In recent months, the discovery of the C9ORF72 mutation has added fresh insight into the causes of frontotemporal dementia and amyotrophic lateral sclerosis. Now, a series of new studies describes the frequency of the mutation and how the mutation reveals itself clinically in a spectrum of phenotypes in patients with either disease.
The series of studies found that the mutation most often is associated with behavioral variant frontotemporal dementia (FTD), and occurred in 2%-5% of patients with sporadic FTD and 15%-48% of patients with familial FTD. For amyotrophic lateral sclerosis (ALS) patients, the mutation occurred in 4%-7% of sporadic cases and 22%-43% of familial cases. Another 20%-40% of patients who show symptoms of both diseases had the mutation; the rate reached almost 50% among these patients with a family history of ALS or FTD. Some studies reported finding the mutation in 0%-28% of patients who present with the progressive nonfluent aphasia variant of FTD.
The eventual clinical impact of identifying the C9ORF72 mutation is the availability of a population of at-risk carriers of the mutation to aid research into the preclinical phase of disease, said Dr. Kevin Talbot, professor of motor neuron biology at the University of Oxford, England. "Rather than work in the phase of established disease, which may be intractable to disease-modifying therapy, this provides a new departure to ‘fill in’ a phase in the natural history of ALS which has hitherto not been amenable to study." Dr. Talbot was a coauthor on a study that screened 4,448 patients with ALS and 1,425 patients with FTD for the mutation (Lancet Neurol. 2012 March 9 [doi:10.1016/S1474-4422(12)70043-1]).
Dr. Paul Schulz
The discovery of the mutation and the subsequent characterization among patients who have FTD, ALS, both FTD and ALS, or primary progressive aphasia are just the first steps of many before treatments can be based on the new knowledge, said Dr. Paul Schulz of the department of neurology at the University of Texas, Houston, where his lab examines the mechanisms underlying normal cognition and neurodegenerative disorders.
To illustrate his point, Dr. Schulz cited how the genes for myotonic dystrophy and Huntington’s disease were discovered in 1992 and 1994, respectively, but researchers still know little about them. "We don’t know what they do, how the mutations cause problems, and how to replace them."
Preliminary findings underpinning the discovery of C9ORF72 were made in 2006 when investigators discovered that either FTD and ALS or a combination of both diseases were linked to a region on chromosome 9p21 in members of some families with the diseases. The big step came in September 2011 when two research groups independently identified the precise nature of the long-sought-after mutation (Neuron 2011;72:245-56; 257-68). It proved to be a GGGGCC hexanucleotide repeat in the noncoding region of the C9ORF72 gene.
Originally, no mutation had been found even after repeated sequencing of the investigational region on chromosome 9p21, but eventually, the two research groups examined the pattern of inheritance and noticed that only the good gene appeared to be inherited rather than one gene from each parent.
"After various experiments, it was realized that the abnormal gene was invisible to gene sequencing because the hexanucleotide bound to itself," related Dr. Schulz. "As a result, it was impenetrable by normal PCR [polymerase chain reaction] amplification. Now that this mechanism of mutation is known, I’m sure gene hunters are looking for others that are also ‘silent.’ "
Mutation Screening in FTD and ALS
In the Lancet Neurology study of 4,448 ALS patients and 1,425 FTD patients from the United States, Europe, and Australia, researchers found the C9ORF79 mutation in 7% of sporadic ALS in white patients and 4.1% of black patients. It was present in 6% of white patients with sporadic FTD. The results of those with familial FTD or ALS were more surprising, with the expansion present in 38% of all patients with familial ALS and 25% in white patients with familial FTD.
A series of four papers published in Brain by groups from the Netherlands; Manchester, England; London, England; and the Mayo Clinic in Rochester, Minn., and Jacksonville, Fla., reported the results of screening large cohorts of patients with FTD totaling nearly 1,200 cases. Overall, 7%-12% of the cohorts were found to have the mutation (Brain 2012;135:693-708; 723-35; 736-50; 765-83).
Another two papers and the same Mayo Clinic paper reported on the frequency of the mutation in patients with ALS. In 563 ALS patients from northern England, including 63 with a family history of ALS, the C9ORF72 expansion was found in 11%, but it occurred more often among patients with familial disease (43%) than with sporadic (7%) disease (Brain 2012;135:751-64).