Among patients with familial ALS, the mutation occurred in 38% of 141 Italian cases (including 57% in 21 Sardinian cases) and in 22% of 41 German cases (Brain 2012;135:784-93).
Mayo Clinic researchers detected the mutation in 7% of 229 ALS patients and in 24% of 34 patients with familial ALS, parkinsonism, or dementia. Only 4% of sporadic ALS cases had the mutation. Among patients with a clinical phenotype of FTD and ALS, the prevalence of the mutation was 22%, but it approached 50% among those with a positive family history (Brain 2012;135:765-83).
Another study that will be reported April 25 at the annual meeting of the American Academy of Neurology focused on 1,488 patients (1,082 with FTD, 328 with ALS, and 78 with both) in the European Early-Onset Dementia consortium. In patients with a family history of dementia or ALS, the relative contribution of C9ORF72 was 10% in the FTD patients, 42% in the ALS patients, and 48% in the FTD-ALS patients.
"All of these statistics mean that this hexameric repeat is fairly common amongst those with familial FTD or ALS, or especially FTD with ALS," according to Dr. Schulz. But familial FTD was present in only 40% of those with FTD, and familial ALS was present in only 5% of ALS patients, he noted.
"This means that most sporadic FTD, ALS, or FTD-ALS patients are not accounted for. In sporadic FTD, which is more common than familial FTD, then the rate of C9ORF72 mutations appears to be between 2% and 5%," Dr. Schulz said.
Effect of Other FTD/ALS Mutations
The new C9ORF72 expansion joins two other mutations found in patients with FTD and/or ALS, namely those affecting the genes for microtubulin-associated protein tau (MAPT) and progranulin (GRN). In a commentary on the studies featured in Brain, Dr. John Hodges of Neuroscience Research Australia and the University of New South Wales in Sydney, NSW, Australia, noted that the results of the London-based group (Brain 2012;135:736-50) provide some insight into how likely it is that a patient would have a C9ORF72 mutation and whether this likelihood could be predicted based upon family history and clinical features.
The researchers found that the prevalences of the three mutations were roughly equal in their sample. They also found – based on their Goldman scoring method for quantifying family history – that 88% of patients with a score of 1 (representing an autosomal dominant family history of FTD or ALS) had a mutation in one of those three genes.
However, the Mayo Clinic samples suggest that the C9ORF72 mutation is the most common FTD mutation, present in one-third of people with a family history.
Links Between FTD and ALS
The C9ORF72 mutation may also provide some insight on the links between FTD and ALS. In all cohorts, the prevalence of C9ORF72 was highest in those with FTD/ALS at 20%-40%, and approached 50% among FTD/ALS cases with a positive family history. Dr. Brad Dickerson, director of the frontotemporal dementia unit and laboratory of neuroimaging at Massachusetts General Hospital in Boston, Mass., said that linking FTD and ALS through this gene was especially important because it would likely lead to research that sheds light on what causes cells in different parts of the brain to be vulnerable in both of these diseases.
"This once again underscores the value that studying one neurodegenerative disease can have for other neurodegenerative disease," he said. "In the case of this gene, advances in understanding its role in FTD will have direct implications for understanding its role in ALS, and vice versa."
Dr. Marsel Mesulam
Dr. Marsel Mesulam, director of the cognitive neurology and Alzheimer’s disease center at Northwestern University in Chicago, said that "exactly how the hopes raised by the C9ORF72 finding will be realized is currently unclear, since we do not yet fully understand the function of C9ORF72." He added that the discovery also generates new puzzles. "Why does the same type of mutation cause ALS in some patients, behavioral FTD in others, and PPA [primary progressive aphasia] in still others?"
Behavioral Variant FTD Most Common
The behavioral variant of FTD was the most common clinical phenotype associated with the C9ORF72 expansion, and was often accompanied by features of ALS as the disease progressed.
Some studies showed that patients with the C9ORF72 mutation also presented with progressive nonfluent aphasia, Dr. Hodges noted in his commentary. Major psychiatric symptoms also were very common, but more details are needed, he wrote. "It appears, therefore, that the majority of patients have the behavioral variant of FTD, although a pattern of progressive [nonfluent aphasia] should not mitigate against screening for the mutation in patients with a strong family history or concurrent features of ALS."