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首页> 外文期刊>BMC Pediatrics >Infantile onset Sandhoff disease: clinical manifestation and a novel common mutation in Thai patients
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Infantile onset Sandhoff disease: clinical manifestation and a novel common mutation in Thai patients

机译：婴儿发病Sandhoff疾病：临床表现和泰国患者的新常见突变

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Sandhoff disease (SD) is an autosomal recessive lysosomal storage disorder, resulting in accumulation of GM2 ganglioside, particular in neuronal cells. The disorder is caused by deficiency of β-hexosaminidase B (HEX-B), due to pathogenic variant of human HEXB gene. This study describes clinical features, biochemical, and genetic defects among Thai patients with infantile SD during 2008–2019. Five unrelated Thai patients presenting with developmental regression, axial hypotonia, seizures, exaggerated startle response to noise, and macular cherry red spot were confirmed to have infantile SD based on deficient HEX enzyme activities and biallelic variants of the HEXB gene. In addition, an uncommon presenting feature, cardiac defect, was observed in one patient. All the patients died in their early childhood. Plasma total HEX and HEX-B activities were severely deficient. Sequencing analysis of HEXB gene identified two variants including c.1652GA (p.Cys551Tyr) and a novel variant of c.761TC (p.Leu254Ser), in 90 and 10% of the mutant alleles found, respectively. The results from in silico analysis using multiple bioinformatics tools were in agreement that the p.Cys551Tyr and the p.Leu254Ser are likely pathogenic variants. Molecular modelling suggested that the Cys551Tyr disrupt disulfide bond, leading to protein destabilization while the Leu254Ser resulted in change of secondary structure from helix to coil and disturbing conformation of the active site of the enzyme. Genome-wide SNP array analysis showed no significant relatedness between the five affected individuals. These two variants were not present in control individuals. The prevalence of infantile SD in Thai population is estimated 1 in 1,458,521 and carrier frequency at 1 in 604. The study suggests that SD likely represents the most common subtype of rare infantile GM2 gangliosidosis identified among Thai patients. We firstly described a potential common variant in HEXB in Thai patients with infantile onset SD. The data can aid a rapid molecular confirmation of infantile SD starting with the hotspot variant and the use of expanded carrier testing.
机译：Sandhoff疾病（SD）是一种常染色体隐性溶酶体储存障碍，导致GM2神经节苷脂的积累，特别是神经元细胞。由于人甲基基因的致病变异，β-六氨基氨基氨基氨酶B（六己氨氨基氨酶B（Hex-B）的紊乱引起的。本研究描述了2008 - 2019年患有婴儿SD的临床特征，生化和遗传缺陷。呈现出发育回归的五个无关乳腺癌，轴痛症，癫痫发作，对噪音的夸大的爆发反应，以及黄斑樱桃红点的呼吸和黄斑樱桃红点是基于缺乏的六进肠酶活性和甲基基因的双烯族变体进行婴儿SD。此外，在一个患者中观察到罕见的呈现特征，心脏缺损。所有患者都在幼儿期内死亡。血浆总十六进制和十六进制活动严重缺乏。六六基因的测序分析鉴定了两个变体，包括C.652g＆ a（p.cys551tyr）和c.761t＆gt的新型变体.c（p.leu254ser），90和10％的突变等位基因分别发现。使用多种生物信息学工具的Silico分析的结果一致认为，P.Cys551tyr和P.leu254ser可能是致病变种。分子建模表明Cys551Tyr破坏二硫键，导致蛋白质不稳定，而Leu254ser导致从螺旋到螺旋到螺旋的次级结构变化，令人满意的酶的活性位点。基因组宽的SNP阵列分析显示出五个受影响的个体之间没有显着的相关性。对照个体中不存在这两个变体。泰国人群中婴儿SD的患病率为1,458,521和604中的载波频率。该研究表明，SD可能代表泰国患者中鉴定的罕见婴儿GM2个性化病变最常见的亚型。我们首先在乳腺发作SD中描述了甲基患者甲基患者的潜在常见变体。数据可以帮助婴儿SD的快速分子确认，从热点变体和扩展载波测试的使用开始。

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