UPDATE: A groundbreaking study just announced by researchers from St. Jude Children’s Research Hospital and the University of Miami Miller School of Medicine reveals a significant genetic overlap between motor neuron diseases like amyotrophic lateral sclerosis (ALS) and hereditary spastic paraplegia (HSP). This urgent discovery could reshape our understanding of these debilitating conditions.
Published today, October 29, 2025, in Translational Neurodegeneration, the study identifies 423 unique disease-causing variants across 222 ALS and 134 HSP patients. Notably, many gene modifications linked to HSP were also found in non-familial ALS patients, suggesting a shared genetic foundation that was largely overlooked until now.
This research is critical because it challenges the long-held belief that ALS and HSP are genetically distinct. “Variants are often dismissed if they are not contextually relevant,” said Gang Wu, PhD, the study’s first author. “But analyzing a large dataset of related disorders reveals that genes associated with HSP can also increase the risk for sporadic ALS.”
Using an innovative analysis tool called CoCoRV, the research team assessed the burden of ultrarare genetic variants contributing to ALS and HSP compared to healthy controls. The findings underscore the potential for a new understanding that could lead to advanced therapies for both conditions.
Each year, thousands are diagnosed with ALS, a progressive disease that leads to muscle weakness and paralysis. HSP, while also causing motor dysfunction, typically begins in the legs. The overlap in genetic variants suggests that treatments could potentially be developed to target both diseases simultaneously.
“The work published today underscores the value of studying multiple related disorders,” stated Michael Benatar, MD, PhD, co-corresponding author. “Leverage knowledge from one disorder to understand another will pave the way for more personalized care.”
Among the newly identified genetic variants is the HSP gene AP4S1, which was found to be significantly enriched in ALS patients of European ancestry. This finding could lead to new diagnostic criteria and treatments that take into account the shared genetic risks of these diseases.
The researchers are calling for further investigation into the genetics of motor neuron diseases in an unbiased manner. As noted by J. Paul Taylor, MD, PhD, co-author and Executive Vice President at St. Jude, “This study furthers our understanding by showing overlapping contributions of canonically distinct genes.”
With this urgent update, the medical community is encouraged to rethink how genetic mutations linked to ALS and HSP are interpreted, ultimately enhancing patient care and treatment outcomes. The implications of these findings extend not only to those currently living with these diseases but also to future patients facing similar challenges.
As research progresses, stay tuned for more updates on the advancements in the understanding and treatment of motor neuron diseases that could change lives worldwide.
