齿状核红核苍白球路易体萎缩症两家系的临床和遗传学特点研究

Clinical and genetic study of two families with dentatorubral-pallidoluysian atrophy

目的分析2个齿状核红核苍白球路易体萎缩症(DRPLA)家系的临床和遗传学特点,总结基因型与表型的相关性。方法收集2018年7月至2019年3月就诊于北京大学第一医院2个以遗传性癫痫和共济失调为主要表现的家系中先证者和相关家系成员的外周血、临床资料和辅助检查结果,通过采用全外显子组测序及毛细管电泳和片段分析检测三核苷酸(CAG)重复次数,对先证者及其家系成员进行基因检测,并对2个家系中所有受累家系成员进行临床和遗传特点分析。结果2个家系符合DRPLA诊断,共11例受累者,均表现为智力运动倒退,其中7例有癫痫发作(包括肌阵挛发作、局灶性发作和全面强直阵挛发作等)。在同一家系中不同受累者间临床表现差异较大,子代较亲代发病年龄更早,病情更重。起病年龄最小者2岁,最大者45岁,其中儿童期起病者5例。11例受累者中,已有5例死亡,死亡原因包括癫痫发作、可疑癫痫性猝死(SUDEP)和病情进展等。6例存活的受累者发现ATN1基因第5外显子CAG重复次数异常。家系2中先证者的爷爷临床表现正常,但也存在ATN1基因第5外显子CAG异常重复,可能为中间等位基因。结论DRPLA的主要临床特点为癫痫发作、共济失调和智力倒退,存在遗传早现现象。儿童期发病者少见,常以癫痫发作为首发症状就诊。该病预后不良,早期明确诊断有助于指导遗传咨询。

Objective To study the clinical and genetics features of two families with dentatorubral-pallido-luysian atrophy(DRPLA),and to summarize the correlation between genotypes and phenotypes.Methods The peripheral blood,clinical data and auxiliary examination results of probands and related members in 2 families with hereditary epilepsy and ataxia were collected from July 2018 to March 2019 in Peking University First Hospital.By whole exome sequencing and detecting the cytosine-adenine-guanine(CAG)repeats with capillary electrophoresis and fragment analysis,the genetic testing was conducted on the probands and their family members.The clinical and genetic characteristics of all affected members in the 2 families were also analyzed.Results Two families were diagnosed with DRPLA.All 11 patients presented with psychomotor retardation,and 7 of them had seizures(including myoclonus,focal seizures and generalized tonic-clonic seizures,etc.).There were significant differences in clinical manifestations among different patients in the same family,and the filial generation had seizures at an earlier age with a more severe phenotype than the parental generation.The youngest onset age was 2 years old,and the largest was 45 years old.Five cases had seizures in childhood.Of the 11 patients,5 cases were deceased,and the cause of death included seizure attacks,sudden unexpected death in epilepsy(SUDEP)and disease progression.The number of CAG repeat times in the fifth exon of the ATN1 gene were found abnormal in 6 surviving patients.The grandfather of the proband in pedigree 2 had normal clinical manifestations,but he also showed abnormal CAG repeats in the fifth exon of the ATN1 gene,which might be an intermediate allele.Conclusions DRPLA is mainly featured by epilepsy,ataxia,psychomotor retardation and anticipation in clinical.This disease is rare in children with seizures as the first symptom,and has poor prognosis.An early diagnosis can facilitate genetic counseling.