肾上腺脊髓神经病五例临床表型及遗传学分析

doi:10.3969/j.issn.1672-6731.2022.04.013

摘要/Abstract

摘要： 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。

关键词: 肾上腺脑白质营养不良, 痉挛性截瘫, 遗传性, 基因, 突变

Abstract: 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.

Key words: Adrenoleukodystrophy, Spastic paraplegia, hereditary, Genes, Mutation

刘晓黎, 张斌, 詹飞霞, 曹立. 肾上腺脊髓神经病五例临床表型及遗传学分析[J]. 中国现代神经疾病杂志, 2022, 22(4): 306-312.

LIU Xiao-li, ZHANG Bin, ZHAN Fei-xia, CAO Li. Clinical phenotype and genetic characteristics of five patients with adrenomyeloneuropathy[J]. Chinese Journal of Contemporary Neurology and Neurosurgery, 2022, 22(4): 306-312.

https://journal11.magtechjournal.com/cjcnn/CN/Y2022/V22/I4/306

参考文献

[1] Engelen M, Kemp S, de Visser M, van Geel BM, Wanders RJ, Aubourg P, Poll-The BT. X-linked adrenoleukodystrophy (X-ALD):clinical presentation and guidelines for diagnosis, follow-up and management[J]. Orphanet J Rare Dis, 2012, 7:51.
[2] Morita M, Imanaka T. Peroxisomal ABC transporters:structure, function and role in disease[J]. Biochim Biophys Acta, 2012, 1822:1387-1396.
[3] Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee. Standards and guidelines for the interpretation of sequence variants:a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology[J]. Genet Med, 2015, 17:405-424.
[4] van Geel BM, Assies J, Weverling GJ, Barth PG. Predominance of the adrenomyeloneuropathy phenotype of X-linked adrenoleukodystrophy in The Netherlands:a survey of 30 kindreds[J]. Neurology, 1994, 44:2343-2346.
[5] Kemp S, Huffnagel IC, Linthorst GE, Wanders RJ, Engelen M. Adrenoleukodystrophy:neuroendocrine pathogenesis and redefinition of natural history[J]. Nat Rev Endocrinol, 2016, 12:606-615.
[6] Raymond GV, Moser AB, Fatemi A. X-linked adrenoleukodystrophy[M]//Adam MP, Ardinger HH, Pagon RA, Wallace SE. GENEReviews. Seattle:University of Washington, Seattle, 1993-2022[updated 2018 Feb 15]. https://www.ncbi.nlm.nih.gov/books/NBK1116/
[7] Engelen M, Barbier M, Dijkstra IM, Schür R, de Bie RM, Verhamme C, Dijkgraaf MG, Aubourg PA, Wanders RJ, van Geel BM, de Visser M, Poll-The BT, Kemp S. X-linked adrenoleukodystrophy in women:a cross-sectional cohort study[J]. Brain, 2014, 137(Pt 3):693-706.
[8] Horn MA, Retterst?l L, Abdelnoor M, Skjeldal OH, Tallaksen CM. Adrenoleukodystrophy in Norway:high rate of de novo mutations and age-dependent penetrance[J]. Pediatr Neurol, 2013, 48:212-219.
[9] Jangouk P, Zackowski KM, Naidu S, Raymond GV. Adrenoleukodystrophy in female heterozygotes:underrecognized and undertreated[J]. Mol Genet Metab, 2012, 105:180-185.
[10] el-Deiry SS, Naidu S, Blevins LS, Ladenson PW. Assessment of adrenal function in women heterozygous for adrenoleukodystrophy[J]. J Clin Endocrinol Metab, 1997, 82:856-860.
[11] Horn MA, Retterst?l L, Abdelnoor M, Skjeldal OH, Tallaksen CM. Age-dependent penetrance among females with X-linked adrenoleukodystrophy[J]. Brain, 2015, 138(Pt 2):e325.
[12] van Geel BM, Bezman L, Loes DJ, Moser HW, Raymond GV. Evolution of phenotypes in adult male patients with X-linked adrenoleukodystrophy[J]. Ann Neurol, 2001, 49:186-194.
[13] Kemp S, Theodoulou FL, Wanders RJ. Mammalian peroxisomal ABC transporters:from endogenous substrates to pathology and clinical significance[J]. Br J Pharmacol, 2011, 164:1753-1766.
[14] Wang Y, Busin R, Reeves C, Bezman L, Raymond G, Toomer CJ, Watkins PA, Snowden A, Moser A, Naidu S, Bibat G, Hewson S, Tam K, Clarke JT, Charnas L, Stetten G, Karczeski B, Cutting G, Steinberg S. X-linked adrenoleukodystrophy:ABCD1 de novo mutations and mosaicism[J]. Mol Genet Metab, 2011, 104:160-166.
[15] Kemp S, Pujol A, Waterham HR, van Geel BM, Boehm CD, Raymond GV, Cutting GR, Wanders RJ, Moser HW. ABCD1 mutations and the X-linked adrenoleukodystrophy mutation database:role in diagnosis and clinical correlations[J]. Hum Mutat, 2001, 18:499-515.
[16] Smith KD, Kemp S, Braiterman LT, Lu JF, Wei HM, Geraghty M, Stetten G, Bergin JS, Pevsner J, Watkins PA. X-linked adrenoleukodystrophy:genes, mutations, and phenotypes[J].Neurochem Res, 1999, 24:521-535.
[17] Pereira Fdos S, Matte U, Habekost CT, de Castilhos RM, El Husny AS, Louren?o CM, Vianna-Morgante AM, Giuliani L, Galera MF, Honjo R, Kim CA, Politei J, Vargas CR, Jardim LB. Mutations, clinical findings and survival estimates in South American patients with X-linked adrenoleukodystrophy[J].PLoS One, 2012, 7:e34195.
[18] Eichler EE, Budarf ML, Rocchi M, Deaven LL, Doggett NA, Baldini A, Nelson DL, Mohrenweiser HW. Interchromosomal duplications of the adrenoleukodystrophy locus:a phenomenon of pericentromeric plasticity[J]. Hum Mol Genet, 1997, 6:991-1002.
[19] Boehm CD, Cutting GR, Lachtermacher MB, Moser HW, Chong SS. Accurate DNA-based diagnostic and carrier testing for X-linked adrenoleukodystrophy[J]. Mol Genet Metab, 1999, 66:128-136.
[20] Shimozawa N, Honda A, Kajiwara N, Kozawa S, Nagase T, Takemoto Y, Suzuki Y. X-linked adrenoleukodystrophy:diagnostic and follow-up system in Japan[J]. J Hum Genet, 2011, 56:106-109.
[21] Montagna G, Di Biase A, Cappa M, Melone MA, Piantadosi C, Colabianchi D, Patrono C, Attori L, Cannelli N, Cotrufo R, Salvati S, Santorelli FM. Identification of seven novel mutations in ABCD1 by a DHPLC-based assay in Italian patients with Xlinked adrenoleukodystrophy[J]. Hum Mutat, 2005, 25:222.
[22] Larner AJ. Adult-onset dementia with prominent frontal lobe dysfunction in X-linked adrenoleukodystrophy with R152C mutation in ABCD1 gene[J]. J Neurol, 2003, 250:1253-1254.
[23] Feigenbaum V, Lombard-Platet G, Guidoux S, Sarde CO, Mandel JL, Aubourg P. Mutational and protein analysis of patients and heterozygous women with X-linked adrenoleukodystrophy[J]. Am J Hum Genet, 1996, 58:1135-1144.
[24] Ligtenberg MJ, Kemp S, Sarde CO, van Geel BM, Kleijer WJ, Barth PG, Mandel JL, van Oost BA, Bolhuis PA. Spectrum of mutations in the gene encoding the adrenoleukodystrophy protein[J]. Am J Hum Genet, 1995, 56:44-50.
[25] Kok F, Neumann S, Sarde CO, Zheng S, Wu KH, Wei HM, Bergin J, Watkins PA, Gould S, Sack G, Moser H, Mandel JL, Smith KD. Mutational analysis of patients with X-linked adrenoleukodystrophy[J]. Hum Mutat, 1995, 6:104-115.
[26] Korenke GC, Roth C, Krasemann E, Hüfner M, Hunneman DH, Hanefeld F. Variability of endocrinological dysfunction in 55 patients with X-linked adrenoleucodystrophy:clinical, laboratory and genetic findings[J]. Eur J Endocrinol, 1997, 137:40-47.
[27] Lan F, Wang Z, Xie H, Huang L, Ke L, Yang B, Zhu Z. Molecular diagnosis of X-linked adrenoleukodystrophy:experience from a clinical genetic laboratory in mainland China with report of 13 novel mutations[J]. Clin Chim Acta, 2011, 412:970-974.
[28] Pan H, Xiong H, Wu Y, Zhang YH, Bao XH, Jiang YW, Wu XR. ABCD1 gene mutations in Chinese patients with X-linked adrenoleukodystrophy[J]. Pediatr Neurol, 2005, 33:114-120.
[29] Pan H, Xiong H, Zhang YH, Wu Y, Bao XH, Jiang YW, Wu XR. X-linked adrenoleukodystrophy ABCD1 gene mutation analysis in China[J]. Zhonghua Yi Xue Yi Chuan Xue Za Zhi, 2004, 21:1-4.
[30] Ping LL, Bao XH, Wang AH, Pan H, Wu Y, Xiong H, Jiang YW, Qin J, Wu XR. Clinical features and genotype-phenotype studies of 89 Chinese patients with X-linked adrenoleukodystrophy[J]. Zhonghua Er Ke Za Zhi, 2007, 45:203-207.
[31] Wang Z, Ke L, Xie H, Yan A, Huang L, Lan F. Pre-symptomatic molecular diagnosis of X-linked adrenoleukodystrophy in Chinese families[J]. Neurol Res, 2010, 32:695-699.
[32] Park HJ, Shin HY, Kang HC, Choi BO, Suh BC, Kim HJ, Choi YC, Lee PH, Kim SM. Clinical and genetic aspects in twelve Korean patients with adrenomyeloneuropathy[J]. Yonsei Med J, 2014, 55:676-682.
[33] Dvoráková L, Storkánová G, Unterrainer G, Hujová J, Kmoch S, Zeman J, Hrebícek M, Berger J. Eight novel ABCD1 gene mutations and three polymorphisms in patients with X-linked adrenoleukodystrophy:the first polymorphism causing an amino acid exchange[J]. Hum Mutat, 2001, 18:52-60.
[34] Salsano E, Tabano S, Sirchia SM, Colapietro P, Castellotti B, Gellera C, Rimoldi M, Pensato V, Mariotti C, Pareyson D, Miozzo M, Uziel G. Preferential expression of mutant ABCD1 allele is common in adrenoleukodystrophy female carriers but unrelated to clinical symptoms[J]. Orphanet J Rare Dis, 2012, 7:10.
[35] Ohi T, Takechi S, Itokazu N, Shiomi K, Sugimoto S, Antoku Y, Kato K, Sugimoto T, Nakayama T, Matsukura S. Two novel mutations in the adrenoleukodystrophy gene in two unrelated Japanese families and the long-term effect of bone marrow transplantation[J]. J Neurol Sci, 2000, 177:131-138.
[36] Kemp S, Ligtenberg MJ, van Geel BM, Barth PG, Wolterman RA, Schoute F, Sarde CO, Mandel JL, van Oost BA, Bolhuis PA. Identification of a two base pair deletion in five unrelated families with adrenoleukodystrophy:a possible hot spot for mutations[J].Biochem Biophys Res Commun, 1994, 202:647-653.
[37] Kemp S, Berger J, Aubourg P. X-linked adrenoleukodystrophy:clinical, metabolic, genetic and pathophysiological aspects[J].Biochim Biophys Acta, 2012, 1822:1465-1474.
[38] Korenke GC, Fuchs S, Krasemann E, Doerr HG, Wilichowski E, Hunneman DH, Hanefeld F. Cerebral adrenoleukodystrophy (ALD) in only one of monozygotic twins with an identical ALD genotype[J]. Ann Neurol, 1996, 40:254-257.[J]. Am J Hum Genet, 1995, 56:44-50.

选择文件类型/文献管理软件名称

选择包含的内容

2 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

RichHTML

PDF

可视化

被引次数

摘要/Abstract

引用本文

使用本文

参考文献

相关文章 15

编辑推荐

Metrics

本文评价

[1]	林丽, 崔珍珍, 何凡, 赵晓玲, 金丹群, 杨斌. IQSEC2基因变异致非典型Rett综合征并发育性癫痫性脑病四例遗传学特点分析[J]. 中国现代神经疾病杂志, 2024, 24(8): 674-683.
[2]	袁于青, 占青青, 谢亮. Ⅱ型亚历山大病一例[J]. 中国现代神经疾病杂志, 2024, 24(6): 502-506.
[3]	狄晓萌, 王佳伟, 段泽君, 刘磊. 脑脊液宏基因组学第二代测序辅助诊断中枢神经系统链球菌感染二例[J]. 中国现代神经疾病杂志, 2024, 24(4): 245-252.
[4]	徐金梅, 刘兵舰, 关鸿志, 单萍, 陈国华, 梅俊华. 重度发热伴血小板减少综合征脑炎一例[J]. 中国现代神经疾病杂志, 2024, 24(4): 253-257.
[5]	武倩, 詹飞霞, 曹立. TH基因变异致多巴反应性肌张力障碍二例[J]. 中国现代神经疾病杂志, 2024, 24(4): 285-289.
[6]	徐滢, 桂雅星. 脂质代谢异常对帕金森病进程的影响及临床意义[J]. 中国现代神经疾病杂志, 2024, 24(3): 131-138.
[7]	王晖, 俞萌, 吕鹤, 张巍, 袁云, 王朝霞. 以急性呼吸衰竭为主要表现的线粒体肌病一例[J]. 中国现代神经疾病杂志, 2023, 23(9): 821-825.
[8]	李萍, 徐艳芳, 胡帅, 曾晓霞, 漆学良. PSAT1基因变异致儿童期鱼鳞病合并青少年期周围神经病的磷酸丝氨酸氨基转移酶缺乏症一例[J]. 中国现代神经疾病杂志, 2023, 23(9): 826-831.
[9]	李冉, 邹慧敏, 邢春叶, 宋进, 郝延磊. GMPPB基因变异致肢带型肌营养不良合并先天性肌无力综合征一例[J]. 中国现代神经疾病杂志, 2023, 23(9): 832-837.
[10]	李海江, 王朝东. 以痉挛性截瘫为首发症状的早发型家族性阿尔茨海默病3型一家系（附点评）[J]. 中国现代神经疾病杂志, 2023, 23(9): 853-858.
[11]	任修德, 李涛, 范吉康, 王希森, 贾晓丹, 杨学军. 胶质母细胞瘤FGFR3-TACC3融合基因介导丙酮酸激酶M2入核促进DNA损伤修复基础研究[J]. 中国现代神经疾病杂志, 2023, 23(8): 745-757.
[12]	吴旭玲, 张安妮, 雷晓阳, 冯占辉, 王维, 贺电. 强直性肌营养不良症1型一例[J]. 中国现代神经疾病杂志, 2023, 23(8): 765-769.
[13]	李跃文, 褚先舟, 李娟, 秦艳, 吴桐, 陈先文. BSCL2基因c.455A>G突变致远端型遗传性运动神经病V型一家系[J]. 中国现代神经疾病杂志, 2023, 23(7): 643-647.
[14]	杜倩, 邓素君, 邹姗, 金珺, 周青山. 宏基因组第二代测序技术在重症中枢神经系统感染中的应用[J]. 中国现代神经疾病杂志, 2023, 23(6): 479-484.
[15]	崔立立, 纪坤乾, 张正华, 张同霞, 赵玉英. 以排尿困难发病的SOD1基因变异致肌萎缩侧索硬化一例[J]. 中国现代神经疾病杂志, 2023, 23(5): 472-476.

模态框（Modal）标题

选择文件类型/文献管理软件名称

选择包含的内容

2 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

RichHTML

PDF

可视化

被引次数

摘要/Abstract

引用本文

使用本文

参考文献

相关文章 15

编辑推荐

Metrics

本文评价