Study Reveals Shared Genetic Roots Between ALS and Hereditary Spastic Paraplegia

Motor neuron diseases, such as amyotrophic lateral sclerosis (ALS) and hereditary spastic paraplegia (HSP), share physical similarities but have been largely viewed as genetically distinct. However, an analysis led by investigators from St. Jude Children's Research Hospital and the University of Miami Miller School of Medicine discovered that there are previously unknown ultrarare gene variants (genetic changes found in extremely few individuals) linked to the diseases, and significant overlap of contributing genes between the diseases among patients without family histories of a motor neuron disease. This new appreciation of the shared genetic origins of different motor neuron diseases is critical to deciphering the origins of these disorders and ultimately developing meaningful therapeutics. The findings were published today in Translational Neurodegeneration.  

While both ALS and HSP cause progressive motor dysfunction, the two disorders also have distinct characteristics. Weakness in ALS may begin in the arms, legs, head or neck. HSP, by contrast, begins in the legs. The causative, or "canonical" genes for these diseases are also largely distinct. However, the researchers hypothesized that motor neuron diseases might share more genetic similarities than had previously been appreciated. Using a tool that tracks genetic variations, the investigators identified 423 unique disease-causing variants across 222 ALS and 134 HSP patients. Of those, many HSP–linked gene modifications were found in non-familial ALS patients, and vice versa.   

Ultrarare Variants Increase Risk of ALS and HSP  

Variants are often dismissed if they are not contextually relevant, such as ALS patients carrying rare variants in HSP genes. 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."  

Gang Wu, PhD, first and co-corresponding author, St. Jude Department of Pathology associate member and Center for Applied Bioinformatics director

The team leveraged an analysis tool developed at St. Jude called CoCoRV to evaluate the enrichment of ultrarare variants contributing to ALS and HSP, compared with healthy controls. The study represented typical patients from multiple centers from United States, Europe and South Africa participating in the Clinical Research in ALS and Related Disorders for Therapeutic Development (CReATe) Consortium's Phenotype-Genotype-Biomarker study.  

The researchers found significant overlap in the burden of ultrarare variants between ALS and HSP, including genetic variants newly identified to contribute to disease risk for both conditions. This included the canonical HSP gene AP4S1, which was found to be significantly enriched in ultrarare variants in ALS patients with European ancestry.  

"One of the foundational principles underlying establishment of the CReATe Consortium was the idea that we should study multiple related disorders, with the expectation that we could leverage knowledge from one, to understand another," said co-corresponding author Michael Benatar, MD, PhD, in the Department of Neurology at the University of Miami Miller School of Medicine. "The work published today underscores the value of this approach"   

The study calls for more investigation into motor neuron disease-associated genes in an unbiased fashion, along with an open-minded approach to interpreting genetic mutations linked to specific diseases. This will ultimately help clinicians provide more personalized care for patients.  

"Extensive progress has been made over the past decade to decode the genetic landscape of motor neuron diseases such as ALS and HSP," said co-author J. Paul Taylor, MD, PhD, St. Jude Executive Vice President, Scientific Director, and Department of Cell and Molecular Biology chair. "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."