Genetic ALS:
an overview of
common mutations

For example, the A4V mutation, which is the most frequent variant in North America, gives rise to a fast-progressing form of ALS that typically leads to death within one year from symptom onset. In contrast, the homozygous D90A mutation is associated with an indolent disease course, with patients reaching respiratory failure after 10 or more years of illness.⁸

SOD1-ALS also manifests in a heterogenous manner in different parts of the world. The highest frequencies are reported in patients in Asia, Taiwan, and Japan.⁶

While mutations in the SOD1 gene were the first to be linked to ALS,⁵ they were hardly the last to help researchers in their pursuit of a deeper understanding of this devastating disease.

First identified in 2011, C9orf72 repeat expansion mutations may not have been among the earliest to be associated with ALS, but they are by far the most common. A pathogenic hexanucleotide (G4C2) repeat expansion in the first intron of C9orf72 accounts for approximately 40% of fALS and 7% of sALS cases. The C9orf72 repeat expansion is the only mutation found in more than 2% of patients with sALS.⁵

Three mechanisms have been proposed for how G4C2 hexanucleotide repeat expansion (HRE) in C9orf72 may induce neurodegenerative changes, including loss of C9orf72 function through haploinsufficiency, toxic gain-of-function due to the generation of aberrant HRE-containing RNA, and toxic gain-of-function through the accumulation of dipeptide repeat proteins translated from hexanucleotide repeat RNA.¹³

C9orf72 repeat expansion mutations are transmitted in an autosomal-dominant fashion, with variable and age-dependent penetrance. Studies have estimated cumulative age-dependent penetrance of 0% at age 35, 50% at 58, and almost 100% by 80.⁵

In addition to the upper and lower motor neuron dysfunction common with ALS, C9orf72 repeat expansion mutations have been linked to frontotemporal lobar degeneration that manifests clinically with behavior changes, executive dysfunction, and language impairment.⁵

The frequency of C9orf72 expansion mutations varies greatly by ethnicity and geography, with the highest frequencies reported in northern Europe and the lowest frequencies reported in Asia.⁵

Following C9orf72 and SOD1 mutations, the most common mutations associated with ALS are in the TARDBP and FUS genes. Mutations in these genes are found in approximately 4% of patients with fALS and 1% of patients with sALS. However, researchers have noted that more studies are needed to determine the true frequency of TARDBP mutations among individuals with sALS.^5,12

First linked to ALS in 2008,¹¹ TARDBP mutations have been identified across a diverse group of geographical regions, suggesting that they may be a factor in who develops genetic ALS worldwide. While TARDBP-ALS is most prevalent in Europe, ALS-associated TARDBP mutations have been identified in Japan, Australia, North America, and China.¹²

ALS-associated FUS mutations were first reported in 2009.¹² While the course of disease among FUS-ALS patients is highly variable, patients with these mutations are known to have shorter lifespans than those with other mutations.⁵ A number of FUS mutations have been linked to an earlier onset of genetic ALS, with some patients showing symptoms before the age of 25.¹²

As with TARDBP mutations, FUS mutations have been identified among patients with genetic ALS across geographic regions, including Europe, Australia, North America, Asia, and Africa.¹²

While researchers can’t be certain how many ALS-associated mutations remain to be identified, new technologies have accelerated the pace of discovery in recent years.¹¹

Since 2014, new sequencing technologies—including genome-wide association studies, whole genome studies, and exome sequencing—have led to the discovery of ALS-associated mutations in 7 additional genes: MATR3, CHCHD10, TBK1, TUBA4A, NEK1, C21orf2, and CCNF.¹¹