In a more than 20-year study of people with amyotrophic lateral sclerosis (ALS), a research team found that 11 percent of people with a diagnosis of sporadic ALS had mutations in genes associated with the familial form of the disease.
Familial ALS is the result of genetic mutations passed down among family members and currently accounts for 5 to 10 percent of all ALS diagnoses. The majority of ALS diagnoses — 90 to 95 percent — are of the sporadic form of the disease, in which genetic risk factors are minor or unclear and no evidence exists of the disease in any of the affected individual's relatives. (For more, see Putting Labels on Types of ALS.)
However, the distinction between familial and sporadic ALS “appears to be less clear than previously assumed," reports the Italy-based research team, which published its findings online June 21, 2012, in Neurology.
"In a clinical setting, this observation suggests that systematic genetic testing should be performed in patients with sporadic ALS," the researchers wrote. But, they noted, genetic counseling for the families of individuals with sporadic ALS who also have ALS-related genetic mutations is "difficult," due to current limitations in the ability to pinpoint the contributions of various other factors.
Known ALS-associated mutations found in those with sporadic ALS
Between 1987 and 2011, 935 people were admitted to the Neurological Institute, an ALS clinic that serves the Lazio Region in Italy. Approximately 6 percent received a diagnosis of familial ALS and 94 percent of sporadic ALS. DNA samples were collected from 480 of those with sporadic ALS and 48 with familial ALS.
In analyzing the DNA samples, investigators found that 11 percent of those with a sporadic ALS diagnosis (53 people) showed mutations in genes associated with the familial form of the disease: superoxide dismutase 1 (SOD1), tar DNA-binding protein 43 (TARDPB, or TDP43), fused in sarcoma (FUS), angiogenin (ANG), ataxin 2 (ATXN2), optineurin (OPTN) and chromosome 9 open reading frame 72 (C9ORF72).
In these 53 people, investigators found 55 ALS-associated genetic mutations: 10 in SOD1; 13 in TDP43; 12 in C9ORF72; three in FUS; three in OPTN; six in ANG; and eight in ATXN2. One person had both an ANG mutation and an SOD1 mutation; another had both an ANG mutation and the C9ORF72 mutation.
ALS-associated genetic mutations were detected in 21 of the 48 familial ALS DNA samples analyzed. The C9ORF72 mutation was found in nine people; SOD1 mutations in seven; a TDP43 mutation was found in one; and ATXN2 mutations in three. No OPTN or ANG mutations were detected in the familial ALS group.
The possible causes of ALS in the remaining 27 people in the familial ALS group include a mutation in a gene that has not yet been identified and/or one or more nongenetic factors.
Possible 'multiple mutations' model
Genetic testing was performed on unaffected relatives in the families of seven of those with a diagnosis of sporadic ALS and ALS-related mutations, and "the same mutations found in patients were detected in most relatives, including very old individuals [past the average age when ALS symptoms normally appear]," the researchers noted.
In addition, analysis showed that the person carrying mutations in both SOD1 and ANG had a more severe course of the disease than is typical in SOD1-related ALS, and the individual with mutations in both C9ORF72 and ANG was the youngest in the group with C9ORF72 mutations (with onset at 38 years).
These findings, the researchers suggested, lend support to the "multiple mutations" hypothesis, in which each identified mutation represents one in a number of contributing factors.
Another possibility is that ANG may act as a modifier gene, exerting influence over the course of ALS that is caused by a mutation in another gene. ANG also could modify the penetrance of other ALS-related genes. (Penetrance is the percentage of individuals with a particular mutation who exhibit associated clinical symptoms — for example, if a gene responsible for ALS has 90 percent penetrance, then 90 percent of people who have the mutation will develop the disease.)
Different mutations equal different disease courses
In the group with sporadic ALS, no significant differences were noted in age of onset, site of onset and survival (as measured from disease onset to death) between those with mutations in known ALS-associated genes and those without any identifiable mutations.
However, a separate evaluation detected clinical differences that corresponded to particular mutations (known as a genotype-phenotype correlation).
Implications for genetic testing and counseling
The research team noted that the discovery of new genes associated with familial ALS "invariably" is followed by the identification of mutations in the same genes in people who have an apparently sporadic form of the disease.
It follows that, as additional familial ALS genes are identified, there will be a significant corresponding increase in the proportion of sporadic ALS that stems, in part or in whole, from a known genetic cause.
The data suggest that variants in the genes that cause familial ALS ultimately may affect a person’s risk of developing sporadic ALS, but further studies are needed for confirmation.
The findings have implications for research and for patient care, as they underscore the possible benefits of genetic testing in sporadic ALS and the complications associated with genetic counseling for the affected individual and family members.
For more on the team’s research, see Contribution of Major Amyotrophic Lateral Sclerosis Genes to the Etiology of Sporadic Disease.