The mystery of why some people develop ALS – 09/23/2023 – Science

In early August, the world received news of the death of professional photographer Bryan Randall. He was the partner of actress Sandra Bullock, who met him working while he was taking portraits at a family party.

Three years ago, at the age of 54, he had unfortunately been diagnosed with amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease, named after the American baseball player who developed the condition in 1939.

In recent years, we have been able to follow several ALS victims known to the public, including young people who did not suffer from other health problems. Still, the mystery surrounding the possible causes of amyotrophic lateral sclerosis remains unsolved.

But recent research has revealed some clues. Could we finally be on our way to deciphering the real causes of this devastating condition?

ALS is a form of motor neurone disease. It is a painful and debilitating condition that causes people to gradually lose their motor neurons — the cells that control voluntary muscle movements. As a result, patients end up slowly losing control of their own bodies.

A recent analysis of available data estimated that this condition affects about 5 in every 100,000 people in the United States.

The disease is more common among men and diagnosis occurs, on average, around 60 years of age. But it can also affect significantly younger people.

Most people live only a few years after diagnosis, but there are notable exceptions. One of them was British physicist Stephen Hawking, who was diagnosed with a form of motor neurone disease at the age of 21 and died in 2018, aged 76.

The reasons why people develop ALS are complex. For 10-15% of people who suffer from the condition, the cause is familial. In these cases, a mutation in a specific gene would have been passed down through generations.

It is not known for sure whether you will develop the disease if one of your parents or ancestors had ALS, but there may be stories in the family of those affected about a cousin or grandparent who also had the devastating disease.

It turns out that, when someone develops hereditary ALS, the affected gene is not always the same, even though the consequences are identical. And there are still the 85-90% of people who develop the non-hereditary form of ALS — for them, identifying the cause of the condition is even more difficult.

When a person is diagnosed with ALS and no one in the family says something like “your great-uncle had something like that,” the case is considered a one-time random event, or “sporadic.”

Recent research indicates that genetic mutations may be part of the causes. But they probably involve small changes in a few different genes and not the drastic and obvious biological errors seen in familial ALS.

Changes in up to 40 genes have been identified that increase the risk of suffering from sporadic ALS, but this condition is extremely rare.

Complex genetics

The list of genes that can be affected is quite long, but four of these genes are the most common.

The most common is the C9orf72 gene, related to the regulation of muscle and nerve cells. This genetic change is found in 30% of ALS cases.

In 20% of cases, the fault is in the SOD1 gene, which codes for an antioxidant enzyme that protects cells against injury. And a smaller percentage corresponds to changes in the TARDBP (4%) and FUS (5%) genes. These two genes encode important factors involved in the production of proteins inside the cell.

Non-genetic factors

Depending on the type of ALS, “the disease can be explained by genetic factors in only around 8% to 60%”, according to neurology professor Eva Feldman, from the University of Michigan, in the United States.

But evidence is also emerging that repeated and prolonged exposure to potentially triggering factors in the external environment may increase the risk of developing ALS, particularly in its sporadic form. And these discoveries prompted Feldman and his colleagues to do more research.

“We suspect the existence of what we call the ALS ‘exposome’, which is the sum of toxic environmental exposures that increase the risk [da doença]”, explains Feldman.

The team found that prolonged exposure to organic chemical pollutants, metals, pesticides, particulate matter from construction dust, and poor air quality may contribute to an increased risk of amyotrophic lateral sclerosis.

The director of the North American organization ALS Association, Neil Thakur, states that there is no absolute cause and effect relationship for ALS.

“It’s always a combination of factors”, according to him. “Even if you have a risk factor or genetic profile, there is no 100% certainty that you will suffer from ALS.”

But Thakur points out that there is evidence that exposure to particulate matter from diesel fuel, jet fuel and campfires, as well as pesticides and aerosols, can increase the risk of developing ALS.

He states, for example, that military personnel suffer high exposure to these materials and, apparently, they are more likely to contract the disease.

There is also evidence that the presence of lead in drinking water, smoking and contact sports can trigger amyotrophic lateral sclerosis. But many uncertainties still remain.

Studies into the effects of lifelong alcohol intake and cigarette smoking before an ALS diagnosis indicate that being a complete non-smoker does not necessarily protect you against the disease – but it is clear that these factors influence your risk of developing other conditions and there are many reasons to reduce smoking and drinking.

One of the difficulties faced by doctors and scientists researching the causes of ALS (and motor neurone diseases in general) is the fact that they, fortunately, are rare diseases.

Among the small number of patients, not all are willing or able to participate in research studies. And there are many genetic and lifestyle differences that can influence results.

Even if genetic changes are found in 4% of cases, for example, there may not be enough people in that group to see clear differences between those who were exposed to a specific chemical pollutant and those who were not.

“It takes a long time to recruit enough people for an ALS clinical trial, as the disease progresses very quickly and patients can only participate in the early stages of the disease,” explains Thakur. “If you have ALS in your family and have an ALS gene, you can see if you can participate in studies, which would help you and others.”

Feldman adds that examining the combined risk of genetic and environmental factors “is a challenge” for his research team. They suspect that countless genes — dozens and perhaps even hundreds of them — may contribute to what they call the “polygenic risk profile” of ALS.

This risk profile is “additional to the traditional risk of isolated genes”, according to her. The team is now researching how this polygenic risk profile may interact with environmental factors to cause ALS.

Looking for good news

Amyotrophic lateral sclerosis currently has no cure. But the agency that regulates and inspects food and drugs in the USA (FDA) has approved several treatments that can help reduce the speed of its progression and give people a little more time.

These medications have a series of mechanisms. They can reduce levels of certain substances in the brain and spinal cord and even prevent nerve cell death.

Apparently, it may also be useful to target treatments to combat the effects of a specific defective gene. As an example, a recent initial trial of a drug designed to combat damage caused by the SOD1 mutation yielded promising preliminary results.

But just knowing which genetic mutations may be responsible for the diagnosis of ALS in patients may not provide much comfort to people suffering from the disease. Therefore, the aim of the ALS Association is to provide support and guidance for those with the condition and their families.

“The ALS Association’s strategy is to make it possible to live [com ELA] until we have a cure,” says Thakur.

The organization advocates high-quality care, involving healthcare professionals with a range of different backgrounds, that can allow people to lead more active lives for a few more months, according to its director. And the association also plans to publish guidance on how to reduce the risks of possible factors that contribute to the development of ALS.

But the big challenge is obtaining funds to conduct the necessary research.

In addition to determining how much each gene or environmental risk factor may represent, more studies are needed to find a way to apply the knowledge eventually acquired.

“The real question is not why people suffer from ALS, but what can we do to prevent or treat it,” Thakur points out.

Regardless of its causes, the march of this progressive disease will continue. Relatives and friends will need to react with love and patience to each level of deterioration in their loved ones, as Sandra Bullock did.

But greater understanding of the science behind this devastating condition may one day lead to more effective treatments and, who knows, even help prevent the emergence of new cases.

And good news like this is always welcome.

read the original version of this report (in English) on the website BBCFuture.