脊髓小脑性共济失调6型一家系临床、病理和分子生物学特点

doi:10.6040/j.issn.1671-7554.0.2015.344

摘要/Abstract

摘要： 目的探讨脊髓小脑性共济失调6型(SCA6)一家系中患者的临床、病理、分子生物学特点,并评价治疗效果。方法采集SCA6家系临床资料,行基因测序。对其中3例进行肌肉活检,测定肌肉组织中过氧化物酶体增殖物激活受体辅激活因子1α(PGC-1α)的表达;给予治疗,应用共济失调等级量表(SARA)和临床总体印象量表(CGIS)评价临床治疗效果。结果该家系共9例患者(2例已死亡)首发症状均为小脑性共济失调,主要表现为进行性行走不稳和直线行走困难,并伴有构音障碍、水平眼震。4例行基因检测示CAG重复异常。2例肌肉病理结果示轻度肌源性损害病理改变,伴线粒体功能异常,1例示大致正常肌组织。3例肌肉组织中PGC-1α的表达较正常对照组表达降低。治疗后患者临床症状明显改善。结论 SCA6患者存在肌肉组织线粒体功能异常及PGC-1α表达降低,提示线粒体功能异常可能在SCA发病过程中起重要作用。给予保护线粒体功能治疗能明显改善患者的临床症状。

关键词: 线粒体, 肌肉活检, 脊髓小脑性共济失调, 过氧化物酶体增殖物激活受体辅激活因子1α, 基因

Abstract: Objective To investigate the clinical, pathological, molecular biological features and the treatment outcome for a pedigree of spinocerebellar ataxia type 6(SCA 6). Methods Physical examinations and gene sequencing were performed. Muscular biopsies were performed in 3 patients. The expression of peroxisomeproliferators activatedreceptor-coactivator-1α(PGC-1α)in the myocyte was detected. Patients were treated with drugs, and the treatment outcome of 4 patients were measured with the scale for the assessment and rating of ataxia scores(SARA)and clinical global impressions scale(CGIS). Results The basic manifestations of the patients were slowly progressive cerebellar ataxia, mainly manifested unstable gait and difficulty in walking straight, and accompanied with nystagmus and dysarthria. nystagmus and dysarthria. An abnormal CAG repeats existed in the SCA6 gene. In muscle biopsies, 2 patients showed mild muscle damage with mitochondrial dysfunction and 1 showed normal. But PGC-1α expression decreased in all patients. The clinical symptoms of the patients were improved markedly. Conclusion Mitochondrial dysfunction and depression of PGC-1α exist in the muscle of SCA6 patients. These findings imply that impaired function of mitochondrial may play a critical role in the process of SCA, and the treatment with mitochondrial protective agents can exert therapeutic benefits.

Key words: Mitochondria, Peroxisome proliferator-activated receptor-γ, coactivator 1α, Muscle biopsy, Gene, Spinocerebellar ataxia

中图分类号:

R744.7

栾海辉,许巍,王牧川,吴林,王玲玲,马俊,刘艺鸣. 脊髓小脑性共济失调6型一家系临床、病理和分子生物学特点[J]. 山东大学学报（医学版）, 2016, 54(2): 63-67.

LUAN Haihui, XU Wei, WANG Muchuan, WU Lin, WANG Lingling, MA Jun, LIU Yiming. Clinical, pathological and molecular biological study on a Chinese family of Spinocerebellar Ataxia type 6[J]. JOURNAL OF SHANDONG UNIVERSITY (HEALTH SCIENCES), 2016, 54(2): 63-67.

参考文献

[1] Matilla-Dueñas A, Ashizawa T, Brice A, et al. Consensus paper: pathological mechanisms underlying neurodegeneration in spinocerebellar ataxias[J]. Cerebellum, 2014, 13(2):269-302.
[2] Tsoi H, Yu AC, Chen ZS, et al. A novel missense mutation in CCDC88C activates the JNK pathway and causes a dominant form of spinocerebellar ataxia[J]. Med Genet, 2014, 51(9):590-595.
[3] 王俊岭,沈璐,雷立芳,等. 中国大陆脊髓小脑性共济失调家系和散发病例的最新基因突变分析[J]. 中南大学学报(医学版), 2011, 36(6):482-489. WANG Junling, SHEN Lu, LEI Lifang, et al. Spinocerebellar ataxias in mainland China: an updated genetic analysis among a large cohort of familial and sporadic cases[J]. Journal of Central South University(Medical Science), 2011, 36(6):482-489.
[4] Jacobi H, Minnerop M, Klockgether T. The genetics of spinocerebellar ataxias[J]. Nervenarzt, 2013, 84(2):137-142.
[5] Craig K, Takiyama Y, Soong BW, et al. Pathogenic expansions of the SCA6 locus are associated with a common CACNA1A haplotype across the globe: founder effect or predisposing chromosome?[J]. Eur J Hum Genet, 2008, 16(7):841-847.
[6] 谢秋幼,李洵桦,梁秀龄.脊髓小脑性共济失调6型的分子遗传学诊断及临床特点[J].临床神经病学杂志, 2004, 17(5):321-323. XIE Qiuyou, LI Xunhua, LIANG Xiuling. Molecular genetic diagnosis and clinical characteristics of spinocerebell arataxia type 6[J]. Clin Neurol, 2004, 17(5):321-323.
[7] Fan HC, Ho LI, Chi CS, et al. Polyglutamine(PolyQ)diseases: genetics to treatments[J]. Cell Transplant, 2014, 23(4-5):441-458.
[8] 熊杰,冯亦璞.丁基苯酞对局灶性脑缺血过程中线粒体损伤的保护作用[J]. 药学学报,2000, 35(6):408-412. XIONG Jie, FENG Yipu. The protective effect of Butylphthalide against mitochondrial injury during cerebral ischemia[J]. Acta Pharmaceutica Sinica, 2000, 35(6):408-412.
[9] 周杰,雷立芳,料鑫鑫,等. 脊髓小脑性共济失调3型/Machado-Joseph病ICARS与SARA评分相关因素分析[J]. 中南大学学报(医学版),2011, 36(6):498-503. ZHOU Jie, LEI Lifang, LIAO Xinxin, et al. Related factors of ICARS and SARA scores on spinocerebellar ataxia type3/Machado-Joseph disease[J]. Journal of Central South University(Medical Science), 2011, 36(6):498-503.
[10] Subramony SH, Fratkin JD, Manyam BV, et al. Dominantly inherited cerebello-olivary atrophy is not due to a mutation at the spinocerebellar ataxia-I, Machado-Joseph disease, or Dentato-Rubro-Pallido-Luysian atrophy locus[J]. Mov Disord, 1996, 11(2):174-180.
[11] Garcia-Planells J, Cuesta A, Vilchez JJ, et al. Genetics of the SCA6 gene in a large family segregating an autosomal dominant “pure” cerebellar ataxia[J]. J Med Genet, 1999, 36(2):148-151.
[12] Restituito S, Thompson RM, Eliet J, et al. The polyglutamine expansion in spinocerebellar ataxia type 6 causes a beta subunitspecific enhanced activation of P/Q-type calcium channels in Xenopus oocytes[J]. J Neurosci, 2000, 20(17):6394-6403.
[13] Li L, Saegusa H, Tanabe T. Deficit of heat shock transcription factor 1-heat shock 70 kDa protein 1A axis determines the cell death vulnerability in a model of spinocerebellar ataxia type 6[J]. Genes Cells, 2009, 14(11): 1253-1269.
[14] La Spada AR, Taylor JP. Repeat expansion disease: progress and puzzles in disease pathogenesis[J]. Nat Rev Genet, 2010, 11(4):247-258.
[15] van Raalte DH, Li M, Pritchard PH, et al. Peroxisome proliferator-activated receptor(PPAR)-alpha: a pharmacological target with a promising future[J]. Pharm Res, 2004, 21(9):1531-1538.
[16] Esterbauer H, Oberkofler H, Krempler F, et al. Human peroxisome proliferator activated receptor gamma coactivator 1(PPARGC1)gene: cDNA sequence, genomic organization, chromosomal localization, and tissue expression[J]. Genomics, 1999, 62(1):98-102.
[17] Lin J, Handschin C, Spiegelman BM. Metabolic control through the PGC-1 family of transcription coactivators[J]. Cell Metab, 2005, 1(6):361-370.
[18] Kelly DP, Scarpulla RC. Transcriptional regulatory circuits controlling mitochondrial biogenesis and function[J]. Genes Dev, 2004, 18(4):357-368.
[19] Leone TC, Lehman JJ, Finck BN, et al. PGC-1alpha deficiency causes multi-system energy metabolic derangements: muscle dysfunction, abnormal weight control and hepatic steatosis[J]. PLoS Biol, 2005, 3(4):e101. Epub 2005 Mar 15.
[20] Cui L, Jeong H, Borovecki F, et al. Transcriptional repression of PGC-1alpha by mutant huntingtin leads to mitochondrial dysfunction and neurodegeneration[J]. Cell, 2006, 127(1):59-69.
[21] Weydt P, Pineda VV, Torrence AE, et al. Thermoregulatory and metabolic defects in Huntington’s disease transgenic mice implicate PGC-1alpha in Huntingtons disease neurodegeneration[J].Cell Metab, 2006, 4(5):349-362.
[22] Lin J, Wu H, Tarr PT, et al. Transcriptional co-activator PGC-1 alpha drives the formation of slow-twitch muscle fibres[J]. Nature, 2002, 418(6899):797-801.
[23] Handschin C, Chin S, Li P, et al. Skeletal muscle fiber-type switching, exercise intolerance, and myopathy in PGC-1alpha muscle-specific knock-out animals[J]. Biol Chem, 2007, 282(41):30014-30021.
[24] Bawa B, Abbott LC. Analysis of calcium ion homeostasis and mitochondrial function in cerebellar granule cells of adult CaV 2.1 calcium ion channel mutant mice[J]. Neurotox Res, 2008, 13(1):1-18.

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