Common Genetic Causes Across Motor Neuron Diseases Identified
Summary
- Scientists from the University of Miami Miller School of Medicine and other institutions compared rare genetic variants found in motor neuron disease patients, identifying overlapping genetic risks that highlight the diseases’ shared origins.
- The investigators, including the Miller School’s Dr. Michael Benatar, 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.
- 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.
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 the University of Miami Miller School of Medicine, including Michael Benatar, M.D., Ph.D., chief of the Miller School’s Neuromuscular Division, and St. Jude Children’s Research Hospital discovered that there are previously unknown, ultrarare gene variants linked to the diseases and significant overlap of contributing genes between the diseases among patients without family histories of a motor neuron disease.
In addition to Dr. Benatar, other study co-authors from the Miller School include:
• Joanne Wuu, Sc.D., research associate professor of neurology and associate director of research at the ALS Center
• Jacob McCauley, Ph.D., a professor in the Dr. John T. Macdonald Foundation Department of Human Genetics and director of the Center for Genome Technology
• Stephan Züchner, M.D., Ph.D., chief genomics officer and professor in the John T. Macdonald Department of Human Genetics
• Volkan Granit, M.D., M.Sc.
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 in Translational Neurodegeneration.
“One of our foundational principles 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 Dr. Benatar, a professor of neurology and public health sciences and the Walter Bradley Chair in ALS Research at the Miller School and executive director of the University of Miami ALS Center. “The work published today underscores the value of this approach.”
Tracking Genetic Variations
While both ALS and HSP cause progressive motor dysfunction, the two disorders 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, Dr. Benatar and colleagues 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
The team leveraged the analysis tool 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 the 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.
“Variants are often dismissed if they are not contextually relevant, such as ALS patients carrying rare variants in HSP genes,” said co-corresponding author Gang Wu, Ph.D., from the St. Jude Department of Pathology. “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.”
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.
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.
The study was supported by the National Institutes of Health (U54NS092091), the National Cancer Institute (P30CA021765), the ALS Association (17-LGCA-331 and 16-TACL-242), the Wellcome Trust (226519/Z/22/Z) and the American Lebanese Syrian Associated Charities (ALSAC), the fundraising and awareness organization of St. Jude.
Tags: ALS, amyotrophic lateral sclerosis, Department of Neurology, Dr. Jacob McCauley, Dr. Joanne Wuu, Dr. John T. Macdonald Foundation Department of Human Genetics, Dr. Michael Benatar, Dr. Stephan Zuchner, genetics, neuromuscular division, neurons