肾上腺脊髓神经病五例临床表型及遗传学分析

Clinical phenotype and genetic characteristics of five patients with adrenomyeloneuropathy

目的报道5例肾上腺脊髓神经病患者,结合相关文献和肾上腺脑白质营养不良数据库总结疾病临床表型及基因变异特点。方法与结果纳入2008年5月至2021年12月上海交通大学附属第六人民医院和上海市奉贤区中心医院收治的5例肾上腺脊髓神经病患者,均以痉挛性截瘫为主要表现;1例(例2)极长链脂肪酸水平升高,1例(例5)促肾上腺皮质激素水平升高;仅1例(例5)可见右侧额顶叶多发缺血灶以及脑干和小脑缺血灶,3例(例2、例3、例5)可见椎间盘突出或脊椎退行性变。基因检测显示5例均存在致病性变异,例1为ABCD1基因外显子1 c.421G>A(p.Ala141Thr)半合子变异、例2为ABCD1基因外显子1 c.454C>G(p.Arg152Gly)半合子变异且为国内外首次报道、例3为ABCD1基因外显子1 c.521A>G(p.Tyr174Cys)半合子变异、例4和例5均为ABCD1基因外显子1 c.293C>T(p.Ser98Leu)半合子变异。进一步检索肾上腺脑白质营养不良数据库,共收录1255种ABCD1基因变异,可发生于各外显子、内含子和5’非翻译区,尤以外显子1(43.12%,370/858)和外显子6(10.02%,86/858)常见。结论以痉挛性截瘫为主要表现的肾上腺脑白质营养不良的诊断应综合临床表现和影像学检查,ABCD1基因检测是明确诊断的重要依据。ABCD1基因外显子1和6为热点变异位点。

Objective To report 5 patients with adrenomyeloneuropathy(AMN),and to summarize the clinical phenotype and gene mutation characteristics in combination with literature and mutation database.Methods and Results Five patients with AMN who were treated in the Department of Neurology,Shanghai Sixth People's Hospital Affiliated to Shanghai Jiaotong University and Shanghai Fengxian District Central Hospital from May 2008 to December 2021 were selected.Spastic paraplegia was the main manifestation in all the 5 patients.Laboratory test showed that Case 2 had abnormal levels of very long⁃chain fatty acids(VLCFA),and Case 5 had higher level of adrenocorticotropic hormone(ACTH).Cranial MRI showed multiple ischemic foci in the right frontal parietal lobe,brainstem and cerebellum in Case 5.Three patients(Case 2,Case 3,Case 5)underwent spinal MRI and showed protrusion of intervertebral disc or degenerative change of vertebral body.Gene detection showed that all 5 patients had pathogenic mutation located in exon 1 of ABCD1 gene,Case 1 was c.421G>A(p.Ala141Thr)hemizygous mutation,Case 2 was c.454C>G(p.Arg152Gly)hemizygous mutation,Case 3 was c.521A>G(p.Tyr174Cys)hemizygous mutation,Case 4 and Case 5 from the same family,all of them were c.293C>T(p.Ser98Leu)hemizygous mutation,which were"pathogenic"mutations,and the c.454C>G mutation was first reported in this study.This study summarized the genetic variation of ABCD1 gene in the adrenoleukodystrophy(ALD)mutation database.The ALD mutation database contained 1255 genetic variations,which were distributed in exons,introns and 5'untranslated region(5'UTR)regions,of which exon 1(43.12%,370/858)and exon 6(10.02%,86/858)were the most common.Conclusions The diagnosis of ALD with spastic paraplegia as its main manifestation needs to be combined with clinical manifestations and imaging examinations.ABCD1 gene detection is important for diagnosis.Exon 1 and 6 are hotspot exons of ABCD1 gene.