亚历山大病12例中国患儿临床及遗传学研究

Clinical and genetic study of twelve Chinese patients with Alexander disease

目的了解12例中国亚历山大病（Alexander disease，AD）患儿的临床表型及遗传学特点，为在国内开展该病的分子诊断及遗传咨询打下基础。方法根据2001年vander Knaap等提出的AD头颅MRI诊断标准进行临床诊断，对临床诊断的AD患儿及其父母进行GFAP基因突变检测，并对上述患儿进行0．50-3．67年临床随访。结果于2007年4月至2010年6月共收集12例AD患儿。初次于我院就诊的平均年龄为4．87岁（0．75-12．00岁）。初次就诊时主诉：运动发育落后（3例），惊厥发作（7例）或跌倒后出现下肢运动障碍（2例）；体征：头围44-58cm，较相应年龄平均头围高6．45％（1．80％-13．95％）；采用脑瘫粗大运动功能分级系统（gross motor function classification system，GMFCS）中文版对运动进行分级：GMFCSI级8例，GMFCSII级3例，GMFCSV级1例；8例患儿自幼认知功能发育迟滞。至2010年12月进行随访时，距初次就诊间隔0．50-3．67年，患儿平均年龄8．75岁（4．10-13．00岁），患儿运动及认知功能基本保持稳定。其中5例病程中伴发作性加重现象（41．67％）。11例病程中有惊厥发作。12例均检测到GFAP杂合错义突变，均为新发突变。共发现lO种GFAP突变，其中3种为未报道的新突变。R79与R239突变为热点突变。8例的突变位于第1外显子。结论12例中国患儿临床表型特点为：疾病进展速度较国外报道相对缓慢，病程中发作性加重较为常见，惊厥发生率高。基因型特点与国外报道一致，本研究中发现的3种GFAP新突变丰富了已知突变谱。

Objective To delineate the phenotype and genotype characteristics in 12 Chinese children with Alexander disease （AD） , which is helpful for the molecular diagnosis and genetic counseling in China. Methods Clinical diagnosis of AD was based on MRI criteria proposed by van der Knaarp in 2001. Included AD patients were followed up for 0. 50-3.67 years. Mutations in GFAP were detected by DNA sequencing. Results The 12 cases of AD were clinically diagnosed. Age of first visit was 4. 87 years （0. 75-12. 00 years） , with 3 types of chief complaints ： developmental delay in 3, recurrent seizures in 7, unable to walk after falling in 2. Average head circumference was 52. 34 cm （44-58 cm） , which larger than age-matched average by 6.45% （ 1.80%-13.95% ）. On the first visit, scaling according to Gross motor functional classification system （ GMFCS ） was performed, with GMFCS I in 8, II in 3, V in 1. Mild to severe cognitive dysfunction were found in 8, and seizures in 11 cases. The 12 patients were followed up for 0. 50-3.67 years, their motor and cognitive function remained stable. Episodic aggravations provoked by fever or falling were observed in 5 cases （ 41.67% ） . Heterozygous missense mutations of GFAP were detected in 12 patients. All mutations were de novo; 3 out of 10 mutations identified were novel. R79 and R239 were hot mutations, which was consistent with previous reports. Mutations were located in exon 1 in 8 cases. Conclusions The phenotype in these patients is characterized by slower progression compared withreports from other population and high incidence of seizures. And episodic aggravations provoked by fever or falling were more common. The genotype characteristics are consistent with previous reports. The results of this research expanded the number of patients with Alexander disease found to have GFAP coding mutations in China.