More Than Half of ALS Cases Have a Genetic Cause; Women Have Greatest Risk of Developing the Disease, Irish Study Suggests

More than 50% of the cases of amyotrophic lateral sclerosis (ALS) disease are linked with a genetic cause, and first-degree relatives of an ALS member — especially daughters of ALS mothers — show the highest risk to inherit it, according to an Irish population-based study.

The study “Lifetime Risk and Heritability of Amyotrophic Lateral Sclerosis” was published in the journal JAMA Neurology.

Familial ALS is linked with more than 30 genetic mutations in four genes — superoxide dismutase 1 (SOD1), the TAR DNA Binding Protein-43 (TARDBP), Fused in Sarcoma (FUS) , and Chromosome 9 Open Reading Frame 72 (C9ORF72) — accounting for 55% of the familial cases of ALS in Europe.

Despite being a disease with known complex origin, disease heritability is still unclear. Heritability refers to the “proportion of variance in the risk of developing a condition that is explained by genetic factors,” the researchers wrote.

Researchers set out to determine the extent of ALS heritability and how sex affects disease transmission. The team explored parent-offspring disease incidence using the Irish ALS Register. The database includes diagnosed ALS patients in Ireland who have been followed for more than 25 years.

In total, the Irish ALS Register includes 2,128 ALS patients, registered from January 1995 to December 2017. Researchers focused their analysis on the period from Jan. 1, 2008 to Dec. 31, 2017, and included 1,117 of the 1,123 registered cases of ALS. Of these, 32 had parents with ALS. Twenty-three patients underwent testing for mutations in the C9orf72 gene, and 14 tested positive.

The analysis revealed that the offspring of ALS parents develop the disease earlier — mean age 52 years compared to their parents, who developed ALS at an average of 69.6 years. Moreover, the risk of developing ALS was higher in first-degree relatives of individuals with ALS (1.4%) compared to the general population (0.3%).

Moreover, researchers observed that 52.3% of the ALS cases had a genetic basis, compared to 36.9% of those with no known genetic risk.

They noted that the risk of ALS was higher among women whose mothers had ALS, estimated at 66.2%, and lowest for women whose fathers were affected (34.3%). Among the C9orf72-negative patients, the highest risk of developing ALS also was for mother-daughter pairs, at 48.5%.

Overall, the study showed that 50% of ALS cases had a genetic influence, but in the absence of known genetic mutations in parents, their offspring “remain at increased risk of developing ALS compared with the general population,” the researchers wrote.

The higher risk found among mothers and daughters suggests a sex influence on ALS genetics.