肯尼迪病的临床分析及分子遗传学诊断

目的 本文通过5例经基因检测明确诊断的肯尼迪病（Kennedy＇s disease,KD）患者,探讨KD的临床表现和辅助检查特点及诊断.方法 收集5例疑似KD患者的详细病史、体格检查、血液生化、肌电图和肌肉病理等资料,用PCR扩增并测序方法测定雄性激素受体（AR）基因1号外显子CAG的重复序列拷贝数.结果 KD主要临床表现是四肢肌肉萎缩、无力和肢体震颤,舌肌萎缩和构音障碍；部分患者出现内分泌症状和肌酸激酶（CK）增高.肌电图可见广泛神经源性损害和感觉神经传导速度下降.肌肉病理为神经性损害.患者AR基因CAG重复序列的重复次数为48 ～ 58次.结论 KD有相对独特的临床、电生理及病理特征,确诊有赖于AR基因的（CAG）n拷贝数的检测.     

Sperm acrosin levels in semen: comparison between ACCU-SPERM and Kennedy's methods

Summary. The purpose of this experiment was to evaluate the accuracy, specificity, and sensitivity of a new acrosin activity assay, ACCU-SPERM, and to correlate these results with the original Kennedy method. Thirty-nine specimens (26 patients and 13 donors) of 54 (72%) were found to be in the normal range (>25 μIU acrosin/10⁶ sperm) by the Kennedy method; the other 15 specimens were in either the indeterminate or subfertile range (< 14 μIU). However, according to the ACCU-SPERM method, (normal: 6.6–27 AAI; infertile: < 3.6), 90% of specimens (49 of 54) whose acrosin activity was measured were in the subfertile or infertile range. Similarly, only 28% (4 of 14) of donors in the ACCU-SPERM method were in the normal range in contrast to the 93% (13 of 14) in Kennedy. After calculating the ACCU-SPERM normal range in our laboratory using the linear regression curve between the acrosin values generated by the Kennedy and ACCU-SPERM methods, we again compared results of the two methods. The new normal range of > 1.82 AAI in ACCU-SPERM corresponded to > 25 μIU in the Kennedy method; similarly a value of < 1.35 AAI in ACCU-SPERM corresponded to < 14 μIU in the Kennedy technique. Analysis of the results generated by the two methods revealed a poor correlation with a positive concordance of 51% and a negative concordance of 50% in both assays. These results strongly suggest that the ACCU-SPERM method for measurement of acrosin activity is not a reliable assay.     

X-linked recessive bulbospinal neuronopathy (Kennedy's syndrome): a neurophysiological study

We examined 8 men with X-linked recessive bulbospinal neuronopathy. Quantitative electromyography showed large amplitude motor unit action potentials of prolonged duration and increased polyphasia. There was a pronounced loss of motor units in all but one muscle at maximal volition even in muscles with normal or only mildly decreased force. Denervation activity was present in 53% sampled limb muscles, and fasciculation was recorded in 33% of limb muscles. Nerve conduction studies showed small amplitude sensory action potentials in 6 out of 8 patients. The motor and sensory conduction velocity was normal or borderline slow. The electrophysiologic findings were consistent with chronic partial denervation (motor axonopathy) combined with large fibre sensory axonopathy.     

肯尼迪病患者的临床表型与基因型分析

目的探讨肯尼迪病(Kennedy’s disease,KD)患者的临床特征和基因特点,以加强对KD的认识,减少误诊漏诊率。方法纳入2013年1月~2017年4月广州军区广州总医院神经内科收治的8例经基因确诊的KD患者,分析其临床特征、实验室检查、肌电图、神经电图和基因特点,使用肌萎缩侧索硬化症评分量表(amyotrophic lateral sclerosis rating scale,ALSFRS)作为运动功能量表进行病情评估,分析临床特征及其与CAG重复序列数目的关系。结果所有患者均为成人发病,平均年龄为(36.63±4.14)岁,确诊病程平均为(12.13±3.44)y,均表现为四肢无力和肌肉萎缩,6例出现舌肌萎缩和构音障碍、肢体震颤、口周面肌束颤,4例性功能下降,6例乳腺发育。实验室检查结果 7例肌酸激酶(creatine kinase,CK)增高,8例甘油三酯增高,6例尿酸增高,2例睾酮增高。肌电图提示所有患者均表现为广泛神经源性损害,运动神经和感觉神经动作电位波幅降低,部分神经传导速度下降。AR基因CAG重复序列的重复次数为44~58次,CAG拷贝数与发病年龄呈负相关(r=-0.753,P=0.031),与ALSFRS评分呈负相关(r=-0.733,P=0.039),与CK水平无关(r=0.250,P=0.550)。结论 KD的临床特点为缓慢进展的延髓和脊髓肌肉萎缩无力,伴有肢体震颤、面肌束颤,部分可有内分泌功能及代谢紊乱。CAG拷贝数越多,则发病年龄越早,运动功能评分越低。CAG拷贝数可作为KD病情的预测指标。     

Kennedy病的临床特点及诊断

目的通过1例经基因检测明确诊断的Kennedy病患者,探讨Kennedy病的临床特点及诊断。方法根据临床症状、神经系统体征、肌电图和神经传导速度、家族史等特点对临床疑诊Kennedy病患者,检测其雄激素受体基因第1个外显子的CAG重复片断。结果本病病程进展缓慢,肌酶和血睾酮增高,肌电图示神经源性损害,雄激素受体基因第1个外显子的CAG重复数为51。结论Kennedy病有相对独特的临床特点,确诊有赖于雄激素受体基因第1个外显子的CAG重复片段数的检测。     

Kennedy's disease: genetic diagnosis of an inherited form of motor neuron disease

:Kennedy's disease (X-linked spinal and bulbar muscular atrophy) is an inherited form of motor neuron disease that may be diagnosed genetically using the polymerase chain reaction (PCR). This form of motor neuron disease principally affects the proximal limb girdle muscles as well as those involved with deglutition and phonation. Onset is usually late, in the fourth to fifth decades of life, and progression is slow. Moderate gynecomastia and testicular atrophy are usually present, suggesting a defect in androgen receptor function. Being inherited in an X-linked recessive manner, only males are affected, with females as the unaffected carriers.
The genetic abnormality that causes Kennedy's disease is an enlargement of the androgen receptor (AR) gene, which is located on the proximal long arm of the X chromosome. In patients with this disease, a region in the gene containing repeated CAG triplet nucleotides is approximately twice the size of that found in normal people. Using PCR to amplify this region of the AR gene, this study confirms this genetic mutation in 12 males from eight different families. All these families live on the east coast of Australia. This mutation was not found in five patients with other forms of motor neuron disease. Twelve heterozygote females, the daughters of affected males and carrier females, have also been identified. In addition, there are 14 asymptomatic and as yet untested sons of carriers, ranging in age from less than one year to over 40 years of age. Each has a 50% chance of inheriting the abnormal gene from his mother and thus developing Kennedy's disease.
This study shows that Kennedy's disease may be diagnosed genetically using whole blood, and discusses the ethics of prenatal and presymptomatic testing, particularly in males under 16. (Aust NZ J Med 1993; 23: 187–192.)     

Kennedy''s disease: clinical and molecular study of two Italian families

Kennedy's disease, or spinal and bulbar muscular atrophy (SBMA), is a rare X-linked motoneuron disorder with variable signs of androgen insensitivity. It is associated with the expansion of a trinucleotide CAG repeat within the androgen receptor (AR) gene. We here report our clinical and molecular findings in two Italian families with Kennedy's disease. The increased size of the CAG repeat was demonstrated in four affected males and seven carrier females.The support of Telethon-Italia to A.S. (Grant No. 560) and F.T. (Grant No. 553) is gratefully acknowledged.     

Kennedy病患者感觉神经检测

目的 对Kennedy病患者进行神经电生理和病理研究,了解其感觉神经功能及结构状况.方法 对14例Kennedy病患者进行肌电图和神经传导速度、三叉神经-颈反射(TCR)、接触性热痛诱发电位(CHEP)检测及腓肠神经活检.对照组进行相应研究.结果 Kennedy病患者感觉神经传导速度正常或轻度减慢(减慢者占7.2%).感觉神经动作电位波幅明显降低,为(0.65～2.85)μV;三叉神经-颈反射潜伏期延长[初始峰潜伏期为(38.9±7.0)ms]、波形双侧不对称;痛觉诱发电位表现为CHEP潜伏期延长[手背、前臂的掌侧面和C7部位刺激时,CHEP初始峰潜伏期分别为(613±57)ms、(595±32)ms、(489±37)ms]或波形消失;腓肠神经活检示大的有髓鞘纤维减少.结论 Kennedy病累及感觉系统,大、小感觉神经纤维均可受累.     

肯尼迪病三核苷酸序列数目与发病年龄的关系

目的 探讨肯尼迪病患者三核苷酸(CAG)重复序列数目与发病年龄的关系.方法 对30例基因确诊的肯尼迪病患者进行雄激素受体基因第一外显子测序,计算其CAG重复序列数目,并分析其与患者发病年龄间的关系.对所有患者进行Appel量表评分以评价其运动功能缺损程度,并分析Appel量表评分与CAG重复序列数目及病程的关系.结果 CAG重复序列数目与发病年龄呈负相关(r=-0.671,P<0.01);Appel量表评分与病程呈正相关(r=0.855,P<0.01)但与CAG重复序列数目无明显相关性(r=0.100,P=0.601).结论 与其他CAG重复序列疾病一样,肯尼迪病患者的CAG重复序列数目决定了其发病年龄,但与病情轻重无关.     

Kennedy病的临床特点(附2例报告)

目的探讨Kennedy病(KD)的临床特点。方法回顾性分析2例KD患者的临床资料。结果 2例患者表现为肌无力及肌萎缩,可伴有乳房发育、肌束震颤、感觉异常及性功能障碍。肌酸激酶及血脂升高,但内分泌水平正常;EMG可见感觉神经受损。AR基因检测示CAG重复次数为44~48次。2例患者经治疗,肌无力症状有所改善。结论 KD表现为肌无力、肌萎缩、肌肉震颤、反射减弱,主要累及下运动神经元,可伴有男性乳房发育、感觉异常、糖脂代谢紊乱及肌酶升高。AR基因检测为其诊断金标准。