset disease and presumably convey a mild phenotype. (C) 2007 Elsevier Inc. All rights reserved.