Therapeutic advances in spinal muscular atrophy

Spinal muscular atrophy (SMA) is a rare neuromuscular condition, characterized by loss of motor neurons as a result of a mutation in the survival motor neuron gene. This results in muscle wasting and in the most common and severe type, death before 24 months. Over the recent years there has been a dynamic shift in the therapeutic options for these patients involving both approved therapies, including gene therapy, and access to clinical trials in genetic modifying therapies to indirectly improve the survival motor neuron protein level and hence strength, muscle promotor therapies, up/down regulation of modifier genes and SMN independent therapies. This review addresses the pathogenesis of SMA and the resultant therapies available as well as the current clinical trials and future development.     

SMN2 and NAIP gene dosages in Vietnamese patients with spinal muscular atrophy

Background: The SMN1 gene is now recognized as a spinal muscular atrophy (SMA)-causing gene, while SMN2 and NAIP have been characterized as a modifying factor of the clinical severity of SMA. Gene dosage of SMN2 is associated with clinical severity of SMA. But the relationship between gene dosage of NAIP and clinical severity of SMA remains to be clarified, although complete deletion of NAIP is frequent in type I patients.
Methods: To evaluate the contribution of the SMN2 and NAIP gene dosages to SMA, quantitative real-time polymerase chain reaction was used to measure copy numbers of SMN2 and NAIP in 34 Vietnamese SMA patients lacking SMN1 (13 type I, 11 type II and 10 type III patients).
Results: The SMN2 copy number in type I patients was significantly lower than that in type II–III patients, which was compatible with the previous reports. In contrast, 25 out of 34 patients had only zero or one copy of NAIP , while 50 out of 52 controls had two or more copies. For NAIP (+) genotype, six out of 13 type I patients, eight out of 11 type II patients and six out of 10 type III patients carried one NAIP copy.
Conclusions: The SMN2 copy number was related to the clinical severity of SMA among Vietnamese patients. The presence of one NAIP copy, that is, heterozygous NAIP deletion, was common in Vietnamese SMA, regardless of clinical phenotype.     

儿童型脊髓性肌萎缩症遗传学研究进展

儿童型脊髓性肌萎缩症是常见的遗传性神经肌肉病,为常染色体隐性遗传.SMN1基因纯合缺失和微小突变是该病的主要病因,其高度同源拷贝SMN2基因可调节疾病的严重性,两个基因间功能的不同是编码区单个核苷酸不同致沉默突变使SMN2转录翻译大为降低.组蛋白脱乙酰基酶抑制剂在临床治疗实验中已显示出较好前景.     

Molecular analysis of the SMN and NAIP genes in Iranian spinal muscular atrophy patients

Background:  Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder characterized by degeneration of spinal cord anterior horn cells, leading to muscular atrophy. SMA is clinically classified into three subgroups based on the age of onset and severity. The majority of patients with SMA have homozygous deletions of exons 7 and 8 of the survival motor neuron ( SMN ) gene. The purpose of the present study was to determine the frequency of SMN and neuronal apoptosis inhibitory protein ( NAIP ) gene deletions in Iranian SMA patients. Experience in prenatal diagnosis of SMA in this population is also reported.
Methods:  To study the frequency of deletions of SMN and NAIP genes in an Iranian sample group, 75 unrelated SMA patients (54 type I, eight type II and 13 type III) were analyzed according to the methods described by van der Steege et al and Roy et al .
Results:  Homozygous deletion of SMN1 exons 7 and/or 8 were identified in 68 out of 75 patients (90%). Deletion of exon 5 of the NAIP gene was found in 40/54 of type I, 2/8 of type II and 1/13 of type III patients.
Conclusions:  Deletion of the SMN1 gene is a major cause of SMA in Iran, and NAIP gene deletions were common in the present patients with type I SMA. Also, the incidence of NAIP deletion is higher in more severe SMA.     

Deletion analyses of SMN1 and NAIP genes in Malaysian spinal muscular atrophy patients

BACKGROUND: The survival motor neuron 1 (SMN1) gene has been recognized to be responsible for spinal muscular atrophy (SMA) because it is homozygously deleted in more than 90% of SMA patients, irrespective of their clinical severity, whereas the neuronal apoptosis inhibitory protein (NAIP) gene is now considered to be a modifying factor of the severity of SMA. In Malaysia, it remains to be elucidated whether deletion of the SMN1 gene is also a main cause of SMA or whether deletion of the NAIP gene is found in the SMA patients. METHODS: To clarify the pathogenesis of SMA in Malaysia, a deletion analysis of the SMN1 and NAIP genes was performed in 24 Malaysian SMA patients. Deletion analysis of exons 7 and 8 of the SMN1 gene was performed according to the method described by van der Steege et al., while deletion analysis of exon 5 of the NAIP gene was performed according to a method described by Roy et al. RESULTS: Homozygous deletion of SMN1 exon 7 and exon 8 were identified in 19 out of 24 patients (79%). As to the NAIP gene, deletion of exon 5 was detected in six out of 24 patients (25%). NAIP gene deletion was correlated with severity of the disease. CONCLUSIONS: Deletion of the SMN1 exon 7 is a major cause of SMA in Malaysia, and NAIP gene deletions are not rare in type I SMA in Malaysia. The lower percentage of the SMN1 gene deletion may be due to the possibility that the present study included some patients without SMN1 gene abnormality and/or some patients with non-deletion type mutations in the SMN1 gene.     

诺西那生钠治疗症状前5q脊髓性肌萎缩症1例疗效分析

为探讨诺西那生钠治疗症状前5 q脊髓性肌萎缩症(SMA)的临床疗效,回顾性收集1例症状前5 q SMA患儿的临床资料、药物治疗经过及随访结果,并结合国外病例报道进行分析.患儿为女性,10月龄,因存在SMA家族史出生后常规MLPA检测发现SMN 1基因7、8号外显子纯合缺失,SMN 2基因2个拷贝数.患儿四肢肌力、肌张力...     

复合杂合变异脊髓性肌萎缩症1例报告

脊髓性肌萎缩症是一种常染色体隐性遗传病,常规基因诊断方法无法检出隐性遗传病携带者,易造成诊断延误,加重家庭及社会负担.先证者,男性,2月龄,生后哭声低弱、四肢无力,肌电图示脊髓前角细胞病变.采取多重连接探针扩增技术、长片段PCR扩增、连锁分析诊断患儿SMN 1基因为1 d+0型复合杂合变异(1 d:c.22_23 ...     

脊髓性肌萎缩症SMN1和SMN2基因拷贝数变异分析

目的:探讨运动神经元存活（SMN）1和SMN2基因拷贝数变异与脊髓性肌萎缩症（SMA）患儿临床表型的关系。方法:以2011年10月至2012年12月在复旦大学附属儿科医院临床诊断SMA患儿为研究对象,采用基因组DNA多重连接探针扩增（MLPA）技术进行SMN1基因缺失和SMN2基因拷贝数变异检测,探讨拷贝数变异与SMA临床分型的关系。结果:41例临床诊断SMA患儿行基因检测,其中SMN1基因第7和（或）8外显子缺失37例（90.2％）进入分析,男女之比为1∶0.8,发病年龄为（7.5±7.0）个月。Ⅰ型20例（54.1％）,Ⅱ型15例（40.5％）,Ⅲ型2例（5.4％）,发病年龄分别为（2.9±1.8）、（10.7±1.9）和（30.0±8.5)个月。37例SMN1基因第7和（或）8外显子缺失患儿中,18例SMN2基因第7和8外显子拷贝数为2个,其中13例（72.2％）为Ⅰ型,5例（27.8％）为Ⅱ型;19例SMN2基因第7和8外显子拷贝数增加（拷贝数3或4）,其中7例（36.8％）为Ⅰ型,10例（52.6％）为Ⅱ型,2例（10.5％）为Ⅲ型,两组差异有统计学意义。5例患儿父母行SMN1基因检测,共检出杂合缺失9例,其中4例患儿父母均为SMN1基因第7和8外显子杂合缺失,1例患儿父亲为SMN1基因第7和8外显子杂合缺失,母亲未检测到纯合或杂合缺失。结论:SMN1基因第7和（或）8外显子纯合缺失是SMA致病主要原因,SMN2基因拷贝数增加与SMA表型严重程度呈负相关。     

中国脊髓性肌萎缩症患儿的SMN基因学研究

目的：明确中国人各型脊髓性肌萎缩症(SMA)患儿SMN1基因外显子7和8缺失,SMN基因转变及微小突变情况。方法：对106例患者,采用PCR-RFLP检测基因缺失,RFLP筛查基因转变,并对PCR产物进行测序分析。基因转变率比较采用Fisher精确检验法进行统计学分析。结果：SMA患儿纯合SMN1外显子7和/或8缺失比率为91.5%,发现1例SMA中存在SMN1外显子7保留,而SMN1非编码外显子8缺失。在SMN1外显子7缺失而无外显子8缺失的患者中,各型间基因转变率差别无统计学意义,在SMN1外显子7缺失的SMA中,其基因转变率为8.3%。SMN第7外显子附近未发现基因微小突变。结论：SMN1基因外显子7和/或8缺失为中国SMA患儿的主要病因。SMA中存在SMN基因转变现象。SMN1基因外显子8的单独缺失可能致病。SMN1基因外显子7附近可能不是此病微小突变的热点区域。［中国当代儿科杂志,2010,12（7）：539-543］     

31例儿童脊髓性肌萎缩症临床与基因分析

目的探讨脊髓性肌萎缩症(SMA)的临床表型及基因型特点。方法回顾分析2014年2月至2019年5月确诊的31例脊髓性肌萎缩症患儿的临床资料。结果 31例SMA患儿中,男女比例1.8:1;6月龄内起病12例(38.7%),～18月龄起病17例(54.8%),18月龄后起病2例(6.5%)。首发症状为肌张力低下13例(41.9%),肌力下降9例(29.0%),步态异常5例(16.1%),生长迟缓4例(12.9%)。肌无力主要以近端受累为主,下肢重于上肢,腱反射减弱或消失。在感觉或认知方面均无变化。采用MLPA行基因检测,31例患儿中,SMN1基因外显子7和外显子8纯合缺失29例(93.5%),仅外显子7缺失2例(6.5%),均为2型患儿。不同类型SMA的临床表型与SMN1基因缺失类型之间差异无统计学意义(P0.05)。2型和3型SMA患儿的SMN2基因拷贝数高于1型,3型SMA患儿的SMN2基因拷贝数明显高于2型,不同SMA临床表型与SMN2拷贝数分布差异有统计学意义(P0.05)。30例(96.8%)患儿的父母亲明确诊断为SMN1基因杂合缺失;1例患儿父亲明确诊断为SMN1杂合缺失,母亲未检测到。结论 SMN1基因的检测和分析对SMA患儿具有诊断意义。SMA临床表型的严重程度与SMN2基因拷贝数增加呈反比。     

小儿脊髓性肌萎缩

脊髓性肌萎缩是一组常染色体隐性(AR)遗传的进行性并通常为对称性肌无力与萎缩的疾病.5q型常见,由5q13 上SMNI基因缺失(95%的病例)或突变(约5%的病例)引起.分为4型.18个月内起病的Ⅰ型与Ⅱ型往往因呼吸吞咽不良、不能站坐走与继发骨折等而坝后严重.非-5q型为一组异源性运动神经元病,临床表现与前者有所不同.5q型的诊断根据病史、血清肌酶、肌电图、肌活检而确诊靠基因检查,如纯合子缺失用PCR-SSCP等检测、点突变用点突变序列检测.胎儿细胞基因检测可提供产前诊断.治疗是多方面的.对症治疗与支持治疗要求有关各科专家积极合作.随着医疗技术的进步.患者的寿命与活动状况均有改进.分子治疗已初露曙光.     

The role of palliative care in advanced muscular dystrophy and spinal muscular atrophy

OBJECTIVE: This study examines the potential role for palliative care services in the care of individuals with muscular dystrophy and spinal muscular atrophy, and the support of their families. METHODOLOGY: Semistructured interviews were conducted in South Australia with nine bereaved and four current family members of individuals with muscular dystrophy or spinal muscular atrophy. Issues explored during interview included: (i) the family perceptions of the difficulties in caring; (ii) the psychological and physical resources which were available to assist them; and (iii) family recall of the management of the terminal phase of the illness. RESULTS: Significant issues identified included: (i) a lack of coordination of care and access to skilled, competent carers; (ii) a lack of support for siblings; (iii) inadequate bereavement care; and (iv) limited discussion of options of ventilatory support and advance directives. CONCLUSIONS: The terminal care for individuals with muscular dystrophy and spinal muscular atrophy and their families requires improvement. Although many individuals with these conditions will die following an acute event, palliative care services may be appropriate for those who require a period of terminal care at home.     

脊髓性肌萎缩症治疗研究进展北大核心CSCD

脊髓性肌萎缩症(spinal muscular atrophy,SMA)是一种常染色体隐性遗传的神经肌肉疾病,主要特征为进行性肌无力和肌肉萎缩。该病是导致患儿在婴幼儿期死亡的首要遗传病。SMA治疗的研究领域近年来发展迅速,部分相关治疗药物已经成功获批上市。该文以SMA近年的治疗研究进展作一综述。     

117例儿童脊髓性肌萎缩症自然病史分析

目的 对重庆及周边地区脊髓性肌萎缩症（spinal muscular atrophy,SMA）的自然病史进行分析,为开展SMA的综合管理、基因修饰治疗提供临床依据。 方法 回顾性分析117例SMA患儿的临床资料及生存现状。 结果 117例患儿中,1型SMA 62例（53.0%）、2型45例（38.5%）、3型10例（8.5%）,中位起病年龄分别为2、10、15月龄。1型SMA起病、就诊、确诊时间均早于2、3型SMA（P<0.05）,1型SMA就诊时间窗（起病年龄至就诊年龄）短于2、3型SMA（P<0.05）。肺炎为首发症状、抬头无力、哭声无力、进食费力多见于1型SMA（P<0.05）,2型SMA脊柱侧弯和下肢关节挛缩发生率高于1型（P<0.05）。117例（100%）SMA患儿均为SMN1基因纯合缺失,其中以7号外显子纯合缺失最常见（68.4%,80/117）。1型SMA的6年生存率仅为10%±5%,低于2、3型SMA（P<0.05）。起病年龄≤3月龄、肺炎为首发症状、抬头无力为1型SMA死亡的危险因素（P<0.05）。2型SMA运动能力可呈非线性倒退。 结论 各型SMA患儿临床表现、生存率均存在异质性,1型SMA生存率低,2型SMA运动能力可呈非线性倒退,临床上应早期识别及管理SMA。     

脊髓性肌萎缩症患儿营养管理研究进展

脊髓性肌萎缩症(SMA)是一种严重的神经肌肉疾病,因运动神经元存活基因1(SMN 1)缺陷引起.由于肌肉无力、活动量少、消化道症状以及吞咽困难等原因,患儿发生营养不足和营养过剩的概率常明显高于正常儿童,因此SMA的营养管理至关重要.文章就SMA患儿的营养评估、可能出现的营养问题以及相关营养干预策略进行阐述.     

儿童脊肌萎缩症23例临床特点及遗传学分析

目的 探讨脊肌萎缩症的临床特点和遗传方式。方法 对23例脊肌萎缩症患儿的临床资料进行总结,并用Weiber先证法分析其发病的遗传规律。结果 临床特点为出生后双下肢呈对称性弛缓性瘫痪且进行性加重,四肢近端无力,肌张力、肌力低下;肌电图主要表现为神经原性损害。隐性遗传分离分析表明,12个家系23例患儿发病方式符合常染色体隐性遗传。结论 脊肌萎缩症的临床发病早且病死率高,在遗传咨询中注意作相关产前基因检查,可避免该类患儿的出生。     

Pulmonary function and scoliosis in children with spinal muscular atrophy types II and III

Aims:    The objectives were to evaluate the clinical course of spinal muscular atrophy (SMA) types II and III patients necessitating scoliosis surgery at the National University Hospital, Singapore.
Methods:    A retrospective review of SMA types II and III patients, born over a 10-year period between 1983 and 1992, was conducted.
Results:    There were eight patients: four with SMA type II and four with SMA type III. The mean age at scoliosis surgery was 9 years 7 months (range 7 years 6 months−12 years 4 months). The mean preoperative Cobb angle was 65.4° (range 43−90°) and the mean postoperative Cobb angle was 22.6° (range 12−45°), with a mean correction of 64.8% (range 47.7−77.8%). The decline in percentage predicted forced vital capacity (FVC) was 7.7% (95% CI: 12.4% to 3.0%) per year preoperatively and this was reduced to 3.8% (95% CI: 5.8% to 1.9%) per year postoperatively. The mean length of preoperative and postoperative lung function follow-up was 6.3 months (range 0.03−31 months) and 44 months (range 0−110 months), respectively.
Conclusions:    This study suggests that pulmonary function in SMA types II and III continues to decline after scoliosis surgery, though the rate of decline is less marked. Overall, the combined results from this study and all other previously published studies are conflicting in regard to the effect of scoliosis surgery on pulmonary function in SMA types II and IIII, though half of the studies (3 of 6) did demonstrate a continued decline in lung function postoperatively. This decline in pulmonary function despite spinal stabilization is likely secondary to the progressive neuromuscular weakness of the disease.     

Preliminary immunological studies in spinal muscular atrophy

Evidence of impaired cell-mediated immunity in children with spinal muscular atrophy was obtained using lymphocyte transformation with PHA (20 children) and skin tests with tuberculin and DNCB (35 children). Laryngological examination of 16 children demonstrated hypoplasia of lymphatic tissue in Waldeyer's ring and the cervical lymph nodes. An ectodermal defect involving both spinal cord and thymus is suggested.The study was supported by agreement No. 05-002-N, NIH Bethesda     

精准医学时代中国脊髓性肌萎缩症诊治发展之路

脊髓性肌萎缩症(SMA)是一种常染色体隐性遗传神经肌肉疾病,因运动神经元存活基因(SMN)1缺失/变异导致SMN蛋白缺乏致病,临床表现为进行性肌萎缩与肌无力,并常伴呼吸、消化、营养、骨骼等多系统器官损害,属严重致死致残性遗传病,2018年被纳入国家《第一批罕见病目录》.近年来随着精准医学的发展,SMA的药物治疗获得前所...