佩利措伊斯-梅茨巴赫病临床及遗传学特征分析

Clinical and genetic characteristics of Pelizaeus-Merzbache disease

目的探讨佩利措伊斯-梅茨巴赫病(PMD)的临床及分子遗传学特征。方法回归性分析2015年6月至2020年10月郑州大学第三附属医院确诊的12个家系共14例PMD患儿的临床表现和基因突变特点。结果14例均为男性,就诊年龄5 d至10岁,起病年龄1 d至7个月。首发症状表现为眼球震颤9例,大运动发育迟缓3例,呻吟样呼吸、哭声弱1例,异常姿势2例。临床表现:14例均存在发育迟缓,其中10例以运动发育迟缓更为明显;肌张力低下10例,肌张力增高3例;12例存在眼球震颤。临床分型经典型8例,先天型2例,中间型4例。14例患儿头颅磁共振成像(MRI)均表现为脑白质髓鞘化障碍,脑干听觉诱发电位检测异常7例。14例先证者中,7例蛋白脂蛋白1(PLP1)基因为2~8号外显子重复变异;1例为X染色体Xq22.2处重复0.33Mb区域,覆盖了PLP1基因100%的区域;1例c.83G>A变异,1例c.226G>C变异,2例c.259delC变异,2例c.157dupA变异。12例先证者为遗传性突变,均为母源遗传,母亲为无临床症状的携带者。c.83G>A、c.226G>C、c.259delC、c.157dupA均为国际上未报道的新突变。结论PMD的首发症状以眼球震颤最为常见;发育迟缓、肌张力异常、眼球震颤为其最常见的临床症状;头颅MRI提示脑白质髓鞘化障碍。PLP1基因突变中重复变异最多,其次为点突变,c.83G>A、c.226G>C、c.259delC、c.157dupA变异为尚未报道的新突变。

Objective To investigate the clinical and genetic features of Pelizaeus-Merzbache disease(PMD).Methods The clinical manifestations and genetic mutation characteristics of 14 children with PMD from 12 families admitted to the Third Affiliated Hospital of Zhengzhou University from June 2015 to October 2020 were respectively analyzed.Results All of the 14 children were male,the age ranged from 5 days to 10 years.The onset age was from 1 day to 7 months.The first symptoms were nystagmus in 9 children,gross motor development delay in 3 children,moaning breathing and weak crying in 1 child,and abnormal postures in 2 children.Clinical manifestations:14 patients had developmental delay,10 children had more obvious motor developmental delay.There were 10 children of hypotonia,3 children of hypertonia.Nystagmus was present in 12 children.The clinical classification included 8 cases of classic forms,2 cases of connatal forms,and 4 cases of transition forms.The brain magnetic resonance imaging(MRI)showed white matter myelination disorder in all of the 14 children.There were abnormalities in brainstem auditory evoked potentials in 7 children.Among the 14 children,7 children had duplication mutations in exon 2-8 of protein lipoprotein 1(PLP1)gene,1 child had a 0.33 Mb repeat region on Xq22.2 of the X chromosome(covering 100%of the PLP1 gene),1 child had c.83G>A variant,1 child had c.226G>C variant,2 children had c.259Del C variant,and the other 2 children had c.157Dup A variant.All of the 12 probands had genetic mutation,which were inherited from their mothers,and their mothers were asymptomatic carriers.c.83G>A,c.226G>C,c.259Del C and c.157Dup A were new mutations that had not been reported internationally.Conclusion Nystagmus was the most common first symptom of PMD.Developmental delay,dystonia and nystagmus were the most common clinical symptoms.Brain MRI showed white matter myelination disorder.Duplication mutations was the most common in PLP1 gene,followed by point mutations.c.83G>A,c.226G>C,c.259delC and c.157dupA were new mutations that had not been reported.