Home / Developments in genetic ALS research
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Accelerating the pace of genetic discovery
The race to understand “genetic ALS” began before anyone even called it by that name—in 1993—when mutations in the SOD1 gene were first established as a genetic component of the disease.1 The pace of discovery has accelerated since then.
To date, mutations in more than 25 genes have been associated with ALS.2 And while there is no telling just how many ALS-associated mutations remain to be discovered,3 advances in the way researchers make those discoveries have accelerated progress in recent years.2
Since 2014, new sequencing techniques including genome-wide association studies, whole genome studies, and exome sequencing have led to the discovery of ALS-associated mutations in 7 genes: MATR3, CHCHD10, TBK1, TUBA4A, NEK1, C21orf2, and CCNF.2 It was in 2017 that the largest-ever analysis of whole-exome sequencing data in China revealed that mutations in the NEK1 gene were associated with ALS there, a finding that came soon after the discovery of NEK1 as a risk gene in Europe.4
ALS gene frequencies
Adapted from Alsultan et al.
Since 2016, new sequencing techniques have led to the discovery of ALS-associated mutations in three additional genes: NEK1, C21orf2, and CCNF.2
Researchers have also integrated additional techniques to sequencing to identify genetic causes of disease in patients with seemingly sporadic ALS (sALS) patients. In 2020, researchers employed identity-by-descent analysis to examine data from 83 familial ALS (fALS) patients and three sALS patients from Australia. Through their analysis, the researchers were able to identify a genetic link between sALS and fALS cases via shared ancestral haplotypes.6
Prof. Steve Vucic
Prof. Steve Vucic
Professor of Medicine at the University of Sydney Westmead Clinical School
Prof. Vucic, of the University of Sydney Westmead Clinical School, conducts research involving the widely held multi-step theory of ALS, in which it is posited that genetic mutations combine with other factors, such as epigenetic changes and environmental triggers, to bring about disease onset.7
In Prof. Vucic’s view, genetic testing of all patients with or at risk for ALS could help neurologists achieve a deeper understanding of the genetic components of the disease.
Prof. Matthew Kiernan
Prof. Matthew Kiernan
Bushell Chair of Neurology at the University of Sydney and Co-Director of Discovery and Translation at the Brain and Mind Centre
Prof. Kiernan has focused his research on the possible connections between genetic ALS mutations and cortical hyperexcitability.
Prof. Kiernan and his team have discovered that the presence of a genetic ALS mutation can presage the development of cortical hyperexcitability, which, in turn, is often followed months later by the onset of ALS symptoms.8,9
His research on cortical hyperexcitability as a potential biomarker for genetic ALS dovetails with a 2019 study from the United States examining levels of phosphorylated neurofilament heavy protein (pNfH) in the blood and cerebrospinal fluid of individuals with, or at risk for, ALS. Among those with repeat expansion mutations in SOD1, FUS, and C9orf72, elevated pNfH levels preceded disease onset by anywhere from 6 months to 3.5 years.10
Researchers believe that confirming biomarkers such as these may hold promise for the early diagnosis of genetic ALS—a disease which is often diagnosed far too late.11
Prof. Orla Hardiman
Prof. Orla Hardiman
Professor of Neurology/Head of Academic Clinical Medicine & Trinity Inst. of Neurosciences
In Ireland, Prof. Orla Hardiman and her team at Trinity College Dublin have focused on the heritability of genetic ALS.
By studying Irish patients and their children, Prof. Hardiman and her team made fascinating discoveries about the frequency with which genetic ALS develops among at-risk individuals in their country—including what appeared to be an increased likelihood of heritability among mothers and daughters compared with other familial pairings.12
Genetic testing algorithm
Prof. Philippe Corcia of the Centre LSA in Tours, France—and one of the world’s leading proponents of genetic testing as a consideration for all patients living with ALS—has even gone so far as to propose a genetic testing algorithm to assist neurologists as demand increases.20
Prof. Philippe Corcia's potential genetic testing algorithm20
Adapted from Corcia et al.
