Source: China.com
Guide
"It's not that you work hard because of hope, but because you work hard you see hope. Recently, Cai Lei said at the Boao Forum for Asia.
"My condition has not improved," Cai Lei said in a recent interview.
In the past two years, ALS has been widely known to us, and Cai Lei's story of fighting ALS has touched everyone, and at the same time, it has also made us realize the horror of ALS. Although he tried many treatments, set up a laboratory, read papers, and even initiated drug research, he still did not find a cure for ALS.
Source: Popular Science China
How does ALS imprison life step by step, why is ALS so difficult to treat, and what are the available treatment and rehabilitation methods...... Today, Professor Jiang Haishan, an expert in the field of ALS and deputy chief physician of Nanfang Hospital of Southern Medical University, will answer us one by one.
Haishan Jiang is a member of the Neuromuscular Disease Group of the Neurology Branch of the Chinese Medical Association and a standing member of the Neuroscience Committee of the Chinese Association of Research Hospitals.
Jiang Haishan (Deputy Chief Physician, Nanfang Hospital, Southern Medical University)| Guests
Deep dive into science | Interview
01
Classification of motor neuron disorders
Q: ALS is a type of motor neuron disease. Can you give us a science about some of our common motor neuron diseases?
Jiang Haishan: Generally speaking, there are many types of common motor neuropathies. The most common subtype is called "amyotrophic lateral sclerosis". Amyotrophic refers to changes in lower motor neurons, while lateral sclerosis generally refers to changes in upper motor neurons, so "amyotrophic lateral sclerosis" means that both the upper and lower sides are "affected" at the same time.
In addition, there is pure upper motor neuron involvement, which we call "primary lateral sclerosis", there is pure lower motor neuron involvement, which we call "progressive spinal muscular atrophy", and there is also involvement of motor neurons in the brainstem, which we call "progressive bulbar palsy". Here are our 4 most common types.
However, in fact, there are many types that progress slowly, such as the common cervical involvement (motor neuron disease), which is confined to cervical involvement for more than 1 year, which we call "flail arm syndrome", and "flail leg syndrome", which is mainly lumbosacral involvement for more than 1 year, and is not involved in other places. In addition, there are some very special ones, such as Mills syndrome, which mainly affects half of the limb and is confined to one half of the limb for more than 1 year.
Q: How is ALS different from these other MND diseases?
Jiang Haishan: Actually, ALS is a general term for the whole motor neuron disease, and in the earliest days, the naming of this term was different in different regions. The term ALS was not the first to be called in our mainland region, but was first named "ALS" in Taiwan, China, but because this statement is very vivid, it has gradually been accepted by everyone.
At first, we called this disease MND, but MND is more professional and not graphic enough, on the contrary, "ALS" is very vivid, so MND has many names, ALS is just one of its names.
02
Causes and genes of ALS
Q: Are there some differences in the causes of ALS?
Jiang Haishan: There are actually many causes of ALS, which are mainly divided into two categories: the first is familial (fALS) - familial amyotrophic lateral sclerosis, or familial motor neuron disease, and the other is called sporadic motor neuron disease (sALS).
At present, the earliest research paper on this disease in our country is a survey done by Professor Shang Huifang of West China Hospital: research shows that the proportion of ALS with gene mutations is about 11.1%, and the proportion of gene mutations with a family history of genetic mutations can be detected is about 55%, which means that even if you have a family history of ALS, you may not be able to screen out genes, even if it is a sporadic patient, there is also a 11.1% possibility of screening out gene mutations.
Many years ago, our center began to use whole-external sequencing for testing. In fact, we found that people with a family history can have more than 80% or 90% of gene mutations, and there are some special mutations, for example, we have found a family that cannot be found by whole external sequencing, but later found a suspicious gene, and we are also doing some relevant verification. But for sporadic patients, we know from the data we have that 40% of people have genetic mutations.
Q: Mr. Jiang, can you introduce some of the common genes that cause ALS?
Jiang Haishan: At present, the most common gene that causes ALS is the SOD1 gene. But the first thing we found was actually some other genetic mutations. There are different experts and teachers in our country who have written articles about genetic mutations. We found that the genetic mutations may be different in each place, perhaps due to regional differences.
In the southern region, for example, the SETX gene is relatively common. In our center, there are a lot of genetic mutations like ANXA, NEK1, etc., which are not common in many other places. In general, the SOD1 mutation is probably the number one in the world, which is probably the most common genetic mutation worldwide.
Q: Can you tell us about these sporadic cases, and what are the causes of it, and whether it is also related to genes, or is it related to the acquired environment and our dietary habits?
Jiang Haishan: Actually, even if there is a genetic mutation in MND, it will be affected by many factors such as the environment. We have found a significant increase in the incidence of MND recently after COVID.
People with sporadic ALS may face a variety of triggers, including stress infections, anxiety, depression, and more. Therefore, long-term anxiety may cause a series of corresponding physiological changes, which in turn induce changes in the body. We believe that the main initiating factor of ALS is inflammation, which is not only caused by infection, but may also be caused by other factors, such as post-COVID infection or long-term mental stress. These factors may induce an inflammatory response in the body, which in turn can lead to the denaturation of proteins, which can eventually lead to ALS.
The pathogenesis of ALS is very complex, including our common genes such as SOD1, some sporadic unknown genes, and the interaction of environmental factors with genes, which leads to the emergence of different cases.
03
How ALS can make people incapacitated
Q: ALS is also known as a chronic, progressive neurodegenerative disease. Can you tell us more about how it affects our muscles through neuropathy until the patient is finally unable to move?
Jiang Haishan: Actually, it's mainly about how our athletic units are formed. First of all, we have neurons, and the instructions for the formation of neurons are transmitted through the nerves, transmitting signals to the neuromuscular junction and then acting on the muscles, which make up the process of the entire motor unit.
When neurons are degenerated, i.e., when there is a problem with the "High Command", it is unable to produce instructions, which leads to axonal changes in the lower positions, including the nerves. As a result, we often observe progressive changes in the gradual decline of axonal waves in patients with motor neuron disease during electromyography, suggesting neuronal degeneration and consequent lesions.
As the lesion progresses, neuronal degeneration progresses downward, also leading to alterations in the neuromuscular junction. Neuromuscular junction imaging can often be observed with degeneration similar to ethmoid frit, which is also a secondary alteration of motor neuron disease. Previously, Cui Liying, a teacher from Union Medical College Hospital, reported on this change in patients with motor neuron disease when undergoing repetitive electrical stimulation. Unlike our common neuromuscular contact disorders such as myasthenia gravis, myasthenia gravis usually presents with reentry waves because its essential problem is a decrease in vesicles or mediators, whereas motor neuron pluggivosis does not exhibit a significant reentry wave characteristic.
As the condition progresses further downward, the entire muscle will be involved. If the muscles lose the upper innervation, disuse atrophy will gradually occur, and then the muscles will gradually atrophy. In addition, if there are other secondary changes, such as insufficient energy supply to the muscles and problems with adaptation, some associated pathologies may also occur. So in general, damage to motor neurons is the root cause, and once damaged, it triggers a series of pathologies.
As to why we should focus on diseases like ALS, I would say that it is a rare but serious neurological disease that places a huge burden on the quality of life of patients and families. This is not only a concern in the medical field, but also an important issue that should be paid attention to by all sectors of society.
04
Why should we care about ALS?
Q: At present, how many people are affected in the mainland?
Jiang Haishan: Our country lacks abundant flow survey data. Overall, however, the prevalence is around 2/100,000 to 4/100,000, and the data reported varies from person to person.
Source: CPPCC Network
Therefore, we are very much looking forward to the formation of a complete epidemiological survey data in China in the future. At present, this work needs to be further advanced. From this point of view, at a ratio of 4/100,000, there may be about 20-300,000 patients in the mainland, which constitutes a fairly large group. However, due to the severity of the disease, it is known as the "first of the world's five terminal diseases" and the mortality rate is very high, usually between 3 and 5 years. If a patient is not treated properly, life can reach the end of life in as little as 3 to 5 years, so this situation requires a lot of follow-up.
We are faced with the grim fact that the prevalence should theoretically be higher than the incidence. However, we found that the prevalence and morbidity rates were similar, possibly due to the fact that many of the new patients each year reach the end of life within a short period of time, resulting in little difference in prevalence and morbidity. Of course, this conclusion may need to be supported by more flow survey data. Although the incidence of the disease is relatively low on the mainland, the population is still quite large in general due to the large population base on the mainland.
Q: What is the approximate age of ALS onset in mainland China?
Jiang Haishan: The onset of ALS mainly depends on whether it is familial or sporadic. If it is sporadic, it is generally a group of patients over fifty or sixty years old. If it's hereditary, it depends on which mutation it is. The four most common early-onset inherited mutations include the SOD1, SETX, ALS2, and FUS genes. The youngest patient I have ever seen with ALS was 1 year old and had a mutated ALS2 gene. In contrast, the SOD1 gene usually develops around the age of 20 or 30, the SETX gene develops around the age of 10-19 in adolescence, and the FUS gene develops around the age of 20 or 30.
Therefore, the age of onset of ALS is closely related to its etiology. Whether it is a familial case of a genetic mutation, a sporadic case, or even a case affected by certain triggers, it will have a certain impact on the time of onset.
Q: Is ALS a distinction between men and women?
Jiang Haishan: At present, according to the data of our center, the difference in the proportion of male and female patients is not particularly large. Although there are some reports in the literature that there are more male patients, there is basically no significant gender difference in the data from our center.
Q: How long is the average survival time of a patient, and is there a close relationship with the cause of the disease?
Jiang Haishan: Whether it is the age of onset or the course of the disease, it is closely related to the specific etiology. Each cause is different, and some causes progress a little faster. We know that patients like SOD1 have a relatively rapid progression once initiated, some genetic factors, such as SESETX, progress relatively slowly, and some acquired causes, sometimes depending on whether the patient has been actively intervened after the onset of the disease, and whether anxiety and depression affect the whole treatment process after the onset of the disease. In addition, the degree of family support is an important intervention factor for the length of the patient's disease. Therefore, the course of the disease may also be related to the treatment of each patient, for example, your long-term anxiety and depression may be a trigger.
In addition, for the treatment of ALS, standardized treatment methods can slow down the progression of the disease. A prime example is the famous physicist Stephen Hawking. When he was diagnosed with ALS in his 20s, doctors told him he had only one year to live at most, but Hawking eventually lived to be 76 years old, an extension of 50 years.
05
Recent research advances in ALS
Q: What progress and breakthroughs have been made in the research of ALS in recent years?
Jiang Haishan: With the participation of more and more doctors and scientific researchers, the development of ALS has gradually taken on a clear outline. We are preparing for the pre-, mid- and post-production phases, involving drug introduction, drug mechanism studies, and in-depth discussions on pathogenesis. At the same time, the rapid development of the current field of mechanism research, as more and more researchers join, will promote the further expansion of the disease field. We would like to thank Cai Lei for his important driving role. We've done a lot of work to live up to the trust of MND patients and strive to overcome this rare disease as soon as possible.
Q: What do you find the most promising treatments?
Jiang Haishan: There are several aspects of the most promising treatment: first, when the patient first begins to have obvious symptoms in the early stage, there is a better chance of some inflammatory modification. Now we are exploring the new use of old drugs, which can even delay the progression of the disease in the early stages of the patient.
In addition, inflammation may occur during the pathogenesis, which induces protein folding in the body, which in turn induces cascade effects. Therefore, drug therapy that interrupts this cascade effect will also be a very important point.
In addition to this, there are also post-delivery, and these treatments are also very promising for us.
At present, we are also working on this, but the specific treatment methods are still blank, and many things have not yet produced results. The clinical trials of drugs that we are doing now are a very important target in the interrupting cascade effect. But whether it will work or not, we are also waiting to see.
Source | Delve into the science