Knowledge of New Mutation in ALS, Dementia Grows

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]).

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).

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, 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."

Who Should Undergo Screening?

Given that some patients had the C9ORF72 mutation even without a strong family history, "the most important immediate clinical implication is that we will likely begin screening patients for this mutation once a standard laboratory test for this gene becomes available," Dr. Dickerson said.

In a commentary, Rosa Rademakers, Ph.D., of the Mayo Clinic in Jacksonville, Fla., argued that the use of a clinical screening algorithm to decide whether to test for the C9ORF72 mutation in a patient with a family history of ALS or FTD – or when a patient is behaviorally impaired – may not work, because detailed information about family history is often unavailable. Instead, it should be considered in all patients, particularly because 6%-7% of whites with sporadic disease in the Lancet Neurology paper had the mutation, and the clinical phenotype associated with the C9ORF72 expansion extends beyond FTD and ALS. At the moment, however, caution is advised on testing because "our present understanding of the disease penetrance and range of clinical phenotypes associated with this mutation is poor and the smallest repeat size needed for pathogenicity is unknown," Dr. Rademakers wrote.

The sources interviewed for this article did not have any relevant financial disclosures. Dr. Rademakers disclosed that she has a patent pending on the discovery of the hexanucleotide repeat expansion in the C9ORF72 gene.

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]).

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).

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, 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."

Who Should Undergo Screening?

Given that some patients had the C9ORF72 mutation even without a strong family history, "the most important immediate clinical implication is that we will likely begin screening patients for this mutation once a standard laboratory test for this gene becomes available," Dr. Dickerson said.

In a commentary, Rosa Rademakers, Ph.D., of the Mayo Clinic in Jacksonville, Fla., argued that the use of a clinical screening algorithm to decide whether to test for the C9ORF72 mutation in a patient with a family history of ALS or FTD – or when a patient is behaviorally impaired – may not work, because detailed information about family history is often unavailable. Instead, it should be considered in all patients, particularly because 6%-7% of whites with sporadic disease in the Lancet Neurology paper had the mutation, and the clinical phenotype associated with the C9ORF72 expansion extends beyond FTD and ALS. At the moment, however, caution is advised on testing because "our present understanding of the disease penetrance and range of clinical phenotypes associated with this mutation is poor and the smallest repeat size needed for pathogenicity is unknown," Dr. Rademakers wrote.

The sources interviewed for this article did not have any relevant financial disclosures. Dr. Rademakers disclosed that she has a patent pending on the discovery of the hexanucleotide repeat expansion in the C9ORF72 gene.

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]).

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).

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, 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."

Who Should Undergo Screening?

Given that some patients had the C9ORF72 mutation even without a strong family history, "the most important immediate clinical implication is that we will likely begin screening patients for this mutation once a standard laboratory test for this gene becomes available," Dr. Dickerson said.

In a commentary, Rosa Rademakers, Ph.D., of the Mayo Clinic in Jacksonville, Fla., argued that the use of a clinical screening algorithm to decide whether to test for the C9ORF72 mutation in a patient with a family history of ALS or FTD – or when a patient is behaviorally impaired – may not work, because detailed information about family history is often unavailable. Instead, it should be considered in all patients, particularly because 6%-7% of whites with sporadic disease in the Lancet Neurology paper had the mutation, and the clinical phenotype associated with the C9ORF72 expansion extends beyond FTD and ALS. At the moment, however, caution is advised on testing because "our present understanding of the disease penetrance and range of clinical phenotypes associated with this mutation is poor and the smallest repeat size needed for pathogenicity is unknown," Dr. Rademakers wrote.

The sources interviewed for this article did not have any relevant financial disclosures. Dr. Rademakers disclosed that she has a patent pending on the discovery of the hexanucleotide repeat expansion in the C9ORF72 gene.