[A to Z of Lou Gehrig’s disease] Reasons why it's important to identify genetic variants in younger people with ALS
Amyotrophic lateral sclerosis (ALS), more commonly known as Lou Gehrig's disease, is a rare disorder first recognized in the 1930s when the famous New York Yankees baseball player Lou Gehrig died of the disease at the young age of 38. A neurodegenerative disease that selectively destroys motor nerve cells, causing muscles to atrophy and stiffen, ALS is the most rapidly progressive of the many "motor neuron diseases" and has the worst prognosis.
ALS is also a very complex disease. It's the only neurodegenerative disease that affects both the central and peripheral nervous systems. One might think it would be easy to diagnose, but it is not because the symptoms vary depending on which motor neuron is affected, and the disease progresses at different rates. Moreover, the concept of the disease has recently been expanded to “motor neuron network disease” as its link to dementia has been confirmed.
Hanyang University Medical Center is the first medical institution in Korea to run a specialized clinic for ALS. The Hanyang University Medical Center Lou Gehrig's Disease Clinic, which opened in 2001, has led the way in creating a better environment for the diagnosis and treatment of Lou Gehrig's disease in Korea by conducting broad and in-depth research on the disease and helping to introduce new drugs for the disease. Korea Biomedical Review met with Professor Kim Seung-hyun of the Department of Neurology and the Korean Neurological Association chairman to learn about the disease.
The only 'neurodegenerative disease' that invades central and peripheral nervous systems
Question: What is ALS?
Answer: Lou Gehrig's disease is a neurodegenerative disease with an estimated 500 new cases per year in Korea, totaling about 3,000 patients. It is a disease that affects motor neurons. Although there are several types of motor neuron diseases, Lou Gehrig's disease is the most rapidly progressive and has the worst prognosis.
ALS involves both “upper motor neuron disease,” in which the motor nerve bundles from the motor nerve center in the brain (cerebral cortex) are damaged, and “lower motor neuron disease,” in which the motor nerves from the spinal motor nerves in front of the spinal cord to the muscles are damaged. Among neurodegenerative diseases, ALS is the only one that involves both the central and peripheral nervous systems.
In recent years, many studies have confirmed that ALS is associated with cognitive dysfunction and dementia, so the concept has changed from motor neuron disease to “motor neuron network disease.” In the past, it was thought that ALS selectively affects motor neurons, but it is now known that the disease occurs in combination with other degenerative diseases in the brain.
In reality, about 40 to 50 percent of patients with ALS have cognitive dysfunction, and about 5 to 10 percent have overlapping dementia. The remaining 40 to 50 percent have known cognitive impairment. There is also a distinctive type of dementia that occurs in people with ALS, called frontotemporal dementia, which involves the frontal and temporal lobes. It's more commonly associated with personality changes and behavioral disorders.
Q: We understand that the ratio of men to women with ALS is 2 to 1, with a higher proportion of men.
A: In older adults aged 60 to 70, the ratio is 1:1, but before that, the ratio is 2:1, with more men than women. Currently, we think that female hormones help protect against the disease. As female hormones decline with age, women are thought to develop the disease at the same rate as men.
Q: What causes ALS?
A: We don't know yet. Some people with ALS have been found to have the gene that causes the disease, but it accounts for only 5 to 10 percent of all ALS patients. In Korea, the proportion of people with ALS caused by genetic mutations is also low compared to other countries, at less than 5 percent. Also, the genes common in ALS are very different in Korea from other countries.
For instance, C9orf72, the most common gene mutation that causes ALS in Europe, Australia, and the United States, is not found in Korean patients. It has been found in one or two rare cases, all related to foreign ancestors. SOD1 and FUS gene mutations are more common in Korean ALS patients than in foreign countries, with SOD1 being the most common gene mutation in Korea and FUS being the second most common.
Next is the ANXA11 gene mutation, which we discovered and reported and is currently attracting attention because of its high prevalence in Asia. This gene mutation is inherited with a 50 percent chance of autosomal dominant inheritance. Still, it can also be a gene mutation that is not inherited from the parents and is modified or acquired at a later stage.
The ANXA11 gene variant overlaps with frontotemporal dementia in about one-third of cases. We created a sensation in 2020 by publishing this content in Science Translational Medicine, a sister journal of Science, highlighting the association of ANXA11 gene variants with dementia.
About 90 to 95 percent of ALS cases are caused by something other than a gene mutation, and it's not a single factor but a combination of factors. It is believed to be caused by a complex mechanism that combines multiple factors, including oxidative damage to the mitochondria or cytoskeleton, hormonal abnormalities, and environmental factors such as glutamic acid and lead.
There are occupational groups at higher risk of developing this multifactorial disease, including those who work with heavy metals, such as lead, and soccer players, who are often exposed to high physical fatigue during sports and mild brain injuries from headers. Among professional military personnel, there is a high incidence of ALS in infantrymen.
It can also be a side effect of Agent Orange. It is possible to develop ALS from eating very high levels of glutamic acid. In Guam, during World War II, when the Japanese army wiped out all the grains of the natives, the disease suddenly increased hundreds of times after the natives ate bat-eating tree fruits.
When it was discovered that the fruit contained a lot of glutamic acid, it was decided to study Rilutec (riluzole), developed as an anti-epileptic drug with anti-glutamic acid activity, as a drug for ALS. It was confirmed to have a slight therapeutic effect. It was the first drug in the world to be approved by the U.S. Food and Drug Administration (FDA) as a treatment for ALS.
Q: Lou Gehrig's disease is a neurodegenerative disease, so it seems like it would be something you would expect to develop at an older age, but it can affect younger people as well, as was the case with Lou Gehrig. What is the typical age of onset, and what is the age of the youngest patient you've seen with ALS?
A: Most ALS patients develop the disease in their 50s and 60s. The average age of onset of ALS is 59.8 years old, and about 95 percent of people with ALS in Korea do not have a genetic cause. Most people with ALS develop sporadic ALS in their 50s and 60s. The youngest patient I've ever seen was 17 years old, and the disease had a gene mutation that caused it.
Q: Does everyone who has a mutation in the gene that causes ALS get the disease?
A: Not necessarily. It is thought that the development of a disease depends on whether the body has a "defense mechanism" to counteract the gene that causes it. If the gene that causes the disease is toxic, and if the body has evolved a way to counteract it, we may not develop it.
Q: Are people with ALS being tested to identify the causative gene?
A: First and foremost, we are making a real effort to find the causative gene mutation in younger patients. We first test for the genes identified worldwide as causing the disease, and if that doesn't work, we test all the genes to see where the abnormality is. We also check whether gene abnormalities run in the family, including parents.
If we find a gene that hasn't been reported in young patients, we take it and study it in a virtual cell model to see if it causes pathological problems. This process has led to the discovery of more than 50 genes, which are then shared internationally and categorized as high-risk or associated genes.
There are reasons why identifying the genes that cause ALS is so important. Unlike sporadic ALS, which does not have a causative gene, identifying a causative gene will allow for personalized treatment. Gene-targeted drugs are being developed rapidly, so genetic testing is important to identify patients who may benefit from treatment.
In addition, patients with ALS who develop the disease in their 50s and 60s may have developed symptoms at some point while continuing to defend against the disease.
Often mistaken for a stroke or a herniated disk, ALS gets worse after disk surgery
Q: What are the symptoms of ALS, and how should we seek medical attention?
A: Lou Gehrig's disease is characterized by muscle atrophy, tremors, and symptoms that don't stay in one place but spread to other areas. In this situation, a consultation with a neurologist is necessary, and I think it's more helpful for patients to go to a medical center experienced in the diagnosis and treatment of ALS if they strongly suspect it.
Q: What are the symptoms that are often mistaken for ALS?
A: A common symptom often mistaken for ALS is muscle twitching, but this is not a reason to suspect ALS, as twitching is common in people who drink alcohol or smoke and are tired. Also, ALS paralyzes the motor nerves, not the sensory nerves. If you have paresthesia and motor nerve problems, you may have a herniated disk or peripheral neuropathy, not ALS.
Q: ALS is said to kill patients within two to five years of onset, but what is the actual progress?
A: Currently, the survival time for ALS patients is meaningless. The two to five-year survival rate for people with ALS refers to when there was no government support for respiratory organs and nutrition. It was too difficult for patients to afford their respirators then. But it is not anymore.
If the disease progresses and the patient experiences difficulty breathing, we put them on a respirator. If there are nutritional problems, we put them on a gastrostomy, and they live for 10 or 20 years. If there are no complications, they can survive long enough to be able to blink their eyes and talk to their families, although they cannot move their hands and feet.
The disease progresses to respiratory paralysis and the inability to perform any self-care activities for three to five years. Initially, one-third of patients experience problems with speech and swallowing. They may have slurred speech or difficulty eating, and because the cranial nerves that come out of the brain stem also have motor nerves, the first thing they think is a stroke.
The other two-thirds of cases involve the spinal cord, with one-third of cases starting in the arms and one-third starting in the legs. Weakness in the hands and feet is a common symptom; more commonly, some symptoms can be mistaken for a herniated disk. For this reason, many people with ALS have had surgery for a herniated disk, not only in Korea but around the world.
The symptoms of ALS vary widely and can include weakness, flaccidity, and muscle spasms that start in the hands and move up to the shoulders, causing an inability to move the arms, or symptoms that start in the shoulders and move down the arms backward. It can also occur in the legs.
When these symptoms are recognized as being caused by a herniated disk, the disease often worsens after surgery. The disease usually progresses in a way that starts on one side of the body and then spreads to other parts of the body, so a patient who had problems in one arm before the disk surgery may develop problems in the other arm.
There are 5 officially licensed treatments for ALS in Korea
Q: Diagnosing Lou Gehrig's disease seems difficult, but how is it done?
A: Many pathologies need to be differentiated, including disc disease. After ruling out many other conditions, ALS is the last on the list. Depending on the patient, it can be diagnosed after ruling out dozens or more than 100 diseases. The patient's symptoms should be monitored for at least three to six months, and if possible, the diagnosis should not be made until all the symptoms of ALS are present.
I don't think it's right to rush to a diagnosis of ALS, which is as devastating as a death sentence, because some motor neuron diseases are confined to one arm and don't spread elsewhere, and there are no good treatments for ALS. I would wait at least six months, and I even had a patient who wanted to wait a year for all the systemic symptoms to appear.
The diagnosis of ALS is based on an MRI of the neck, back, and brain, as well as a cancer screening. We also test for autoimmune diseases, such as the presence of autoantibodies that attack your body, because sometimes the substances from the cancer can trigger an immune response that damages the nerves. Once other diseases have been ruled out, nerve conduction studies, electromyography, and other tests are performed to determine if the pattern of ALS is present.
Q: Riluzole, which works by reducing the concentration of glutamic acid to inhibit nerve cell damage, and Edaravone, which works by relieving oxidative stress in the motor nerves to inhibit the progression of ALS, are currently licensed treatments for ALS, and many other treatments are being tried. We understand that stem cell therapy is also being conducted at Hanyang University Medical Center's ALS Clinic, but what other treatments are being tried for ALS besides Riluzole and Edaravone?
A: Stem cell therapy is a complex treatment that involves harvesting bone marrow, culturing stem cells, and injecting them into the cerebrospinal cavity. Although the treatment process is painful, it is more effective than Edaravone. Stem cell therapy, which received a conditional item license from the Ministry of Food and Drug Safety in 2014, is used for this treatment, and it is only available in Korea, so patients with ALS from the United States, the Middle East, and other countries are coming to our hospital for treatment.
After the results of the clinical study of stem cell therapy for ALS were published in a paper, patients came from abroad to receive this treatment. The results of the phase 2 clinical trial of the stem cell therapy were selected as the “Best Paper of the Month” in November 2018 by the European Journal of Neuroscience. We are nearing the end of the phase 3 trial, with results expected later next year.
Another drug, Relyvrio, a combination of TUDCA (taurusodiol) and sodium phenylbutyrate, was recently approved in the U.S. and Europe to help block cell death by reducing stress in the mitochondria and extracellular material, among other mechanisms of the disease. The problem is the cost. Relyvrio costs more than 60 million won ($43,620) for a three-month supply. Currently, it is recommended for patients who can afford it.
At an international conference last year, Amylyx, the manufacturer of Relyvrio, inquired about domestic licensing. In conjunction with the Korea Orphan and Essential Drug Center, we created a route to officially import Relyvrio through the formal customs clearance process so domestic patients with ALS can now receive treatment with Relyvrio. This means Korean ALS patients who traveled abroad to obtain the drug can now receive treatment in Korea.
Nuedexta is also an approved treatment in Korea, but it is not approved for ALS. It is used to help patients with dysphonia and dysphagia. Currently, there are five treatments available: Riluzole, Edaravone, stem cell therapy, Relyvrio, and Nuedexta. The combination of treatments is determined by the patient's disease status and financial situation. Twenty years ago, there was only Riluzole, but now there are clinical studies, and more trials are underway.
Riluzole also has side effects, such as liver toxicity and hair loss, which prevent 30 percent of people with ALS from using it. Edaravone is an expensive, non-formulary treatment, so it's mostly used by those with insurance that covers actual expenses. Stem cell therapy is also not an option for people who are hepatitis carriers or have recently had shingles. For patients who, for one reason or another, are not eligible for approved treatments, our hospital offers free injections of erythropoietin, a treatment for anemia in patients with chronic kidney failure, on a donation basis.
Although the Ministry of Food and Drug Safety does not approve erythropoietin injections for the treatment of ALS, clinical studies have confirmed its anti-inflammatory response and increased cell survival factors. We have been giving it to patients unable to receive treatment for various reasons for more than 10 years. Erythropoietin is similar in appearance to EGFR, a signal required for neuronal differentiation and neuronal survival, which protects neurons and helps neurodevelopment.
While erythropoietin injections don't produce dramatic muscle strength gains, they are still given to patients with ALS who report that a single injection helps them stay active for two to three weeks. However, patients whose hemoglobin levels have risen more than 15 percent from baseline cannot be given erythropoietin injections, so they are given once a month at intervals while monitoring blood test results.
Q: Are there any new drugs used for ALS overseas that are unavailable in Korea, and what clinical trials are underway to develop new drugs for ALS?
A: Biogen's gene therapy for SOD1 gene mutation, Qalsodi (tofersen), won accelerated approval in the U.S. last year, but it is not yet licensed in Korea. However, a clinical trial opportunity was found in Korea, and eight patients could receive the treatment. People with SOD1 gene mutation who do not yet have symptoms are tested regularly. If the indicators of motor neuron damage increase, customized gene therapy is given before symptoms appear.
In addition, our hospital is conducting a clinical study of Biogen's gene therapy for the FUS gene mutation, which does not yet have a drug name in Asia. Two patients with ALS visited our hospital from China to participate in the clinical trial of gene therapy for the FUS gene variant, which is not uncommon in Korea. Our hospital is also conducting other clinical studies, such as exploring the development of treatments targeting genes specific to Korea.
Delayed gastrostomy can worsen symptoms...timing is everything
Q: Where do you think ALS treatment is headed in the future?
A: Personalized treatment is the way to go, not just for those with the causative gene but also for sporadic ALS. Ten percent of sporadic patients have problems controlling inflammation, which can be personalized using biological markers. Also, various factors that cause the disease and how these factors affect the disease should be customized to determine the combination of drugs for early, mid, and late stages.
Q: Lou Gehrig disease patients’ respiratory muscles eventually weaken, and when do you recommend starting respiratory rehabilitation therapy?
A: We recommend that patients start respiratory rehabilitation when their lung capacity drops below 60 percent or when they experience shortness of breath when lying down to sleep to prevent it from worsening. I would start respiratory rehabilitation when there is evidence that the disease has affected the respiratory muscles, not before.
Q: The muscles involved in chewing and swallowing food are also weakened in people with ALS, and gastrostomies are used to prevent inhalation pneumonia and maintain nutrition. However, we've heard waiting until it's too late is better.
A: Gastrostomy is recommended when the patient is in grade two when they lose weight and swallowing function is tested and graded from zero to four (grade four is the best condition). If you do the surgery at grade two, the symptoms stabilize after the gastrostomy. Still, if you delay the gastrostomy for about eight months, the symptoms get much worse during the delay, which we recently confirmed in our hospital and will be published in a paper soon.
Q: Weight and blood sugar management are said to impact the disease, what is the best way to manage it?
A: Severe weight loss is not good for people with ALS. People who weigh some weight do better than those who are very thin. There are also theories that diabetes causes the disease, but there are also theories that it protects against it. There is still some confusion about the treatment, but the consensus is that blood sugar should be controlled when it is very high, but not too strictly lowered below 100 mg/dL, unlike in people with diabetes alone.
Q: Complications, including pneumonia, are very dangerous for people with ALS. How do you recommend daily management to avoid them?
A: To avoid inhalation pneumonia, use a good suction machine at home. It's also important to take care of the respiratory system. If you don't use your muscles, it can lead to joint contractures and pain later in life, which can be prevented by maintaining your range of motion through rehabilitation. In addition to the hospital, family members can continue to perform passive joint exercises at home to move the patient's joints, which will not restore paralysis but will reduce pain.
Q: Finally, what would you like to say to people living with ALS and their families?
A: Some people lose hope when they have ALS, and I wish they could be more positive about the disease. I would encourage them to feel fortunate that they are still able to walk even though they are losing muscle strength or that they are still able to blink and talk to their family even though they are bedridden.