ARTICLE IN BRIEF
Several teams of investigators report unique behavioral and clinical characteristics of patients with the mutant C9ORF72 gene, which is implicated in amyotrophic lateral sclerosis and frontotemporal dementia.
NEW ORLEANS—A wealth of new data on chromosome 9 open reading frame 72 (C9ORF72), the newest and most common gene for amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), is beginning to clarify the clinical characteristics of patients carrying the gene. The emerging picture is that the mutation is associated with typical motor features of ALS, causes behavioral variant FTD in most cases in which dementia occurs, and may lead to earlier onset and, perhaps, a slightly more rapid disease course than sporadic ALS.
Experts assessing the changing landscape of ALS also indicate it is time to revise the criteria for familial ALS to include FTD, and offered an algorithm for deciding when a genetic test is appropriate.
The gene, whose function is not known, contains a hexanucleotide GGGGCC repeat sequence in the first intron. The normal number of repeats is between 2 and 23, and disease appears to emerge when the number is greater than 40. Genes with more than one thousand repeats have been reported, but it is currently impossible to obtain an exact number when the repeat grows too long. The mutation is believed to have arisen about 6300 years ago.
PREVALENCE AND GENETICS
“The C9 expansion repeat and associated haplotype has now been found worldwide,” said Kevin Boylan, MD, assistant professor of neurology at Mayo Clinic in Jacksonville, FL. Dr. Boylan's group — one of several to describe new data on the mutant at the AAN annual meeting here — examined 310 serial patients diagnosed with ALS. Of these, 39 had familial ALS, as defined by the presence of a first-or second-degree relative with the disease. Within this group, 12, or 39 percent, had a C9ORF72 mutation. In addition, 11 (4 percent) of 271 sporadic ALS patients also carried mutations. Several other mutations were also found in the sporadic group, “but clearly the C9 expansion was far more prevalent among this group,” Dr. Boylan said. The mutation appears to be autosomal dominant in almost all cases.
Two other groups reported very similar findings. Orla Hardiman, MD, clinical professor of neurology at Trinity College in Dublin, Ireland, and colleagues tested 600 DNA samples from a national ALS DNA bank, and found that the mutation accounted for 40 percent of familial ALS in the population. Adriano Chio, MD, professor of neurology at University of Torino in Italy, examined DNA from 126 familial and 601 sporadic ALS cases. Among Italians not from Sardinia, 40 percent of familial and 3 percent of sporadic patients carried the expansion. Among Sardinians, the figures were 55 percent and 8 percent. Incomplete penetrance may account for the mutation among apparently sporadic ALS cases, rather than de novo mutation, which researchers believe is probably quite rare.
In Dr. Boylan's study, all patients had classical ALS, with a male/female ratio of 1.2, similar to that seen in gene-negative patients, he said. The age at onset ranged from 33 to 73 years, with a median of 51 years. “What is of note is that a large number of patients were age 40 to 50 at onset,” earlier than the median for all familial ALS. There was a suggestion of anticipation in some kindreds, with onset in younger generations earlier by 10 years or more compared with the next oldest generation, he said. The proportion of patients with bulbar onset in his study was only 17 percent, but other groups have reported much higher figures.
The rate of frontotemporal dementia in this diagnosed ALS cohort was 25 percent, but Dr. Boylan noted that the true rate may differ, as more patients develop FTD over time.
In Dr. Hardiman's sample, all patients with gene expansions had evidence of cognitive or behavioral impairment. A common theme among all groups was that the dominant type of FTD is the behavioral variant, characterized by personality and mood changes, and socially inappropriate behavior. Dr. Boylan noted that some patients instead have a predominantly aphasic form of FTD. “Cognitive signs may precede motor signs by more than a year, and this may affect the initial diagnosis,” he said.
That point was amplified by the results from a collaborative study by the groups of Rosa Rademakers, PhD, of Mayo Clinic in Jacksonville and Ian Mackenzie, MD, of the University of British Columbia (UBC) in Vancouver, and presented by Ging-Yuek Hsiung, MD, assistant professor of neurology at UBC. In 30 patients from 16 unrelated families with C9ORF72 mutations, initial diagnoses included behavioral variant FTD, ALS, alcoholic dementia, mild cognitive impairment, psychosis/schizophrenia, and atypical Alzheimer's disease. Despite the common genetic basis, “initial clinical presentations can be quite variable and may overlap with other clinical syndromes,” they concluded, noting that early diagnosis “requires a high clinical acumen.” Over long-term follow-up, half the subjects developed ALS, which negatively affected survival.
The median survival for the 14 patients who have died within Dr. Boylan's study cohort was 2.8 years, slightly longer than for sporadic ALS, he said. However, a third of the group is still living, so the figure is provisional. Dr. Hardiman's data suggest that survival may be slightly shorter, a finding supported by several other studies, Dr. Boylan said.
There is a characteristic neuropathology caused by the gene, with ubiquitin-positive neuronal cytoplasmic inclusions in the hippocampus, cortex, and cerebellum, “to the point where pathologists looking at these in some of the papers make the distinction of C9 positive or not based on these pathology findings,” he said.
Drs. Boylan, Hardiman, and Chio all raised the question of the definition of a positive family history for ALS. Beyond having a first- or second-degree relative affected by ALS, clinicians must clearly now consider dementia, and perhaps parkinsonism — which several groups have reported as increased among close relatives — in the family history. “Half the patients in our study had no family history of ALS, but there was a significant percent with dementia or Parkinson's disease,” Dr. Boylan said.
“FTD, or a family history of FTD, clearly needs to be incorporated into the criteria we have for familial ALS,” Dr. Hardiman said. She also noted that her study found a wide range of other neuropsychiatric diseases, including alcoholism, depression, bipolar disorder, schizophrenia, and suicide within the cohort families.
“The classical definition of familial ALS is no longer acceptable,” Dr. Chio agreed, “and a new operative definition, including presence of FTD in the patient or family history should be included.”
“In the clinical setting,” he continued, “presence of comorbid FTD, or young onset of ALS, should lead to genetic counseling.”
Dr. Hardiman proposed a screening algorithm for genetic testing. If there is no family history (including of FTD), and no behavioral impairment as measured by the Frontal Systems Behavior Scale (FrSBe), “do not offer the gene test,” she said. “If you don't have a family history of ALS, and you are not impaired on the FrSBe, the likelihood of having the repeat is very low. Conversely, if there is a strong family history of ALS, and the patient is behaviorally impaired, there is a very high likelihood, almost 70 percent, of having the variant.”
One important issue raised by these results “is to what degree this might explain some of our sporadic patients in the clinic,” said Benjamin Brooks, MD, director of the Carolinas Neuromuscular ALS/MDA Center in Charlotte, NC, who was not involved with the study. “Potentially this is 5 percent of our sporadic patients.”
Second, he said, the picture is emerging of a clear separation between cognitively affected and unaffected ALS patients, which may have important etiologic, and therefore possibly therapeutic implications.