What Causes ALS? National Registry Seeks Answer

At face value, the purpose of the National Amyotrophic Lateral Sclerosis (ALS) Registry seems quite straightforward: collecting data on the U.S. population with ALS.

But there’s a lot more to it.

The registry, funded by the Agency for Toxic Substances and Disease Registry (ATSDR) arm of the Centers for Disease Control and Prevention (CDC), collects epidemiological information through its 18 risk factor surveys and is a biorepository with 8,700 samples being used by researchers across the country. It’s also a funding source for studies that look at the environmental and genetic factors behind the disease.

More than half of the registry’s $10 million annual budget goes to research projects. To date, it has funded 19 studies, including research looking into the environmental risk factors of ALS, assessing risk among veterans, and seeking to understand disease risk in Latin Americans.

Behind all the research funding and collaboration among scientists studying ALS lies one primary goal for understanding the devastating disease that is estimated to affect from 12,800 to 19,800 people in the U.S.

“We’re trying to build a case here at the CDC to figure out what causes ALS and the risk factors behind ALS,” Paul Mehta, MD, principal investigator of the National ALS Registry, said in a phone interview with ALS News Today.

Not just a registry

Congress passed the bill that mandated forming the registry under the ATSDR on Sept. 23, 2008. It wasn’t until two years later, in October 2010, that the program was officially launched. With the help of government monitoring systems, Mehta and his team have been consistently adding ALS patients to the registry.

“We’re actually the only agency out there that is looking at the [causes] and the risk factors behind ALS,” Mehta said.

Some neurologists at the time were skeptical of the ability of the registry to get enough data on ALS, given that physicians were not required to report a diagnosis of the disease to the government, according to Hiroshi Mitsumoto, MD, a neurologist at the Eleanor and Lou Gehrig ALS Center at Columbia University in New York City. Things have changed in the nearly 11 years since its inception.

“It’s becoming so important and helping so many studies,” Mitsumoto said. He used the registry to recruit patients for his own ARREST ALS study, with one patient as far away as Alaska. The study, which previously was funded by ATSDR, examined the role of oxidative stress — the generation of highly reactive molecules that can cause damage to cellular structures — in ALS.

“They have biomarkers, they have biorepositories, tissue samples, and just driving important epidemiological studies of ALS. I think this is incredible,” he said.

Interested researchers can fill out forms to request either biospecimens, environmental and/or genetic data from the registry, or assistance with recruiting patients for a clinical or epidemiological study, as Mitsumoto did. The registry has made access to all data free with the exception of a fee for biospecimen shipping.

Data the registry collects, research it funds, and the data it shares with scientists are all going to a greater understanding of the environmental factors that are thought to lead to the disease.

Researchers have yet to find a definite genetic link to sporadic ALS, which affects 90% of the patient population. Adding more data may help unravel the complex interaction between a person’s environment, genetics, and predisposition to ALS.

“I think there’s a lot more unknown than known about ALS,” Mehta said. 

The environment and ALS

However, there are numerous factors that have been linked to a person’s likelihood of developing ALS later in life, including military service, exposure to viruses and cyanobacteria, organic pollutants, pesticides, and traumatic brain injury. Military veterans are twice as likely to develop ALS as those who haven’t served, and one Harvard study funded by the registry is trying to find out if viral infections are to blame.

Eva Feldman, MD, PhD, director of the ALS Center of Excellence at Michigan Medicine, has teamed up with her physician colleague, Stephen Goutman, MD, director of the Pranger ALS Clinic, to see how persistent organic pollutant exposures (POP) might cause the disease in people in Michigan, a state with one of the highest rates of ALS in the country. And one of the tools they use to understand the relationship between POP and disease is the registry.

Goutman is always trying to get his patients to sign up for the registry, even providing iPads in his clinic’s waiting room to streamline the process. He also has worked with Mehta to make the registry’s portal more user-friendly. The registry reduced the number of times a user would have to change their password, for example.

“If we can build the resource and show the need, we can improve funding streams,” Goutman said in a joint Zoom interview with Feldman. “We can really support the need for additional dollars to go to ALS research and why this is such a critical problem.”

The registry, in addition to funding Feldman’s research, also has said it would house any data on ALS if the Michigan state legislature votes to make ALS a reportable disease. Mehta and his team also are helping Elijah Stommel, MD, PhD, a neurologist at the Dartmouth Hitchcock Medical Center, lobby Vermont, where many of his patients are from, to make ALS reportable.

Big data

Mehta estimates that about 70–80% of the registry’s data comes from the Centers for Medicare and Medicaid Services. Data voluntarily inputted by patients via the National Registry portal or received by the U.S. Department of Veterans Affairs make up the remaining share.

The registry is not exhaustive either. Individuals on private insurance are not normally included because personally identifiable information needs to be matched with the entry in the system to avoid duplication. Often, that level of detail will not be found on existing private insurance databases. 

ALS patients who have signed up through the registry have completed a total of 90,000 surveys. Before COVID-19 forced in-home specimen collection to halt on March 17, 2020, the registry reported in its 2020 annual meeting executive summary that there was an average of 20 sample collections per month. Through June 30, 884 in-home blood and urine samples were collected; 202 were saliva only, and 27 were postmortem tissue.

Mehta said the registry has just wrapped up its metro surveillance project, which takes a more granular approach to causes of ALS, not dissimilar to Feldman’s work in Michigan. It focused on areas with a higher proportion of minorities, including states like Texas and Florida, and cities including Detroit, Baltimore, Atlanta, and Los Angeles, for fear they may be left out of the registry. Data was gleaned by asking neurologists for case reports during certain time periods, depending on the location.

“It’s a way for us to look at the epidemiology of ALS at the local level, not the person nationally,” Mehta said.

That surveillance project has led to a number of papers discussing demographic factors and ALS incidence and severity. It did, however, back up data that shows people with ALS are “more likely to be male, white, non-Hispanic and older,” the project’s webpage states.

Mehta said getting closer to figuring out what causes ALS can first help doctors get an accurate diagnosis for a disease, a process that now can take up to a year. When scientists are able to establish stronger links between the environment, genetics, and ALS, they may be able to mitigate the onset of the disease and even develop a treatment, or even a cure, down the road. That’s where the registry comes in.

“It’s essential that we all support it as vigorously as possible because it is what’s going to allow us to better understand the disease, which we have to do to develop treatments,” Feldman said. 

More information about joining the registry is available here.