【作者】 赵玫；

【导师】 丁素菊； 张社卿；

【作者基本信息】 第二军医大学 ， 神经病学， 2008， 博士

【摘要】 研究目的:Kennedy病,又称为X-连锁隐性遗传性脊髓延髓型肌萎缩,是迟发的缓慢进展的运动神经元疾病。1968年由Kennedy首先进行描述,1991年由La Spada将致病基因定位于X染色体长臂近端Xq11-12区域。其临床特征是男性成年期发病,以进行性四肢近端肌肉无力、萎缩和真性延髓麻痹为突出表现,可伴有男性乳房女性化、睾丸发育不良甚至不育等。随着疾病的进展可出现四肢远端肌肉的无力和萎缩。本病致病原因是X染色体上雄激素受体基因第一个外显子的三核苷酸(CAG)重复序列扩增。这一区域在正常人群中具有多态性,重复数为10—36,Kennedy病人这一区域的重复数为40—62,重复数超过40就可使蛋白进入致病范围,重复数越高的个体越早出现临床症状。近十几年来国外对本病的研究取得很大进展,但国内对本病的认识较晚,迄今为止有关本病的报道较少。2006年张社卿首次报道了国内经基因诊断证实的第一个Kennedy病家系,本文报道我们最近发现的经基因诊断证实的又一个Kennedy病家系,并对其临床、病理和分子遗传学特征进行进一步的讨论,建立关于Kennedy病较为完整的资料,为下一步的基因治疗奠定理论基础。研究方法:该家系中先证者为男性,38岁,已婚,汉族。以“进行性乳房增大12年,蹲下站起困难7年,四肢无力1年”为主诉于2006年12月15日收入长海医院神经内科。16岁洗澡时发现双侧乳房较同龄人增大,30岁时弯腰拿东西、蹲下起立时不能立即站起,上述症状缓慢进展。于一年前出现四肢无力,影响务农。在当地医院多次就诊,诊断不明。25岁结婚,育有一子,健康。根据患者叙述,其二舅(已故)生前有类似症状,为此展开家系调查,共检查3代41位个体。对先证者进行肌酶谱、肌电图、内分泌功能检查,神经肌肉活检。所有个体均经本人一人进行系统的神经系统体格检查,经家族中全体成员知情同意后,采集外周静脉血常规提取基因组DNA。按照La Spada等设计的引物序列,PCR扩增了雄激素受体(androgen receptor,AR)基因第一个外显子的CAG重复片段。结果:先证者(Ⅲ-11个体)重复数为54;还发现一例患者(Ⅳ-2个体),其CAG重复数为55;一例症状前个体(Ⅳ-8个体),其CAG重复数为54。此外,还发现三例女性携带者(分别是Ⅱ-6个体、Ⅲ-3个体、Ⅲ-15个体)。结论:我们的研究结果表明:1在本病能被充分认识和诊断的国家及地区,Kennedy病的发病率估计为1/40,000,在我国很多病例未能及时正确诊断导致其实际报道数的严重不足,原因与多数临床医师对本病的认识不足有关;2 Kennedy病临床表现无特异性,基因诊断是诊断该病的金标准;3 Kennedy病病程进展缓慢,与肌萎缩侧索硬化或延髓麻痹比较病程明显延长,预后相对良性;4神经活检显示周围神经脱髓鞘改变,肌肉活检表现为神经源性肌萎缩;5由于国内报道的病例数较少,目前尚不能对病情进展速度、发病年龄与CAG重复数之间的相关性进行探讨。更多还原

【Abstract】 Objective:Kennedy’s disease,also known as spinal and bulbar muscular atrophy,is a late-onset form of motor neuron disease which is slowly progressive in nature.First described by Kennedy et al.in 1968,the genetic basis was identified in 1991 when La Spada et al.mapped the gene to the proximal long arm of the X-chromosome(Xq11-12). Kennedy’s disease is characterized by slowly progressive bulbar and proximal muscle weakness usually beginning in the shoulder and pelvic girdles with frequently occurring gynaecomastia,tremor,testicular atrophy,impotence and infertility.Distal muscle involvement may be later detectable in an advanced course of disease.The molecular basis of SBMA is the expansion of trinucleotide CAG repeat,which encodes the polyglutamine tract,in the first exon of the androgen receptor(AR) gene.The region is polymorphic within the normal population,numbering between10-36 repeats,whereas in Kennedy’s disease this repeat region is expanded to number between 40 and 62.Expansion of this region to beyond 40 repeats places this protein in the pathogenic range.Individuals with higher numbers of repeats generally tend to develop symptoms at an earlier age.In recent ten years,research about Kennedy disease has been made much advance abroad,,however in China the research about Kennedy disease began much later.We report the genetically proven Kennedy disease pedigree in China mainland in order to explore its clinical presentation,pathological features and molecular mechanism.Method:The proband is a 38-year-old man.Since age of 16 year old,he found his breast was bigger than his peers in bathroom.Since age of 30 year old,he found he could not stand up immediately after squatting down.At age of 37,he began to feel myasthenia of limbs,and his weakness gradually worsen.So his daily life and farmwork has been affected unavoidably.At the age of 25,he married a healthy woman and had a boy later.He had visited sevsral local hospitals,but could not get a definite diagnosis.According to the proband’s statement,we conduct a thorough survey of the family.Informed consent was obtained from all family members in this pedigree and genetic counseling provided as appropriate.Genomic DNA were extracted from peripheral blood according to standard procedures.The CAG repeated sequence in the exon 1 of AR geng was amplified by PCR and sequenced directly.Result:The sequencing results show that the proband has 54 CAG repeats and other affected individual has 55 CAG repeats,and one presymptomatic individual has 54 CAG repeats.3 famale carriers also have been diagnosed. Conclusion:These results demonstrate that SBMA is often misdiagnosed because of lack of knowledge about SBMA,so the report of this disease in our country is severely neglected.Gene determination is the most reliable method of diagnosis and presymptomatic individuals can also be found in advance.The progression of SBMA is usually much slower than that of bulbar atrophy or atrophic lateral sclerosis(ALS).Nerve biopsy revealed demylination change in peripheral nerve;and muscle biopsy revealed muscle atrophy origining from nerve.Because of lack of reported cases,we can not explore the correlation between CAG length and progression rate of the disease or age of onset.更多还原