Significant overlap in ultrarare variant burden was found between ALS and hereditary spastic paraplegia (HSP), with several HSP-linked gene modifications also present in non-familial ALS patients, indicating cross-disease genetic risk.

Researchers advocate studying multiple related motor neuron disorders together to improve understanding and clinical care, calling for unbiased exploration of motor neuron disease–associated genes and open interpretation of genetic mutations.

The findings support more accurate diagnosis and personalized management for patients and encourage a broader view of genetic contributions across motor neuron diseases.

Key researchers include Gang Wu and Michael Benatar, with contributions from St. Jude, the University of Miami, Mayo Clinic, and other institutions.

Funding came from NIH, NCI, ALS Association, Wellcome Trust, and ALSAC, with support across institutions including St. Jude and Mayo Clinic.

The study incorporated multi-center data from the U.S., Europe, and South Africa as part of the CReATe Consortium’s Phenotype-Genotype-Biomarker study, illustrating a cross-disease, international approach.

Using CoCoRV, the study evaluated ultrarare variant enrichment against healthy controls while leveraging CReATe data from diverse centers to support cross-disease insights.

Researchers from St. Jude and the University of Miami identified ultrarare gene variants contributing to multiple motor neuron diseases, including ALS and HSP.

An analysis of 423 disease-causing variants across 222 ALS and 134 HSP patients used CoCoRV to assess enrichment of ultrarare variants versus healthy controls.

Co-corresponding author Gang Wu and co-author Michael Benatar push for unbiased, open-minded interpretation of genetic mutations linked to specific diseases to advance therapeutics.

The analysis used the CoCoRV tool to assess ultrarare variant enrichment and drew on data from the CReATe Consortium’s Phenotype-Genotype-Biomarker study across centers in the U.S., Europe, and South Africa.

The Translational Neurodegeneration publication highlights how cross-disease insights can inform therapeutic development and diagnostic strategies.

The study was published in Translational Neurodegeneration on October 29, 2025, supported by NIH, NCI, ALS Association, Wellcome Trust, and ALSAC.