3例Kennedy病患者的临床、病理与分子遗传学研究

目的探讨肯尼迪病的临床、病理和分子遗传学特点。方法总结3例临床疑似肯尼迪病患者的临床资料,对其进行神经电生理、神经-肌肉活检及雄激素受体基因第1外显子的分子生物学检测。结果 3例患者均青年起病,病情缓慢进展。表现为肢体近端和延髓受累为主的下运动神经元损害;其中,例2出现性功能下降,例3出现男性乳房发育;3例血清肌酸激酶水平均明显增高;性激素水平均出现异常;肌电图呈广泛的神经源性损害,例1伴有感觉神经波幅降低及传导速度减慢。雄激素受体(androgen receptor gene,AR)基因的CAG重复序列数分别为45、45、52次。结论肯尼迪病主要表现为脊髓和延髓肌肉的萎缩和无力,早期基因检测有助于确诊。     

基因确诊的肯尼迪病两例临床与分子生物学特点

目的确诊2例肯尼迪病患者，并对其临床和分子生物学特点进行报道。方法总结2例临床拟诊肯尼迪病患者的临床资料，对其雄激素受体基因第1外显子进行分子生物学检测，并分析其临床表型特征。结果2例患者均表现为以肢体近端和延髓受累为主的下运动神经元损害，其中，例1合并少精子症。二者血清肌酸激酶水平均明显增高，并存在明显的脂质代谢异常。基因检测结果显示，例1的雄激素受体基因第1外显子中CAG重复序列数为52个，例2的CAG重复序列数为48个，证明2例均为基因检测确诊的肯尼迪病患者。结论肯尼迪病的临床特点是进展缓慢的以肢体近端和延髓部受累为主的下运动神经元综合征，伴有内分泌或代谢异常。我们重复了肯尼迪病的实验室检测方法，肯尼迪病的确诊需依靠基因检测。     

肯尼迪病12例报告

目的了解中国肯尼迪病的临床和实验室特点,以避免误诊。方法分析12例肯尼迪病患者的临床表现及肌电图特点,测定血清肌酸激酶水平和雄性激素受体基因1号外显子cAG序列重复拷贝数。结果58．3％的患者有阳性家族史。起病年龄平均（33．8±8．2）岁。从起病到确定诊断时间平均（10．9±6．9）年。最显著的临床表现是舌肌萎缩和舌肌纤颤。与西方患者相比,中国肯尼迪病患者可能具有男性乳房女性化程度较轻、生育能力下降不显著等特点。血清CK轻中度甚至重度升高,肌电图可出现感觉神经传导的异常。结论中国肯尼迪病与西方患者主要临床特点相似,部分症状可能有差别,基因检查是确诊的主要手段。     

不伴感觉神经受累的肯尼迪病5例临床特征分析

目的分析不伴有感觉异常肯尼迪病的临床特征、血清学检查、电生理检查等,以指导临床诊断降低误诊率。方法收集经基因明确诊断的肯尼迪病5例,详细询问其病史,进行全面的体格检查包括详尽的神经系统查体,收集并分析其实验室检查指标、电生理检查特点,及基因测定AR基因1号外显子CAG重复序列。结果5例患者均无明显阳性家族史,均为男性,平均起病年龄(39.8±7.2)岁,从发病到确诊平均病程(9.0±5.2)年,3例患者起病部位为双下肢近端无力,1例患者为口周及颊部"肉跳"感,1例患者为男性乳腺发育;最显著的临床表现为舌肌萎缩、舌肌纤颤、四肢近端肌肉无力;5例患者均无临床及电生理测定的感觉异常。结论肯尼迪病是一种累及下运动神经元的神经变性疾病,感觉不受累的患者也应考虑肯尼迪病,确诊依赖基因测定。     

亮丙瑞林治疗肯尼迪病的开放式研究

肯尼迪病的病因为位于Xq11-12的雄激素受体(androgen receptors,AR)基因发生突变[1].动物实验结果表明,亮丙瑞林可有效改善肯尼迪病转基因鼠的临床症状[2].为检验亮丙瑞林对于肯尼迪病患者的疗效,我们进行了亮丙瑞林治疗肯尼迪病的开放式临床研究.     

深感觉障碍表现突出的肯尼迪病1例报告及神经电生理特征

<正>肯尼迪病(KD)又称脊髓延髓肌肉萎缩症,是一种少见的X隐性遗传的神经元变性疾病,临床以缓慢进展的肌无力、肌萎缩、肌束震颤、延髓麻痹等下运动神经损害为主要表现,可伴有感觉神经受累及雄激素不敏感综合征等表现~([1,2]),但感觉障碍一般为临床下表现,然而KD的肌电图特征却以感觉神经传导异常最为明显,且感觉异常比运动异常更多见~([3])。现将1例深感觉障碍表现突出的肯尼迪病总结如下,并结合文献探讨肯尼迪病的临床表现及肌电图特征。1临床资料1. 1病史患者,男,47岁,因"四肢无力、走路不稳进行性加重10 y,声音嘶哑2 y"就诊于我院神经内科门诊。患     

基因确诊的肯尼迪病1例报告

<正>肯尼迪病,又称脊髓延髓肌肉萎缩症,是以缓慢进展的肌无力和肌萎缩为特点的一种少见的X连锁隐性遗传的下运动神经元变性疾病,是第一个外显子雄激素受体基因CAG重复序列扩增所致。现将我院收治的1例经基因确诊的肯尼迪病报道如下。1病例资料患者,男,46岁,因右下肢无力19 y,双下肢无力8 y,左上肢麻木1 y,加重20 d入院。患者于入院前19 y无明显诱因出现右下肢无力,表现为蹲下后站起时费力,同时自觉右     

肯尼迪病3个家系的临床、基因型和遗传特征分析

目的分析3个肯尼迪病(Kennedy disease,KD)家系的临床、基因及遗传特征。方法收集3个KD家系患者的详细病史、体格检查、血生化及电生理检查等资料,用基因分析的方法测定先证者及家族成员雄性激素受体(androgen receptor,AR)基因的CAG重复序列拷贝数。结果 3个家系发现的5例KD患者主要临床表现为四肢肌肉萎缩、无力和肢体震颤,舌肌萎缩、纤颤;实验室检查发现肌酸激酶升高;肌电图检查可见失神经电位;神经传导速度检查提示感觉神经受损。KD患者AR基因CAG重复次数在42~49。3个家系的遗传方式符合X连锁隐性遗传。结论 KD主要影响男性患者,病情缓慢进展,主要表现为脊髓和延髓肌肉的萎缩和无力。基因检测有助确诊,并可检测出携带者,以进行家系遗传分析。     

肯尼迪病一例报告并文献复习

肯尼迪病(Kennedy's disease,KD)又称脊髓延髓肌萎缩症,是一种运动神经元病,以下运动神经元损害为主要临床特征,可伴有不完全性雄激素不敏感综合征、感觉神经和内分泌系统受累的表现.现将珠江医院神经内科最近经基因确诊的1例KD报道如下.     

肯尼迪病的临床分析和分子遗传学诊断

目的 分析3例肯尼迪病的临床表现、电生理及遗传学特征。方法 收集2018年11月-2019年7月本院收治的3例肯尼迪病患者的临床资料包括病史、体格检查、实验室检查、电生理等,检测患者及家族成员雄性激素受体(Androgen Receptor)基因的CAG重复数。结果 3例患者均中年男性,表现为四肢近端和延髓肌无力、肌束震颤萎缩、乳腺发育,缓慢发病,进行性加重。EMG均显示广泛神经源性损害, 感觉神经传导存在异常。基因检测CAG重复数分别为43、51和51。结论 肯尼迪病的临床特点为成年男性,肢体缓慢进行性无力,伴多肌肉萎缩、震颤,同时合并雄激素不敏感综合征, EMG呈运动神经源性损害的表现,CAG重复数显著增多。     

Familial Progressive Bulbar-Spinal Muscular Atrophy: Case Report with Muscle Biopsy Study

A case of familial progressive bulbar and spinal muscular atrophy was presented. The patient was a 59–year-old male with chief complaints of gait disturbance and nasal voice. His illness started at the age of 39 and very slowly progressed over 20 years. The clinical symptoms and signs were characterized by muscle weakness and atrophy due to lower motor neuron disease in the brain stem below the lower pons and the spinal cord. The electromyograms and muscle biopsy findings are basically neurogenic. In spite of the bulbar signs, the course of the disease is extremely slow. The diagnostic criteria was proposed after reviewing eight other cases reported in the literature.     

Phenotypic manifestations associated with CAG-repeat expansion in the androgen receptor gene in male patients and heterozygous females: a clinical and molecular study of 30 families

Spinal and bulbar muscular atrophy (Kennedy disease) is an adult form of X-linked motor neuron disease caused by the expansion of a polymorphic CAG-repeat sequence in the first exon of the androgen receptor gene. We studied clinical and molecular features of 36 patients and 19 heterozygous females. Phenotypic manifestations and disease severity broadly varied among our spinal and bulbar muscular atrophy patients. The size of CAG expansion significantly influences the age of disease onset, but neither clinical features nor disease severity. The majority of carrier women presented signs of chronic denervation at neurophysiological examination and, in three cases, low-amplitude sensory action potentials were recorded. Notably, a few women developed mild signs of bulbar motor neuron impairment later in life. The identification of a large number of patients by the use of the molecular test further supports the hypothesis that Kennedy disease had been previously underdiagnosed, probably because of the great variability of clinical presentation. Although an early diagnosis may not be crucial for treatment, given the lack of effective therapy, the molecular testing can be of great relevance for disease prognosis and genetic counseling.     

Efficacy and safety of leuprorelin acetate for subjects with spinal and bulbar muscular atrophy: pooled analyses of two randomized-controlled trials

Journal of Neurology - Spinal and bulbar muscular atrophy (SBMA) is an adult-onset, hereditary neuromuscular disease characterized by muscle atrophy, weakness, contraction fasciculation, and bulbar...     

进行性脊肌萎缩症129例临床分析

目的探讨进行性脊肌萎缩症(PSMA)的临床特点、诊断与鉴别诊断。方法回顾性分析129例PSMA患者的临床资料。结果本组患者均隐袭起病,逐渐加重,男性多见,发病年龄65.9%患者>50岁。首发症状以单侧上肢无力和肌萎缩为多见(65.9%),均表现为下运动神经元损害的症状和体征,51.9%患者出现延髓麻痹症状;肌电图检查均提示神经源性损害;易误诊为颈或腰椎病。结论本病是一组慢性进行性下运动神经元疾病,病变可累及延髓。诊断主要依据临床表现和肌电图。     

Pathogenesis‐targeting therapeutics for spinal and bulbar muscular atrophy (SBMA)

Spinal and bulbar muscular atrophy (SBMA) is an hereditary, adult‐onset, lower motor neuron disease caused by an aberrant elongation of a trinucleotide CAG repeat, which encodes the polyglutamine tract, in the first exon of the androgen receptor (AR) gene. The main symptoms are slowly progressive muscle weakness and atrophy of bulbar, facial and limb muscles. The cardinal histopathological findings of SBMA are an extensive loss of lower motor neurons in the anterior horn of the spinal cord as well as in brainstem motor nuclei and intranuclear accumulations of mutant AR protein in the residual motor neurons. Androgen deprivation therapy rescues neuronal dysfunction in animal models of SBMA, suggesting that the molecular basis for motor neuron degeneration in this disorder is testosterone‐dependent nuclear accumulation of the mutant AR. Suppression of disease progression by leuprorelin acetate has also been demonstrated in a phase 2 clinical trial. In addition, the clarification of pathophysiology leads to appearance of candidate drugs to treat this devastating disease: heat shock protein (HSP) inducer, Hsp90 inhibitor, and histone deacetylase inhibitor. Advances in basic and clinical research on SBMA are now paving the way for clinical application of pathogenesis‐targeting therapeutics.     

脊髓延髓肌肉萎缩症的临床特点

目的探讨脊髓延髓肌肉萎缩症(SBMA)的临床特点。方法对8例基因确诊的SBMA患者的临床资料进行回顾性分析。结果本组患者均为中青年男性。首发症状为双下肢无力3例,四肢无力1例,乳房增大2例,双上肢姿位性震颤2例。主要临床表现为进行性肢体无力、肌肉萎缩,下肢重,病情进展缓慢。患者均出现束颤,出现双上肢姿位性震颤3例,舌肌萎缩和震颤5例,乳房增大4例,性功能减退2例。血清肌酸激酶均增高,血脂异常5例,性激素水平异常7例。肌电图均呈广泛神经源性损害。雄激素受体(AR)基因CAG重复序列数均>40次。结论 SBMA主要表现为缓慢进展的脊髓和延髓下运动神经元性瘫痪,确诊有赖于AR基因CAG重复序列的检测。     

Pathogenesis, animal models and therapeutics in spinal and bulbar muscular atrophy (SBMA)

Spinal and bulbar muscular atrophy (SBMA) is a hereditary neurodegenerative disease characterized by slowly progressive muscle weakness and atrophy of bulbar, facial, and limb muscles. The cause of SBMA is expansion of a trinucleotide CAG repeat, which encodes the polyglutamine tract, in the first exon of the androgen receptor (AR) gene. SBMA chiefly occurs in adult males, whereas neurological symptoms are rarely detected in females having mutant AR gene. The cardinal histopathological finding of SBMA is loss of lower motor neurons in the anterior horn of spinal cord as well as in brainstem motor nuclei. Animal models carrying human mutant AR gene recapitulate polyglutamine-mediated motor neuron degeneration, providing clues to the pathogenesis of SBMA. There is increasing evidence that testosterone, the ligand of AR, plays a pivotal role in the pathogenesis of neurodegeneration in SBMA. The striking success of androgen deprivation therapy in SBMA mouse models has been translated into clinical trials. In addition, elucidation of pathophysiology using animal models leads to emergence of candidate drugs to treat this devastating disease: HSP inducer, Hsp90 inhibitor, and histone deacetylase inhibitor. Utilizing biomarkers such as scrotal skin biopsy would improve efficacy of clinical trials to verify the results from animal studies. Advances in basic and clinical researches on SBMA are now paving the way for clinical application of potential therapeutics.     

Neurogenic and myogenic contributions to hereditary motor neuron disease

Spinal muscular atrophy and spinal and bulbar muscular atrophy are characterized by lower motor neuron loss and muscle atrophy. Although it is accepted that motor neuron loss is a primary event in disease pathogenesis, inherent defects in muscle may also contribute to the disease progression and severity. In this review, we discuss the relative contributions of primary pathological processes in the motor axons, neuromuscular junctions and muscle to disease manifestations. Characterizing these contributions helps us to better understand the disease mechanisms and to better target therapeutic intervention.     

MRI Evidence of Early Muscle Atrophy in MuSK Positive Myasthenia Gravis

Muscle atrophy, particularly of facial and bulbar muscles, seems to be a relatively common long‐term consequence of musclespecific tyrosine kinase‐myasthenia gravis (MuSK‐MG), perhaps reflecting the chronic state of disease or long‐term therapy with corticosteroids. We performed magnetic resonance imaging (MRI) to assess muscle wasting in the facial and bulbar muscles in two female MuSK‐MG patients, with short duration of symptoms prior to diagnosis and prior to commencement of steroid therapy. The study revealed marked atrophy of temporalis, masseters, and lingual muscles with fatty replacement. MRI evidence of early muscle atrophy in MuSK‐MG may indicate that MuSK antibodies per se may predispose to muscle atrophy.