Long repeat sequences in the C9ORF72 gene have cropped up in cases of multiple system atrophy (MSA) and depressive pseudodementia, according to two new case studies. The findings, published in JAMA Neurology on April 14 and 21, respectively, do not prove that the C9ORF72 repeat expansions cause either disorder. However, they raise the possibility that the mutation—which is strongly linked to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD)—has more tricks up its sleeve than previously thought. The same repeats have been found in some people with Alzheimer's and Huntington’s diseases, as well. Why the expansions may manifest in such a variety of disorders remains to be seen.

"These are very well-done and provocative studies,” said David Irwin of the University of Pennsylvania in Philadelphia, who was not involved in either study. “They raise our awareness of the potential for this mutation to exist in patient populations where we wouldn’t normally think of it.”

Repeat Offender?

Cytoplasmic inclusions containing the C9ORF72 dipeptide (red) show up in neurons of the hippocampus (top panel) and granule cells of the cerebellum (bottom panel) in a patient with depressive pseudodementia (left panel), but not in a control (right panel). [Image courtesy of the American Medical Association, © 2014. All rights reserved.]

Hexanucleotide repeat expansions (see Alzpedia) are the leading cause of familial and sporadic ALS and FTD (see Sep 2011 news story). The repeats occur within an intron of C9ORF72, a gene of unknown function. While healthy people have fewer than 30 repeats, people with ALS/FTD can harbor from hundreds to thousands. A recent study reported that the repeats contort DNA and RNA into a configuration called a G-quadruplex, which disrupts expression of the gene (see Mar 2014 news story), and despite their location within an intron, the repeats manage to be translated into strings of dipeptides (see Feb 2013 news story). Researchers can detect these dipeptide repeats within neuronal inclusions in people with ALS or FTD, but whether they play a role in disease pathology is unclear. 

Regardless of how C9ORF72 repeat expansion exerts its toxic effects, studies suggest that the pathology can manifest in multiple regions of the brain, resulting in entirely different disorders. ALS is characterized by the degeneration of motor neurons in the motor cortex and spinal cord, while FTD claims neurons in the frontal and temporal lobes. ALS therefore affects movement, whereas people with FTD suffer from psychiatric and cognitive symptoms. A recent study led by Carlos Cruchaga at Washington University in St. Louis found no link between C9ORF72 and Parkinson’s disease (see Harms et al., 2013); however, Cruchaga’s group did identify an association between the expansions and Alzheimer’s (see Harms et al., 2013). Another recent study identified C9ORF72 expansions in a subset of people diagnosed with Huntington’s disease who did not harbor the characteristic repeats in the huntingtin gene that cause that disorder (see Hensmen et al., 2014).

The present papers hint that the expansions may have more widespread effects still. Dennis Dickson at the Mayo Clinic in Jacksonville, Florida, found the C9ORF72 expansions in patients with “depressive pseudodementia.” People with pseudodementia—a classification that is controversial—display signs of dementia thought to be triggered by an underlying psychiatric disorder, such as depression, rather than by a pathology that causes dementia in its own right. First author Kevin Bieniek of the Mayo Clinic in Rochester, Minnesota, and colleagues wanted to see if they could find an underlying pathology responsible for this clinical description. They examined a collection of 31 postmortem brains from patients diagnosed with depressive pseudodementia; the brains showed no signs of neurodegeneration or atrophy.

The researchers used the recently developed C9RANT antibody, which recognizes the dipeptide repeats produced by the C9ORF72 expansion. With that, they identified two brain samples harboring neuronal inclusions that were chock full of the dipeptides. The samples came from men (one aged 66 years, the other 71) with a history of depression. Both contained dipeptide inclusions in the hippocampus, neocortex, amygdala, basal ganglia, thalamus, and cerebellum, which had the highest burden. One of the patients had experienced drug-induced parkinsonism, and the other had been diagnosed with AD based on a cognitive assessment. The patients both had a smattering of neurofibrillary tangles, and the patient diagnosed with AD also had sparse Lewy bodies. Neither of the patients had amyloid plaques or any signs of motor neuron disease.

It is unclear what role the C9ORF72 expansions may have played in the patients’ symptoms, Dickson said. “The dipeptide repeat inclusions give you a potential structural basis for the dementia,” he said. “The problem is, we don’t have evidence that the dipeptide inclusions directly cause disease.” Both Dickson and Irwin suggested that it is possible the inclusions themselves caused depressive or dementia symptoms, which could have been precursors to a neurodegenerative disease such as ALS or FTD. Jill Goldman of Columbia University in New York, who was not involved in this study but was first author on the second one, also wondered about the possibility that psychiatric symptoms could be prodromal markers in patients with a family history of ALS or FTD, however, she cautioned that disorders such as depression are quite common.

The other study, led by Sheng-Han Kuo of Columbia University, raised the possibility that the repeats may also trigger MSA, a movement disorder characterized by glial and neural α-synuclein inclusions and neurodegeneration of the cerebellum. First author Goldman and colleagues described detailed clinical reports of a brother and sister who each harbored around 1,000 C9ORF72 repeats, but with dramatically different outcomes. The 65-year-old sister came down with typical signs of MSA, which include lack of coordination, difficulty walking, urinary incontinence, and dangerous drops in blood pressure upon standing. Eventually, her physical symptoms worsened, and she began to develop cognitive impairment, similar to symptoms seen in FTD patients. Brain scans showed major degeneration in her cerebellum. Her brother, on the other hand, began developing the muscle-weakening symptoms of ALS at the age of 62, at which time his disease rapidly progressed. The siblings’ father had succumbed to ALS at the age of 49. Why one sibling developed an MSA-like disorder and the other ALS is unknown, but the researchers suspect a combination of genetic and environmental factors may have pushed each patient’s C9ORF72 pathology down a separate path.

Is the association between the repeat and the sister’s unusual condition causal or coincidental? MSA is not considered a heritable disease, which makes the idea that it could be due to C9ORF72 expansions unlikely, said Dickson, who was not involved in this study. He added that the MSA case had not been confirmed pathologically by staining for α-synuclein inclusions, making the true diagnosis uncertain. 

Goldman said that the likelihood of the MSA-like case cropping up by chance in a family with the C9ORF72 mutation and a history of neurodegenerative disease seemed small, but she cannot yet explain the association.

While the patient’s symptoms were similar to MSA, it is possible that the underlying pathology could be related to the C9ORF72 expansions, Irwin told Alzforum. “Perhaps this is a mimic of MSA, where an underlying C9ORF72 and TDP-43 pathology, rather than synucleinopathy, may, for whatever reason, be affecting the cerebellum and autonomic function.”

Irwin, who was not involved in the research, said that if non-synuclein pathology is found to explain this case of “MSA,” it may make clinicians think twice about what causes MSA-like symptoms in patients with a family history of FTD or ALS.

Matthew Harms of Washington University agreed with Irwin that the studies call for increased vigilance about family history. “Clinicians seeing such patients should realize that they may be dealing with an alternative expression of the C9ORF72 phenotype.” 

Harms added that larger genetic studies would be needed to definitively link C9ORF72 expansions to diseases other than FTD or ALS. In fact, guidelines for genetic studies published in the April 24 Nature called for more caution in drawing causal relationships between genes and disease in large genetic studies (see MacArthur et al., 2014), let alone in small case studies. However, Harms said that rather than trying to prove that C9ORF72 causes diseases such as MSA or pseudodementia, the more interesting question is what secondary genetic or environmental factors lead to different disease manifestations of the C9ORF72 expansion. “My strong hunch is that the variability in clinical phenotype stems strongly from selective neuronal populations being more or less effective at dealing with the C9ORF72 pathology,” Harms said. Performing a screen for secondary genetic factors in a population of C9ORF72 expansion carriers with different diseases would be one way to determine what factors point disease down one path or another, he added.

While neither Dickson’s nor Goldman’s studies directly prove that the expansions are responsible for the clinical pathology of disorders other than ALS or FTD, they do raise the possibility that C9ORF72 has potential to manifest in multiple ways. “That is what is freaky about it,” Goldman said. “There’s so much about the gene that we don’t understand.”—Jessica Shugart


No Available Comments

Make a Comment

To make a comment you must login or register.


Alzpedia Citations

  1. C9ORF72

News Citations

  1. Corrupt Code: DNA Repeats Are Common Cause for ALS and FTD
  2. RNA-DNA Pairs: At the Root of C9ORF72 Repeat Damage?
  3. RNA Twist: C9ORF72 Intron Expansion Makes Aggregating Protein

Paper Citations

  1. . Parkinson disease is not associated with C9ORF72 repeat expansions. Neurobiol Aging. 2012 Oct 29; PubMed.
  2. . C9orf72 hexanucleotide repeat expansions in clinical Alzheimer disease. JAMA Neurol. 2013 Jun 1;70(6):736-41. PubMed.
  3. . C9orf72 expansions are the most common genetic cause of Huntington disease phenocopies. Neurology. 2014 Jan 28;82(4):292-9. Epub 2013 Dec 20 PubMed.
  4. . Guidelines for investigating causality of sequence variants in human disease. Nature. 2014 Apr 24;508(7497):469-76. PubMed.

Further Reading


  1. . The neuropathology associated with repeat expansions in the C9ORF72 gene. Acta Neuropathol. 2014 Mar;127(3):347-57. Epub 2013 Dec 20 PubMed.
  2. . C9ORF72 hexanucleotide repeats in behavioral and motor neuron disease: clinical heterogeneity and pathological diversity. Am J Neurodegener Dis. 2014;3(1):1-18. Epub 2014 Mar 28 PubMed.
  3. . The widening spectrum of C9ORF72-related disease; genotype/phenotype correlations and potential modifiers of clinical phenotype. Acta Neuropathol. 2014 Mar;127(3):333-45. Epub 2014 Feb 4 PubMed.

Primary Papers

  1. . Multiple system atrophy and amyotrophic lateral sclerosis in a family with hexanucleotide repeat expansions in C9orf72. JAMA Neurol. 2014 Jun;71(6):771-4. PubMed.
  2. . Expanded C9ORF72 hexanucleotide repeat in depressive pseudodementia. JAMA Neurol. 2014 Jun;71(6):775-81. PubMed.