Summary: Some patients with ALS/motor neuron disease (MND) and frontotemporal dementia (FTD) carry the same rare genetic defects that cause other neurodegenerative diseases. These defects, known as short tandem repeat expansions, are the cause of more than 20 neurodegenerative diseases including spinocerebellar ataxias and myotonic dystrophy.
The study suggests a shared risk factor and mechanism that cause nerves to die in different neurodegenerative diseases, which may lead to shared therapeutic strategies in the future.
Researchers identified rare genetic defects in the genomes of some people with non-inherited, or sporadic, ALS/motor neuron disease (MND) and frontotemporal dementia (FTD).
The study found that almost 18% of sporadic ALS and FTD patients carried a DNA repeat expansion thought to be involved in other degenerative diseases.
The discovery suggests shared risk factors and shared mechanisms that cause nerves to die, opening up new opportunities to uncover common risk factors for neuron death and shared therapeutic strategies.
Source: Macquarie University
New research has discovered that some patients with ALS/motor neuron disease (MND) and frontotemporal dementia (FTD) carry the same rare genetic defects that cause other neurodegenerative diseases.
Researchers from the Macquarie University MND Research Centre and The Walter and Eliza Hall Institute of Medical Research have identified the defects in the genomes of some people with non-inherited, or sporadic, ALS and FTD.
ALS/MND results in the death of the neurons, or motor nerves, connecting the brain and spinal cord to the muscles. These are the cells that control our ability to move, breathe and swallow. The disease is progressive and eventually fatal.
FTD also causes the death of neurons in part of the brain, resulting in a range of progressive symptoms such as memory loss, unusual behavior, personality changes and communication problems. It is the same form of dementia with which actor Bruce Willis was recently diagnosed, and unlike older-onset dementia, it tends to affect people under 65.
The majority of cases in both diseases – about 90 percent in the case of MND and 60-70 percent in FTD – are sporadic, with the rest occurring in families.
These gene defects, known as short tandem repeat expansions, are the cause of more than 20 neurodegenerative diseases including spinocerebellar ataxias and myotonic dystrophy. This Australian study has been the most comprehensive assessment of these gene defects in ALS and FTD patients worldwide.
Macquarie University Postdoctoral Research Fellow Dr Lyndal Henden says the findings were a surprise.
“We found almost 18 percent of sporadic ALS and FTD patients carried a DNA repeat expansion thought to be involved in other degenerative diseases,” she says.
“Finding this genetic connection between ALS and FTD offers a fresh opportunity to uncover common risk factors for neuron death, and it will have implications for understanding both diseases.”
Macquarie University Associate Professor Kelly Williams directed the study, and says the team suspected there could be some overlap with other diseases, but not to such an extent.
“This suggests shared risk factors among these diseases, shared mechanisms that cause nerves to die – and perhaps shared therapeutic strategies in the future,” she says.
“While the causes of sporadic ALS and FTD remain unknown, this is an important step in a long-term effort to identify the risk factors for developing one of these diseases.”
Work can now begin to understand how these shared repeat expansions contribute to neuron death.
The study, published in the latest edition of the journal Science Advances, is the culmination of 10 years of research that could not have been possible without the cooperation of patients with ALS and FTD, who have donated biological samples for DNA at both Macquarie University and the University of Sydney.
Short tandem repeat expansions in sporadic amyotrophic lateral sclerosis and frontotemporal dementia
Pathogenic short tandem repeat (STR) expansions cause over 20 neurodegenerative diseases. To determine the contribution of STRs in sporadic amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), we used ExpansionHunter, REviewer, and polymerase chain reaction validation to assess 21 neurodegenerative disease-associated STRs in whole-genome sequencing data from 608 patients with sporadic ALS, 68 patients with sporadic FTD, and 4703 matched controls.
We also propose a data-derived outlier detection method for defining allele thresholds in rare STRs. Excluding C9orf72 repeat expansions, 17.6% of clinically diagnosed ALS and FTD cases had at least one expanded STR allele reported to be pathogenic or intermediate for another neurodegenerative disease.
We identified and validated 162 disease-relevant STR expansions in C9orf72 (ALS/FTD), ATXN1 [spinal cerebellar ataxia type 1 (SCA1)], ATXN2 (SCA2), ATXN8 (SCA8), TBP (SCA17), HTT (Huntington’s disease), DMPK [myotonic dystrophy type 1 (DM1)], CNBP (DM2), and FMR1 (fragile-X disorders).
Our findings suggest clinical and pathological pleiotropy of neurodegenerative disease genes and highlight their importance in ALS and FTD.