Rare genetic mutations associated with Parkinson’s disease increase the risk of developing ALS

People with rare genetic mutations linked to Parkinson’s disease have more than three times the risk of developing amyotrophic lateral sclerosis (ALS), a neurodegenerative condition that causes progressive muscle weakness, compared to those without such mutations. This new research, presented at the 149th Annual Meeting of the American Neurological Association, found the strongest association between ALS and mutations related to Parkinson’s. Additionally, rare variants linked to other neurodegenerative diseases were also tied to faster ALS progression and shorter survival times. "While identifying these mutations may not directly change treatment, it can help physicians personalize patient care," said Maurizio Grassano, MD, PhD, lead author of the study and neurologist at the ALS Center at the University of Turin, Italy. ALS, also known as Lou Gehrig's disease, leads to the degeneration of motor neurons, the cells that control muscle movement. The disease usually starts with mild weakness in one part of the body, such as the arms or legs, but eventually worsens, spreading to more areas and leading to paralysis. To better understand the genetic factors contributing to ALS, researchers in Italy analyzed 153 neurodegeneration-associated genes in 791 ALS patients and 757 control participants without the disease. The study excluded patients with known familial ALS mutations. Among the ALS group, 18.3% had at least one significant mutation linked to neurodegenerative disorders, compared to 14.4% of the controls. Some of these mutations had never been previously identified. Novel mutations were found in 11.4% of ALS patients and 6.9% of controls. The research revealed that having a mutation in neurodegeneration-related genes raised the likelihood of developing ALS by 1.3 times, with that risk increasing to 1.8 times for novel or ultra-rare mutations. The strongest link was observed with mutations associated with Parkinson’s disease, which increased the risk of ALS by 3.6 times. Rare Parkinson’s-related mutations were particularly associated with the flail arm phenotype of ALS, a type that primarily affects the arms while sparing the legs, face, and throat muscles. Novel mutations were also linked to significantly shorter survival times in ALS patients. Beyond Parkinson’s, the study also found a heightened risk of ALS in people with genetic mutations linked to peripheral neuropathies, disorders that affect nerves outside the brain and spinal cord. “These findings expand our understanding of the genetic overlap between ALS and other neurodegenerative conditions by focusing on rare genetic variants rather than common ones,” Grassano explained. The researchers noted a shared genetic mechanism between ALS and other conditions like Parkinson’s, pointing out that pathways related to the lysosome—the cellular process responsible for breaking down and recycling materials—are disrupted in both diseases. This suggests that similar pathways may contribute to motor neuron destruction in ALS. In an era of widespread genetic testing, it’s increasingly common to discover gene variants that may not be directly related to a person’s primary diagnosis. This growing knowledge will help guide future research on diagnosing and treating ALS, the researchers concluded. The higher prevalence of neurodegeneration-related mutations in ALS patients suggests that the increased risk of ALS could be driven by a greater chance of carrying mutations associated with other neurodegenerative diseases like Parkinson’s. “These insights will help shape future studies into the diagnosis and treatment of ALS,” Grassano added.