COL4A1/COL4A2基因变异相关婴儿痉挛症的临床特点及预后

Clinical characteristics and prognosis of COL4A1/COL4A2 gene variants related infantile spasms

背景COL4A1/COL4A2变异可引起脑穿通畸形、脑血管疾病等,但目前关于COL4A1/COL4A2变异表现为婴儿痉挛症(infantile spasms,IS)的报道较少。目的总结COL4A1/COL4A2变异相关IS患儿的临床特点及预后,进一步提高临床医生对本病的认识。方法回顾性分析2019年5月-2020年8月就诊于解放军总医院第一医学中心儿内科的6例COL4A1/COL4A2变异相关脑病患儿的临床资料及基因检测结果。结果6例患儿中,男2例,女4例,起病中位年龄为6月龄(3~9月龄),均表现为痉挛性发作及脑电图呈高峰失律,明确诊断为IS。6例均伴有不同程度的精神运动发育落后。小头畸形5例,先天性白内障1例,小眼症2例,肌酸激酶升高1例,偏瘫3例,运动障碍3例。6例头颅MRI均异常,表现为脑室扩张、脑室周围白质软化和(或)脑白质体积减小,其中3例胎儿期即出现头颅MRI异常,表现为脑室扩张。5例COL4A1变异患儿均为杂合的新生变异,其中剪切变异2例:c.3406+1 G>T,c.280-1 G>A;错义变异3例:c.4088G>A p.Gly1363Asp,c.2441G>T p.Gly814Val,c.3968G>A p.Gly1323Asp(NM_001845)。1例COL4A2变异,c.1148C>T p.Pro383Leu(NM_001846),为杂合的新生变异,变异类型为错义变异。6例均曾行IS一线治疗(促肾上腺皮质激素、氨己烯酸或口服皮质醇),其中1例经氨己烯酸治疗后发作控制1年余,余5例发作均未得到控制。末次随访时6例均存在精神运动发育落后,其中3例COL4A1变异患儿的大运动及认知情况最差。结论COL4A1/COL4A2基因主要为新生变异,可表现为IS。对于COL4A1/COL4A2基因相关的IS,头颅MRI可表现为脑室扩张、脑室周围白质软化和(或)脑白质体积减小,部分患儿在胎儿期即出现头颅MRI异常;另外,可伴有发育落后、小头畸形、偏瘫、运动障碍以及其他系统异常,预后较差。

Background COL4A1/COL4A2 variants can cause a series of diseases such as porencephalia and cerebrovascular diseases,but there are few studies reporting that COL4A1/COL4A2 variants can be manifested as infantile spasms(IS).Objective To summarize the clinical characteristics and prognosis of children with COL4A1/COL4A2 gene variants related IS,so as to furtherly improve clinicians'understanding to this disease.Methods Clinical data and genetic test results of 6 children with COL4A1/COL4A2 gene variants who visited the pediatrics department of the First Medical Center of Chinese PLA General Hospital from May 2019 to August 2020 were analyzed retrospectively.Results Among the 6 cases,there were 2 males and 4 females.The median age of onset was 6 months(range,3-9 months).All the cases showed spastic seizures and the electroencephalography showed hypsarrhythmia,which were clearly diagnosed as IS.All the 6 cases were accompanied with different degrees of psychomotor developmental delay.Microcephaly were found in 5 cases,congenital cataract in 1 case,microphthalmia in 2 cases,elevated creatine kinase in 1 case,hemiplegia in 3 cases,and dyskinesia in 3 cases.All the 6 cases had abnormal findings on brain magnetic resonance imaging(MRI),manifested as ventriculomegaly,periventricular leukomalacia or volume reduction of cerebral white matter,and ventriculomegaly on brain MRI was found in fetus period of three cases.Five cases with COL4A1 variants were heterozygous de novo variants,including 2 cases of shear variants,c.3406+1 G>T,c.280-1 G>A,3 cases of missense variants,c.4088G>A,p.Gly1363Asp,c.2441G>T p.Gly814Val,c.3968G>A p.Gly1323Asp(NM_001845).One case was COL4A2 variant,c.1148C>T p.Pro383Leu(NM_001846),a heterozygous de novo variant,and the variant type was missense variant.All the 6 cases had received the first-line treatment(adrenocorticotropic hormone,vigabatrin or oral cortisol)of IS,among which the onset of 1 case was controlled for more than 1 year after vigabatrin treatment,while the remaining 5 cases were not controlled.At the last follow-up,all the 6 cases had psychomotor developmental delay,among which 3 cases with COL4A1 variants had the worst motor and cognitive performance.Conclusion COL4A1/COL4A2 gene is mainly de novo variants,which can be manifested as IS.For COL4A1/COL4A2 gene related IS,the brain MRI mainly presents as ventriculomegaly,periventricular leukomalacia or volume reduction of cerebral white matter,and some patients may develop brain MRI abnormalities in fetus period.In addition,patients may be accompanied by developmental delay,microcephaly,hemiplegia,dyspraxia and other system abnormalities,with poor prognosis.