Rare genetic mutations linked to Parkinson’s raise risk of ALS
Mutations also tied to faster ALS progression, shorter survival times
People with rare genetic mutations associated with Parkinson’s disease have a more than three times greater risk of developing amyotrophic lateral sclerosis (ALS), a neurodegenerative disorder that leads to progressive muscle weakness, than do those without the genetic variants.
That’s according to new research, presented at the 149th Annual Meeting of the American Neurological Association, that showed that the strongest link between neurodegeneration-related mutations and ALS was with Parkinson’s disease.
Further, having these rare genetic mutations, as well as rare variants linked to other neurodegenerative diseases, was also significantly associated with shorter survival times and faster ALS progression.
“Although identifying these variants may not change treatment, the knowledge can help physicians personalize management of those patients,” Maurizio Grassano, MD, PhD, the study’s lead author and a neurologist at the ALS Center at the University of Turin in Italy, said in a press release.
Risk of ALS was highest for patients with novel gene mutations
ALS, also known as Lou Gehrig’s disease, is characterized by damage to motor neurons, the specialized cells that control muscle movements.
The disease is progressive, normally beginning as mild muscle weakness that affects one body part — typically impacting the functioning of the legs or arms. Eventually, muscle weakness becomes more severe and affects more of the body; it also may develop into paralysis.
To learn more about the mutations underlying the disease, a team of researchers in Italy performed a genetic panel test for 153 neurodegeneration-associated genes. Their study, “Crossing Paths: The Influence of Neurodegeneration-Related Variants on ALS Risk and Phenotype,” involved 791 people with ALS and 757 individuals without the disease, who served as controls. The researchers excluded people with familial ALS whose disease was caused by known ALS mutations.
Among the ALS patients tested, 145 (18.3%) had at least one high-impact mutation in genes related to neurodegenerative disorders. In contrast, 107 (14.4%) of the controls had similar mutations.
Some of these mutations had never been described. In the ALS group, 90 patients (11.4%) carried novel mutations, while among controls, 51 patients (6.9%) had previously undiscovered mutations.
The researchers determined that having a mutation in a neurodegeneration-related gene led to a 1.3 times greater risk of developing ALS. If the mutation was novel or ultra-rare, that risk increased to 1.8 times.
The strongest link between mutations related to neurodegeneration and ALS was with Parkinson’s disease, the results showed. People with genes associated with Parkinson’s had a 3.6 times greater risk of developing ALS.
Rare mutations in Parkinson’s-related genes were associated with a type of ALS known as the flail arm phenotype. That means the disorder affects mainly the arms with fewer symptoms related to the legs, face, or throat muscles.
Novel mutations also were associated with significantly shorter survival times, the data showed.
Researchers find overlap of rare genetic mutations between ALS, Parkinson’s
Beyond Parkinson’s disease, the researchers also found an increased risk of ALS in patients with genetic mutations related to peripheral neuropathies — conditions in which nerves outside the brain and spinal cord are damaged.
“Our findings broaden the understanding of the genetic overlap between ALS and these other disorders by focusing on rare variants instead of common genetic factors,” Grassano said.
In the presentation abstract, the researchers suggested there may be a shared biological link between ALS and other conditions, such as Parkinson’s.
“Importantly, we observed an overlap of rare genetic variants between ALS and other neurodegenerative diseases, shedding light on shared underlying mechanisms,” the team wrote.
For example, in Parkinson’s, the lysosomal pathway — processes related to breaking down and recycling of materials within the cell — are disrupted. This research suggests that a similar pathway may play an important role in the destruction of motor neurons in ALS patients.
In this era of extensive genetic testing, it has become increasingly likely that variants in genes will be detected that are not directly linked to the primary diagnosis. … These insights will help inform future research on diagnosing and treating [ALS].
Overall, the higher percentage of neurodegeneration-related genes among ALS patients suggests that the increased risk of developing that condition may be due to the greater likelihood of having mutations associated with other neurodegenerative diseases, like Parkinson’s.
“In this era of extensive genetic testing, it has become increasingly likely that variants in genes will be detected that are not directly linked to the primary diagnosis,” Grassano said. “These insights will help inform future research on diagnosing and treating [ALS].”
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