A study carried out by the University of Malta shows that patients with the fatal neurological condition amyotrophic lateral sclerosis have different causative mutations to patients from Northern Europe.
“The DNA results caught us by surprise. The most frequently mutated amyotrophic lateral sclerosis (ALS) genes were flawless in Maltese patients,” said the study’s lead researcher Ruben Cauchi, Ph.D., a senior lecturer at the University.
Instead, some of the 24 patients included in the study had mutations in genes occasionally associated with ALS including ATXN2, DAO, DCTN1, and ERBB4, among others.
As reported in the European Journal of Human Genetics, three of the 24 cases were familial and 21 were sporadic, with no known family history of the disease. Of the mutations seen in the sporadic cases, 40% were in genes with a previous link to ALS, whereas 60% were not. Only one of the familial cases had a mutation in a known ALS-associated gene.
Although Malta is part of Europe it is geographically and culturally isolated island population of just over 500,000 individuals, which makes it ideal for genetic biobanking studies. The Malta Biobank was set up at the university on the island in 1989 and now contains more than 100,000 samples.
Around 4 years ago, a national ALS registry was set up on the island to collect samples and data about those diagnosed with the condition to help scientists understand the condition better and help contribute to global research studies.
ALS is a rapid neurodegenerative condition with a strong genetic component, which currently has no cure. An effective treatment has proved difficult to develop, with many clinical trials failing over the last 10-15 years. However, research continues with the hope of finding a treatment or cure.
This study, which was carried out in collaboration with the University Medical Centre Utrecht in The Netherlands, sought to discover whether Maltese ALS patients had similar genetics and phenotypic characteristics to patients with the condition from elsewhere.
The researchers found that none of the Maltese patients had mutations in the genes C9orf72, SOD1, TARDBP and FUS, where the most common mutations associated with ALS are located, particularly in patients from a Northern European background. This agrees with other studies of Southern European countries, where rates of these mutations are also lower.
“This finding confirms the presence of a North–South gradient in the frequency of mutations within these genes across Europe,” write the authors.
As with other populations, almost twice as many men were affected by ALS than women on Malta, although the women who were affected were diagnosed about 5 years earlier than the men at an average age of 59.5 years compared with 64 years. The overall incidence of 2-3 cases per 100,000 people was similar on Malta to elsewhere.
More familial cases of ALS (12.5%) were seen on Malta compared with elsewhere. Normally only 5-10% of cases are familial and 90-95% sporadic.
“Our results underscore the unique genetics of the Maltese population, shaped by centuries of relative isolation. We also established that genetic factors play a significant role in causing ALS in Malta,” noted Cauchi.
The researchers now plan to search for the disease triggers in the patients in the study who did not have mutations in known ALS-related genes.
“Our ‘preliminary’ data excludes the possibility that these patients have deleterious variants in a set of genes associated with other motor neuron disorders including hereditary ataxias, and hereditary motor and sensory neuropathies,” writes the team.