ALS: A fierce diagnosis

May 17, 2016 Article BioVox

Do you remember the Ice Bucket Challenge? Back in 2014, it was used to create awareness and collect donations for research to combat ALS (Amyotrophic Lateral Sclerosis), a severe neurodegenerative disease that typically causes death within two to five years after onset. (Famous scientist Stephen Hawking is one of the few long-term survivors of the disease.) A genetic predisposition for this disease can be found in 15% of the cases, but no cause has been found for the remaining 85%. We spoke with ALS specialist Prof. Philip Van Damme (UZ Leuven) to get a better understanding of this devastating condition.

Attacking the motor neuron

“If you have ALS, the neurons of your motor system start to die,” Van Damme explains. The motor system is used to move your muscles, and it consists of two levels: the upper motor neurons in the cortex, and the lower motor neurons, located in the brain stem and the spinal cord. The muscle movement signal travels from the upper to the lower motor neurons; the brain stem neurons activate the muscles of the face and the bulbar muscles (used for swallowing, chewing and talking), while the spinal cord neurons are responsible for all voluntary movement.

The median survival time is 36 months.

“The disease is mostly diagnosed between 6 to 12 months after the start and progresses very rapidly,” Van Damme says. “The first symptoms can be the loss of muscle force in the limbs, often beginning in one hand. It can also start with articulation and swallowing problems. The median survival time is 36 months. However, there is a lot of variation, and 10 to 15% of the patients have a milder form of the disease.”

Occurring as frequently as MS

It is unclear exactly how many people get the disease every year, but it is estimated that there are 1 to 2 new cases per 100,000 inhabitants in Belgium. However, because the disease is so deadly, there are only 4 to 8 ALS patients per 100,000 people at any one time. ALS pops up between the ages of 45 and 65, and it occurs slightly more often in men. “In a lifetime, 1 in 400 people gets confronted with the disease,” Van Damme says. “This ratio is similar to the neuroinflammatory disease MS, but MS is much better known by the public, because — due to the chronic nature of MS — a patient population builds up.”

Having to tell patients the diagnosis of ALS and that the treatment options are limited is very difficult.

It’s a family curse

A clear genetic cause can be found in about 15% of the patients, who have inherited the autosomal dominant genes that cause ALS. Most of these patients are aware that ALS occurs in their family. “Not all people who carry ALS genes will develop the disease,” Van Damme says. “This depends on the penetrance of the genes, and this is affected by age. The older you become, the more likely that the disease will start to develop. However, some people die due to another cause before they develop ALS.”

In the remaining 85% of the patients, no clear cause can be found. “It is possible that hereditary factors are at the origin of the disease in those patients, but that is still unsure,” Van Damme says. A theory exists concerning a certain endogenous virus that can incorporate itself in the human DNA; the proteins that are expressed by this virus might cause ALS. “We have seen that when these kind of proteins are expressed in the motor neurons of lab animals, this is toxic,” continues Van Damme. “This doesn’t mean that this is the cause for ALS, but it is definitely an interesting route to follow.”

An international consortium is now performing whole-genome sequencing on ALS patients. This will provide the tools to analyze whether the DNA sequences of these endogenous viruses appear more frequently in ALS patients, or whether there are other hereditary factors that cause the disease. These answers should become clear within a couple of years.

Slowing down the disease

“What is very important for patients is the multidisciplinary care, where vital functions such as breathing and swallowing are supported.

Riluzole, currently the only available drug for ALS patients, works by slowing down excitotoxicity, the process in which nerve cells are damaged or killed by overstimulation by neurotransmitters such as glutamate. But while Riluzole might reduce glutamate signaling, it only has a moderate effect, prolonging the lifespan of ALS patients by up two to three months.

“A lot of research is going on to find better treatments,” Van Damme says. “For example, we collaborate with Prof. Catherine Verfaillie, who developed a technique to make stem cells from a skin biopsy and subsequently differentiate these cells to nerve cells. This allows us to study and compare the nerve cells of patients with ALS and those of healthy people in a simple way.”

There are also clinical trials involving new medications that are taking place. One of these concerns a drug that is specifically designed for patients who have a mutation in the SOD1 gene, one of the genes that may cause ALS. “Yes, this cutting-edge Phase I study uses antisense oligonucleotides from Biogen (MA) that bind to the RNA of the SOD1 gene and thereby inhibit the formation of SOD1 proteins,” Van Damme confirms. “Our center in Belgium also participates in this study. Other drugs that are currently also being tested in clinical trials, such as muscle strengtheners from Cytokinetics (CA), focus on slowing down the disease progression. There is also a study going on with a drug from Treeway (NL) that aims to reduce oxidative stress, which is clearly present in ALS.

“What is very important for patients is the multidisciplinary care, where vital functions such as breathing and swallowing are supported,” Van Damme emphasizes. “This clearly improves the quality of life and the lifespan.”

An onerous task

An ALS doctor has an especially hard job, as he can never share good news. “Having to tell patients the diagnosis of ALS and that the treatment options are limited is very difficult,” Van Damme says. “Therefore, it is very important for me that I can also perform research, to give hope to patients and let them participate in finding a cure. Without research, I wouldn’t be able to do this job. I hope one day we will find a treatment that can really make a difference.” ALS remains a rare disease, so it’s still a struggle to get research funds, Ice Bucket Challenge aside. World ALS Day is coming up next month, on June 21. Maybe you would like to organize an activity or make a donation?


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