UPDATE: Groundbreaking research has just revealed critical genetic links between motor neuron diseases, including amyotrophic lateral sclerosis (ALS) and hereditary spastic paraplegia (HSP). A team from St. Jude Children’s Research Hospital and the University of Miami Miller School of Medicine announced today, October 29, 2025, that they have identified previously unknown ultrarare gene variants shared across these conditions, challenging the long-held belief that they are genetically distinct.
This urgent discovery is vital for the millions affected by these debilitating diseases, as it opens new avenues for understanding their origins and developing effective treatments. The study published in Translational Neurodegeneration highlights that many genetic variants previously thought to be exclusive to either ALS or HSP are, in fact, present in both conditions.
The researchers analyzed data from 222 ALS and 134 HSP patients, uncovering 423 unique disease-causing variants. Significantly, they found that gene modifications linked to HSP were also present in ALS patients without family histories of the disease, and vice versa. This overlap suggests that ultrarare genetic variants may increase the risk for both conditions, potentially reshaping how clinicians approach diagnosis and treatment.
Dr. Gang Wu, a lead author from St. Jude, explained, “Variants are often dismissed if they are not contextually relevant, such as ALS patients carrying rare variants in HSP genes. However, our analysis shows that genes associated with HSP can also elevate the risk for sporadic ALS.” This insight is critical for providing personalized care to patients suffering from these conditions.
The team employed an advanced analysis tool known as CoCoRV to evaluate the frequency of these ultrarare variants in ALS and HSP patients compared to healthy controls. Their research involved typical patients from multiple centers across the United States, Europe, and South Africa, contributing to the Clinical Research in ALS and Related Disorders for Therapeutic Development (CReATe) Consortium’s Phenotype-Genotype-Biomarker study.
Among the significant findings, the canonical HSP gene AP4S1 was notably enriched in ALS patients of European ancestry, emphasizing the intertwined nature of these diseases. Co-author Dr. Michael Benatar from the University of Miami commented, “This work underscores the value of studying multiple related disorders to leverage knowledge from one to understand another.”
The study advocates for further investigations into the genetic underpinnings of motor neuron diseases, calling for an unbiased approach to interpreting genetic mutations. This research could lead to a more precise diagnosis and tailored therapies for patients suffering from ALS and HSP.
Dr. J. Paul Taylor, another author from St. Jude, noted, “Extensive progress has been made over the past decade to decode the genetic landscape of motor neuron diseases. This study furthers that cause by showing the overlapping contributions of canonically distinct genes.”
As these findings unfold, the medical community is urged to reconsider the genetic factors involved in motor neuron diseases, potentially transforming the landscape of treatment and improving outcomes for patients worldwide.
Stay tuned for more updates on this developing story as researchers continue to explore the implications of this significant breakthrough.
