儿童β螺旋蛋白相关性神经变性的基因型和表型特点

A phenotypic and genetic study onβ-propeller protein-associated neurodegeneration

目的总结β螺旋蛋白相关性神经变性(BPAN)患儿的临床表型及基因型特点。方法回顾性收集2016年6月至2018年12月复旦大学附属儿科医院、北京大学第一医院、首都儿科研究所、中国医科大学附属盛京医院及上海市儿童医院确诊为WDR45基因变异的17例BPAN患儿病例资料,总结其临床表现、头颅影像表现、脑电图以及基因型特点。结果17例BPAN患儿中女13例、男4例,年龄1.1~8.8岁,17例患儿中16例合并癫痫。首次癫痫发病年龄为3~24月龄,发病年龄中位数为14.5月龄。痉挛发作6例,复杂部分性发作5例。8例患儿仅具有单一发作类型,8例患儿具有超过2种发作类型。9例患儿完全缓解。16例合并癫痫的患儿发作前均已表现出发育迟缓,13例为中、重度发育迟缓。13例患儿头颅磁共振成像(MRI)异常,9例患儿胼胝体薄,10例患儿脑发育不良或者脑萎缩;2例患儿在学龄期前进行头颅磁敏感加权成像(SWI),结果表现为双侧苍白球和脑干腹侧低信号。5例患儿同步脑电监测到痉挛、部分性、全面性强直阵挛、失神和肌阵挛发作。男性发病年龄分别为3、4、5、18月龄,女性患儿发病年龄为17(6~24)月龄。WDR45基因的变异包括3例错义变异,6例无义变异,4例移码变异,4例剪接变异;其中13例女性患儿为杂合变异,3例男性患儿为半合变异,1例男性患儿为嵌合变异,16个不同变异均为De novo,其中5个变异(c.977-1C>T、c.976+1G>C、c.10C>T、c.806del和c.110T>C)未见报道。结论BPAN患儿具有明显的发育迟缓,合并癫痫概率高,女性患儿为主,男性患儿癫痫发病早且发育迟缓程度更重。早期进行头颅SWI检查有助于提供诊断线索。

Objective To summarize the clinical and genetic features ofβ-propeller protein-associated neurodegeneration(BPAN).Methods The clinical data of 17 patients with BPAN with WDR45 gene variants were retrospectively collected at Children’s Hospital of Fudan University,Peking University First Hospital,Capital Institute of Pediatrics,Shengjing Hospital of China Medical University and Shanghai Children's Hospital from June 2016 to December 2018,and their clinical manifestations,electroencephalogram,neuroimaging and genetics were analyzed.Results Seventeen cases(13 females,4 males),aged 1.1-8.8 years,were included.The median age of seizure onset was 14.5 months,from 3 months to 24 months of age,manifested with epileptic spasm in 6 cases and focal seizures in 5 cases.Eight patients had only one seizure type and 8 patients had two or more seizure types.Nine patients had complete remission of seizures.All 16 patients with seizures had developmental delay before the seizure onset,of whom 13 patients had moderate to severe seizures.The brain magnetic resonance imaging(MRI)was abnormal in 13 patients,including cerebral atrophy(10 cases)and thinning of the corpus callosum(9 cases).The brain magnetic susceptibility weighted imaging(SWI)in preschool stage showed prominent T2 hypointense signals in bilateral globus pallidus and brainstem ventral in two cases.Five seizure types(spasm,focal,absence,myodonic and generalized tonic clonic seizures)were found on ictal electroencephalogram(EEG)recordings.Compared to female patients(17(6-24)months of ege),male cases had earlier seizure onset(3,4,5,18 months of age).All patients had de novo variations in WDR45(6 nonsense,4 frameshift,3 missense and 4 splicing variations),with hemizygous variants in 3 males,mosaic variants in a male and heterozygous variants in 13 females,within which 5 variations had not been reported(c.977-1C>T,c.976+1G>C,c.10C>T,c.806del and c.110T>C).Conclusions The patients with BPAN have profound developmental delay and are vulnerable to seizures.The male patients with BPAN tend to have more severer clinical phenotype than females.Early brain SWI could facilitate the timely diagnosis of this disease.