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一针70万的救命药
带你认识罕见病SMA
One injection of life-saving medicine worth of 700,000¥:
let you know the rare disease SMA
中文名：脊髓型肌萎缩症
英文名：spinal muscular atrophy(简称SMA)
别名：Werdnig-Hoffman病；Dubowitz病
Kugelberg-Welander病
突变基因：SMN1
疾病科室：神经内科
English name: spinal muscular atrophy (SMA for short)
Aliases: Werdnig-Hoffman disease; Dubowitz disease; Kugelberg-Welander disease
Mutant gene: SMN1
Disease Department: Neurology
SMA：婴幼儿遗传病头号杀手
8月7日是「国际脊髓性肌萎缩症（SMA）关爱日」。
1891年，奥地利神经病学家Guido Werdnig观察到一对婴儿兄弟，他们在10个月大时开始变得虚弱，这是SMA首次被发现和报道。
脊髓性肌萎缩症（SMA）是一种罕见的遗传性神经肌肉疾病，表现为肌肉萎缩和无力，一些严重的患者甚至会失去呼吸和吞咽能力，悲惨地死去。
[SMA: The number one killer of genetic diseases of infants and young children]
August 7th is 'International Spinal Muscular Atrophy (SMA) Awareness Day'.
In 1891, the Austrian neurologist Guido Werdnig observed two infant brothers who began to become weak when they were 10 months old. This was the first time that SMA was discovered and reported.
Spinal muscular atrophy (SMA) is a rare hereditary neuromuscular disease, whose symptoms are muscle atrophy and weakness. Some severe patients even lose the ability to breathe and swallow and die tragically.
根据发病年龄和严重程度，由重到轻分为4型，婴幼儿患者主要分为Ⅰ型、II型和Ⅲ型。60%患者属于最严重，发病率也最高1型患者，一般在6个月内发病，生命往往不超过两岁。事实上，SMA是造成2岁以下婴幼儿死亡的头号遗传杀手。
II型和Ⅲ型发病稍晚，不至于很早死亡，但同样会逐渐衰弱，饱受肺炎、脊柱侧弯等疾病困扰，终身与轮椅为伴。
According to the age and severity of onset, it is divided into 4 types from degree. Infant patients are mainly divided into type I, II and III. 60% patients are type 1 patients who belong to the most serious group with the highest incidence, who usually develop within 6 months, and they are often less than two years old. In fact, SMA is the number one genetic killer of infants and children under 2 years old.
Type II and Type III have a later onset and will not cause death early, but these patients will also gradually become weaker, suffer from pneumonia, scoliosis and other diseases, and will be accompanied by wheelchairs for life
SMN1：一个基因的误差
SMA是一种基因病。
在人类的5号染色体上，存在两条几乎一模一样的基因，分别叫SMN1和SMN2，SMN基因可以制造出一种名叫SMN蛋白。通常情况下，SMN1基因为主，SMN2基因为辅，SMN1基因承担了在体内指导合成SMN蛋白的主要职责。SMN蛋白的全称是「运动神经元存活蛋白」。顾名思义，SMN蛋白决定了人类运动神经元的存活。运动神经起源于脊髓，存在于全身各处，控制着人体进行呼吸、爬、走、头颈控制以及吞咽等活动的肌肉。
[SMN1: The error of one gene]
SMA is a kind of genetic disease.
On human chromosome 5, there are two almost identical genes, called SMN1 and SMN2. SMN can produce a protein called SMN. Normally, SMN1 is the main gene, and SMN2 is the secondary gene. SMN1 takes the main responsibility of directing the synthesis of SMN protein in the body. The full name of SMN protein is 'survival motor neuron protein.' As the name suggests, SMN protein determines the survival of human motor neurons. Motor nerves originate from the spinal cord and exist throughout the body. They control muscles of the human body for breathing, crawling, walking, head and neck, and swallowing.
如果一旦SMN1基因发生突变，人体内的SMN蛋白就会缺失或显著减少，导致一种叫做脊髓性肌萎缩症（spinal muscular atrophy，SMA）的遗传性疾病，导致运动神经元死亡和肌肉萎缩。
If SMN1 is mutated, SMN protein in the human body will be missing or significantly reduced, leading to a genetic disease called spinal muscular atrophy (SMA), which leads to the death of motor neurons and muscle atrophy.
随着SMA患儿的年龄增长，他们无力的肌肉很难满足。日常活动的需要，身体功能会逐渐丧失。患者连普通的翻身、蹬。腿、爬行都难以实现，这样的肌肉无力还会导致骨骼和脊柱的。变形。随着病程的发展，吞咽和呼吸功能（比如呼吸、咳嗽。、清除气道分泌物）也会受到影响，增加罹患肺炎、呼吸道感染和呼吸困难的风险，严重威胁患者生命问题。与此同时，SMA患者的认知功能、感官系统不受影响。
生而为人，因为一个基因的误差，使得一个人在医学上被定义了生命期限，在绝望中慢慢等待死亡的降临。
As SMA children grow older, their weak muscles can hardly meet the needs of daily activities, and their body functions will gradually lose. It is difficult for patients to perform even ordinary turning, kicking, and crawling. Such muscle weakness can also cause deformation of the bones and spine. As the course of the disease progresses, swallowing and respiratory functions (such as breathing, coughing, and clearing of airway secretions) will also be affected, increasing the risk of pneumonia, respiratory infections, and dyspnea, and seriously threatening the lives of patients. At the same time, the cognitive function and sensory system of SMA patients are not affected.
SMA是如何遗传的？
SMA是一种相对常见的「罕见病」—— 大约每6000-10000名新生儿中，就有一名SMA患者。
按照遗传学概率，每50个人里，就有一个人的体内，隐藏着致命的SMN基因突变。最常见的突变类型为7号外显子的纯合缺失，还有一部分是点突变。
SMA is a relatively common 'rare disease'-approximately one in 6000-10000 newborns has SMA mutation. According to genetic probability, one in 50 people has a fatal SMN gene mutation hidden in the body. The most common type of mutation is the homozygous deletion of exon 7, and some are point mutations.
SMA是一种常染色体隐性遗传疾病。患儿父母双方的基因通常为只有一个SMN1基因异常，所以并不会成为SMA，他们被称作为携带者Aa。只有当父母双方都是携带者Aa，并且各自把缺陷基因a遗传给了孩子，才会导致孩子的基因刚好是aa而致病；如果是Aa或者AA，都不会患病。因此，如果两个携带者Aa结合，每次怀孕都有25%的几率生下SMA患儿。按照中国人口数计算，目前中国约有3万至5万名SMA患者，其中，80%患者都是严重的SMA-I型或者SMA-II型，还不包括未被检查出的潜在患者。
SMA作为一种罕见病，它的认知度低而成本高，常规婚检或孕检都未纳入。也就是说，绝大多数人是在孩子出生之后才知道这一切。
SMA is an autosomal recessive genetic disease. Both parents of the child usually have only one SMN1 gene abnormality, so they do not have SMA. They are called carriers Aa. Only when both parents are carriers of Aa, and they pass on the defective gene a to the child, will the child's gene happen to be aa and have disease; if it is Aa or AA, neither will get sick. Therefore, if two carriers of Aa get married, the probability of them to have a child with SMA is 25%. Calculating according to the population of China, there are currently about 30,000 to 50,000 SMA patients in China, of which 80% are severe SMA-I or SMA-II, not including potential patients who have not been detected.
As a rare disease, SMA has low awareness and high cost, and it is not included in routine premarital examinations or pregnancy examinations. In other words, most people only know all this after the child is born.
产前诊断成第一道防线
早期的基因诊断、遗传咨询和开展产前诊断对于降低SMA患儿的发病率有重要意义。
[Prenatal diagnosis as the first line of defense]
Early genetic diagnosis, genetic counseling and prenatal diagnosis are of great significance for reducing the incidence of children with SMA.
01
婚前筛查
在结婚之前，可以先确定双方家庭中有没有SMA患者，同时进行基因筛查。因为SMA是隐性遗传，进行基因筛查可以查出对方是否携带SMA缺陷基因。只要双方有一方没有携带SMA基因，就不会生下SMA宝宝。
02
如果双方都是携带者，怎么办？
如果夫妻双方都是携带者，生下SMA宝宝的可能性将占25%。想要诞下健康宝宝，可以通过第三代试管婴儿技术，利用胚胎植入前单基因遗传学检测，从源头阻断缺陷基因遗传病，避免下一代出现SMA。
03
产前诊断
如果已经怀孕，可以做产前诊断。在妊娠中期通过羊水穿刺，经检测后得知胎儿染色体异常情况，判断是否需要终止妊娠
1. Pre-marital screening
Before getting married, you can first determine if there are any SMA patients in both families, and perform genetic screening at the same time. Because SMA is inherited recessively, genetic screening can find out whether the other party carries the SMA defective gene. As long as one of the two does not carry the SMA gene, no SMA baby will be born.
2. What if both are carriers?
If both are carriers, the probability of giving birth to an SMA baby will be 25%. If you want to give birth to a healthy baby, you can use the third-generation IVF technology to use preimplantation single-gene genetic testing to block the genetic disease of the defective gene from the source and prevent the next generation of SMA.
3. Prenatal diagnosis
If you are pregnant, you can make a prenatal diagnosis. Through amniotic fluid puncture in the second trimester, the abnormal condition of fetal chromosomes is learned after testing, and it is judged whether it is necessary to terminate the pregnancy.
孤儿药：终结SMA无药可医
SMA从最初发现疾病，到最后有药可医，花了120多年。
直到2016年的圣诞节前夕， SMA都没有针对性的治疗药物。除了支持性治疗和辅助通气等为数不多的治疗方式外，患儿只能在全身肌肉逐渐萎缩的过程中，等待死亡的到来。
罕见病患者用的药被称为「孤儿药」。随着创新药物的发展，美国FDA先后批准了三款治疗SMA的「孤儿药」：
It took more than 120 years for SMA to be discovered from the beginning to the end of the cure.
Until Christmas Eve in 2016, there were no targeted treatments for SMA. Except for few treatments such as supportive treatment and assisted ventilation, children can only wait for death with the atrophy of muscles.
The drugs used by patients with rare diseases are called 'orphan drugs.' With the development of innovative drugs, the US FDA has successively approved three 'orphan drugs' for the treatment of SMA:
01
反义寡核苷酸疗法：nusinersen
nusinersen（美国及欧盟注册商品名Spinraza）是全球首个治疗脊髓性肌萎缩症（SMA）的药物。2019年2月nusinersen进入中国，商品名为诺西那生钠注射液，成为国内首个获批上市治疗SMA的药物。作为一种反义寡核苷酸药物，通过促进SMN蛋白产生，进而改善神经功能并起到控制肌肉的疗效，适用于所有年龄的Ⅰ型、II型和Ⅲ型SMA患者。
1. Antisense oligonucleotide therapy: nusinersen
Nusinersen (US and EU registered trade name Spinraza) is the world's first drug for the treatment of spinal muscular atrophy (SMA). In February 2019, nusinersen entered China under the trade name of nusinersen sodium injection, becoming the first domestic drug approved for the treatment of SMA. As an antisense oligonucleotide drug, it promotes the production of SMN protein, thereby improving nerve function and controlling muscle efficacy. It is suitable for all ages of type I, II and III SMA patients.
02
基因疗法：Zolgensma
Zolgensma是一种治疗Ⅰ型SMA的基因替代疗法，使用重组腺病毒载体AAV9递送外源性SMN1基因导入患者体内，让患者可以正常生成SMN蛋白，从而改善运动神经元功能和生存，一次静脉注射给药治疗即可长期缓解甚至治愈这一疾病。该款药物是全球唯一一款获批上市的SMA一次性治疗方案，定价为212.5万美元，是目前全球最昂贵的药物。
2. Gene therapy: Zolgensma
Zolgensma is a gene replacement therapy for the treatment of type I SMA. It uses recombinant adenovirus vector AAV9 to deliver exogenous SMN1 into patients, so that patients can produce SMN protein normally, thereby improving motor neuron function and survival. Drug treatment can alleviate or even cure this disease for a long time. This drug is the only one-time treatment for SMA approved for marketing in the world. It is priced at US$2.125 million and is currently the most expensive drug in the world.
03
口服小分子疗法：Evrysdi
首款口服疗法Evrysdi于2020年8月获美国FDA批准上市，用于治疗2个月以上婴幼儿和成人型SMA患者。该口服疗法为SMN2基因的小分子mRNA剪接调节剂，可提高正常SMA蛋白的mRNA水平，缓解患者症状。
3. Oral small molecule therapy: Evrysdi
The first oral therapy Evrysdi was approved by the US FDA in August 2020 for the treatment of infants and adults with SMA patients over 2 months old. The oral therapy is a small molecule mRNA splicing regulator of the SMN2 gene, which can increase the normal SMA protein mRNA level and relieve the symptoms of patients.
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