Summary: New research shows that some people with amyotrophic lateral sclerosis (ALS) / motor neuron disease (MND) and frontotemporal dementia (FTD) carry the same rare genetic changes found in other neurodegenerative conditions. These changes are short tandem repeat (STR) expansions, a type of DNA repeat that is already known to cause more than 20 neurodegenerative diseases, including spinocerebellar ataxias and myotonic dystrophy.
The findings point to common genetic risk factors and mechanisms underlying neuronal death across different brain diseases, and they raise the possibility of shared therapeutic approaches in the future.
Key facts:
- Scientists detected rare STR expansions in the genomes of some patients with sporadic (non-inherited) ALS/MND and FTD.
- Nearly 18% of sporadic ALS and FTD patients in the study carried a DNA repeat expansion previously associated with other neurodegenerative disorders.
- The overlap suggests shared pathways of nerve-cell degeneration and opens new avenues for identifying common risk factors and potential treatments that could apply across multiple diseases.
Source: Macquarie University
Overview
Researchers at the Macquarie University MND Research Centre and The Walter and Eliza Hall Institute of Medical Research examined whole-genome data to assess whether STR expansions linked to other neurodegenerative illnesses also occur in patients diagnosed with sporadic ALS/MND and FTD. The study represents one of the most comprehensive examinations to date of disease-associated STRs in these patient groups.
ALS/MND is a progressive, ultimately fatal disorder in which motor neurons — the nerve cells that connect the brain and spinal cord to the muscles — degenerate and die. Loss of these neurons impairs movement, breathing and swallowing. Frontotemporal dementia (FTD) causes selective neuron loss in the frontal and temporal lobes of the brain, producing progressive changes in behavior, personality, language and memory. FTD often affects people under 65 and received recent public attention with the diagnosis of actor Bruce Willis.
Most cases of both diseases occur sporadically: roughly 90% of MND and 60–70% of FTD cases do not show a clear family inheritance pattern. The discovery that a subset of these sporadic cases carry STR expansions known to drive other neurodegenerative conditions suggests a wider role for repeat-mediated mechanisms in neuron loss.
Dr Lyndal Henden, a postdoctoral research fellow at Macquarie University, said the prevalence of these repeat expansions was unexpected. “We detected almost 18% of sporadic ALS and FTD patients carrying a repeat expansion previously thought to be involved in other degenerative conditions,” she explained. “This genetic overlap provides a new path to identify shared risk factors for neuronal death and will influence how we study both disorders going forward.”
Associate Professor Kelly Williams, who led the study, noted that while some overlap with other diseases was anticipated, the extent of shared genetic findings exceeded expectations. “These results indicate common risk factors and mechanisms that drive nerve-cell degeneration, and they suggest the potential for cross-disease therapeutic strategies,” she said. The team emphasizes that uncovering how these repeat expansions contribute to neuron loss is the next critical step.
The paper, published in Science Advances, represents the culmination of a decade of collaborative research and relied on generous patient participation, including biological sample donations from individuals with ALS and FTD at Macquarie University and the University of Sydney.
About this genetics and neurology research news
Author: Georgia Gowing
Source: Macquarie University
Contact: Georgia Gowing – Macquarie University
Image: Image credited to Neuroscience News
Original Research: Open access. “Short tandem repeat expansions in sporadic amyotrophic lateral sclerosis and frontotemporal dementia” by Lyndal Henden et al., published in Science Advances.
Abstract (summary)
Short tandem repeat expansions in sporadic amyotrophic lateral sclerosis and frontotemporal dementia
Pathogenic short tandem repeat (STR) expansions are known to cause more than 20 neurodegenerative diseases. To evaluate the contribution of STRs to sporadic ALS and FTD, the research team applied bioinformatic tools (ExpansionHunter and REviewer) and polymerase chain reaction validation to screen 21 neurodegenerative disease–associated STR loci. The analysis included whole-genome sequencing data from 608 patients with sporadic ALS, 68 patients with sporadic FTD, and 4,703 matched controls.
The group also developed a data-driven outlier detection approach to establish allele thresholds for rare STRs. Excluding expansions in C9orf72, they found that 17.6% of clinically diagnosed ALS and FTD cases carried at least one expanded STR allele previously reported as pathogenic or intermediate for another neurodegenerative disease.
The team identified and validated 162 disease-relevant STR expansions across genes including C9orf72 (ALS/FTD), ATXN1 (SCA1), ATXN2 (SCA2), ATXN8 (SCA8), TBP (SCA17), HTT (Huntington’s disease), DMPK (myotonic dystrophy type 1), CNBP (myotonic dystrophy type 2), and FMR1 (fragile-X disorders).
These results support the notion of clinical and pathological pleiotropy among neurodegenerative disease genes and underscore the significance of STR expansions in the biology of ALS and FTD.