Researchers have identified significant genetic connections between motor neuron diseases, revealing that conditions such as amyotrophic lateral sclerosis (ALS) and hereditary spastic paraplegia (HSP) may share underlying genetic factors. This discovery, led by a team from St. Jude Children’s Research Hospital and the University of Miami Miller School of Medicine, highlights previously unknown ultrarare gene variants linked to these disorders. The findings were published on October 29, 2025, in the journal Translational Neurodegeneration.
Motor neuron diseases like ALS and HSP exhibit both similarities and differences. While both lead to progressive motor dysfunction, ALS symptoms may manifest in the arms, legs, head, or neck, whereas HSP typically begins in the legs. Traditionally, the genetic causes of these diseases have been viewed as distinct. However, the research team posited that there might be more genetic overlap than previously recognized.
Research Methodology and Findings
Utilizing an advanced genetic analysis tool known as CoCoRV, the researchers examined genetic variations in a large cohort. They analyzed data from 222 ALS patients and 134 HSP patients, discovering a total of 423 unique disease-causing variants. Notably, many gene modifications associated with HSP were also identified in patients with sporadic ALS, and vice versa, suggesting a complex interplay of genetic factors.
“Variants are often dismissed if they are not contextually relevant, such as ALS patients carrying rare variants in HSP genes,” said Gang Wu, PhD, the first author and co-corresponding author of the study. “But by analyzing a large dataset with multiple related motor neuron disorders, we found that genes associated with HSP could also increase risk for sporadic ALS.”
This cross-disease analysis revealed a significant overlap in the prevalence of ultrarare variants between ALS and HSP. Among these, the canonical HSP gene AP4S1 was notably enriched in ultrarare variants within ALS patients of European ancestry, underscoring the genetic links between these conditions.
Implications for Future Research and Treatment
The findings of this study call for a broader investigation into the genetic underpinnings of motor neuron diseases. The researchers emphasize the importance of considering genetic mutations across related disorders to enhance personalized patient care. Michael Benatar, MD, PhD, a co-corresponding author, remarked, “The work published today underscores the value of this approach.”
J. Paul Taylor, MD, PhD, who also contributed to the study, noted the progress made in understanding the genetic landscape of motor neuron diseases over the past decade. He expressed optimism about future advancements in diagnosis and treatment, stating, “This study furthers that cause by showing the overlapping contributions of canonically distinct genes, offering a clear path forward to more accurate diagnosis and care.”
The collaborative effort involved numerous institutions across the United States, Europe, and South Africa, emphasizing the global commitment to understanding these debilitating diseases. Funding for this research was provided by the National Institutes of Health, the National Cancer Institute, the ALS Association, and several other organizations.
As researchers continue to explore the genetic complexities of motor neuron diseases, this study represents a significant step towards unraveling their origins and developing effective treatments for those affected by these conditions.
For further details, contact: Michael Sheffield, St. Jude Media Relations, at (901) 595-0221 or email [email protected].
