HEXB gene study and prenatal diagnosis for a family affected by infantile Sandhoff disease

目的:通过对一例婴儿型Sandhoff病男婴及其家系的临床、基因与产前诊断研究,探讨本病的诊断与产前诊断方法.方法:患儿男,生后易惊,易呛咳,8个月起精神运动倒退,无力,经功能训练等多种治疗无效,病情进行性加重.患儿于1岁4个月出现癫痫,1岁5个月时来院就诊,双侧眼底检查发现樱桃红斑,视神经萎缩,脑MRI示双侧基底节区、丘脑异常信号,白质弥漫异常信号.考虑到神经节脑苷脂病的可能,进行了外周血白细胞溶酶体酶活性测定及相关基因分析.患儿母亲再孕18周时来院要求产前诊断,19周时通过羊水细胞基因分析进行胎儿产前诊断.结果:患儿外周血白细胞己糖胺酶A+B活性为O(正常对照41.9 ～ 135.1 nmol·h-1·mg-protein-1),严重缺陷,确诊为Sandhoff病.HEXB基因分析证实患儿存在两个突变,其中外显子14的c.1645G＞ A(p.G549R)为新突变,内含子7 c.IVS7-48T缺失为已知突变.目前患儿2岁3个月,进行性衰竭,频繁抽搐,失明,四肢及躯干张力增高.患儿母亲第2胎羊水细胞HEXB基因分析显示,胎儿未携带与先证者相同的致病突变,未患Sandhoff病,生后经脐带血白细胞己糖胺酶A+B活性正常,HEXB基因分析未见异常,为健康女婴,验证了产前诊断结果.结论:采用酶学与基因分析为一例婴儿型Sandhoff病明确诊断,并首次通过羊水细胞基因分析帮助患者家系的新生婴儿进行了产前诊断.To investigate the phenotype and genotype of a Chinese boy and his family affected by infantile Sandhoff disease.The proband, a boy, was the first child born to a non-consanguineous couple. He showed startle reaction after birth and progressive psychomotor regression from the age of 8 months. From the age of 16 months, he presented seizures. When he was admitted at 17 months old, severe mental retardation and weakness were observed. Fundus examination revealed bilateral cherry-red spots in the macula and optic atrophy. Cranial MRI revealed abnormal signals in the thalamus, basal ganglia and white matter. Enzymatic assay and genetic testing were performed for the diagnosis. His mother visited us at 18 weeks of pregnancy seeking for prenatal diagnosis. HEXB gene diagnosis to the fetus was performed by direct sequencing.Significant deficient total β-hexosaminidase (A and B) activity in peripheral leucocytes of the patient (0.0 nmol/h/mg compared with normal control, 41.9 to 135.1 nmol/h/mg) supported the diagnosis of Sandhoff disease. On his HEXB gene, two mutations were found. c.1645G-A (p.G549R) was novel. c.IVS7-48T was a reported mutation. Now, the patient was 2 years and 3 months old, with progressive general failure, severe epilepsy, blindness and hypermyotonia. Subsequently, the mother visited us at 18 weeks of pregnancy seeking for prenatal diagnosis. HEXB gene analysis of the amniocytes was performed by direct sequencing. Both of the two mutations were not detected from cultured amniocytes. The result revealed that the fetus was not affected by Sandhoff disease. A healthy girl, the sibling of the proband, was born in term. Postnatal enzyme analysis and genetic analysis of the cord blood cells confirmed the prenatal diagnosis.One novel mutation on HEXB gene was identified. Prenatal diagnosis to the fetus of this family was performed by amniocytes gene analysis."十二五"国家科技支撑计划资助项目PubMed中文核心期刊要目总览(PKU)中国科技核心期刊(ISTIC)中国科学引文数据库(CSCD)04403-4104