|Home | About | Journals | Submit | Contact Us | Français|
Numerous kindreds with familial frontotemporal dementia or amyotrophic lateral sclerosis or both have been linked to chromosome 9 (c9FTD/ALS), and an expansion of the GGGGCC hexanucleotide repeat in the non-coding region of chromosome 9 open reading frame 72 (C9ORF72) was identified in the summer of 2011 as the pathogenic mechanism. An avalanche of papers on this disorder is in progress, and a relatively distinctive phenotype is taking form. In this review, we present an illustrative case and summarize the demographic, inheritance, clinical, and behavioral aspects and presumed pathologic underpinnings of c9FTD/ALS on the basis of the available data on more than 250 patients with frontotemporal lobar degeneration syndromes, parkinsonism, or ALS or a combination of these disorders.
Familial frontotemporal dementia (FTD) with or without parkinsonism has been associated with mutations in genes encoding microtubule-associated protein tau (MAPT), progranulin (PGRN), and less commonly valosin-containing protein (VCP), TAR DNA-binding protein (TARDBP), and fused in sarcoma (FUS), whereas familial amyotrophic lateral sclerosis (ALS) has been associated with mutations in genes encoding Cu/Zn superoxide dismutase-1 (SOD1), TARDBP, and FUS [1-9]. Although the phenotype of familial FTD or ALS linked to chromosome 9 or both has been appreciated for many years [10-17], the pathogenic genetic mutation remained elusive until two teams of investigators discovered the mechanism in the summer of 2011 and published their findings shortly thereafter [18,19]. The mutation is an expansion of the GGGGCC hexanucleotide repeat in the non-coding intronic region of the chromosome 9 open reading frame 72 (C9ORF72) gene [18,19], and the disease is known as frontotemporal dementia or amyotrophic lateral sclerosis (or both) linked to chromosome 9 (c9FTD/ALS) [18,20]. A number of papers on c9FTD/ALS have already been published, and a relatively distinctive phenotype is becoming clear. In this review, we present an illustrative case from our index kindred and then summarize the demographic, inheritance, clinical, and behavioral aspects of c9FTD/ALS on the basis of the available data.
The identification of the mutation in our index kindred known as the Vancouver-San Francisco-Mayo Clinic family 20 reflects collaborative work that was conducted by several groups of investigators over the course of almost two decades . One case we have followed over the course of seven years illustrates many of the core cognitive, behavioral, neuropsychological, and neuro-imaging features that cases with c9FTD/ALS frequently exhibit.
A right-handed male began experiencing depression and apathy at age 49. He is patient III.2 in the report by Boxer and colleagues . His father developed ALS at age 35 and died after a two-and-a-half-year course. His paternal aunt presented with behavioral variant fronto-temporal dementia (bvFTD) features at age 46 and shortly thereafter with parkinsonism and ALS and died after a nine-year course. His brother had bvFTD, which was diagnosed at age 49, and parkinsonism, which was diagnosed four years later, and is currently residing in a skilled nursing care facility after a seven-year course. Five other relatives have or had FTD, ALS, or parkinsonism or a combination of these disorders.
The patient presented to our institution at age 53, complaining of severe depression and 'lack of pep'. He had lost his job because of apathy and poor decisions. He lived in a rural area and remarked that, owing to boredom since he could not find work, a favorite activity was to sit in a lawn chair in his yard with a cooler of beer adjacent to him, hold a rifle in each arm, and 'shoot anything that moves'. The targets included squirrels, birds, and insects. Despite his wife's best efforts to curb this activity and keep him from consuming alcohol, he continued to do so. This eventually led to a drunk driving charge, and as a result, all weapons were removed from his residence. His driver's license was temporarily suspended, yet he was able to evade the local police and drive his own or friends' cars, apparently never getting lost or having any accidents. After a six-month period with no driving privileges, he successfully completed a driving safety examination. On one occasion, he picked up a hitchhiker who was seeking shelter, brought him home, but refused to allow the hitchhiker in his home and an altercation ensued.
The patient became increasingly suspicious of his family, neighbors, and local police and health-care providers. Owing to his obstinacy, his wife chose to reside in a separate home and his children chose to no longer interact with him. He remarked that he often heard voices, but other than stating that the Lord was telling him to do good deeds, he would not elaborate on the content of these auditory hallucinations as 'you guys will lock me up and throw away the keys'.
His only source of income was disability benefits. His home was in disarray, and he would drive around town obtaining food from fast-food restaurants, but he managed to live independently. He gained more than 50 pounds since the onset of his symptoms because of hyperphagia and the tendency to consume large quantities of potato chips. His family has worked with the local legal authorities in an attempt to transfer oversight of his medical and financial affairs to his wife, but when he went before a judge, the patient successfully argued that he was competent and absolutely did not want anyone overseeing his affairs.
The longitudinal clinical, behavioral, neuropsychological, and neuroimaging findings in this patient are shown in Figures Figures11 to to3.3. His presenting features were typical of bvFTD, followed shortly thereafter with left hemiparkinsonism that has evolved to an asymmetric akinetic-rigid syndrome without tremor. Asymmetric corticospinal tract signs have also evolved but without features of lower motor neuron dysfunction. His course has been remarkably slowly progressive. As reflected in his neuropsychological performance over time, his episodic memory and visuospatial functions have remained relatively preserved and this likely has allowed him to live independently despite his psychomotor slowing, executive dysfunction, delusions, hallucinations, apathy, and mild parkinsonism.
Neuroimaging findings mirror this remarkably slow clinical progression. Very minimal atrophy has evolved over the course of seven years of serial magnetic resonance imaging (MRI) scans. A flourodeoxyglucose positron emission tomography (FDG-PET) scan image of the brain, performed eight years after the onset of his symptoms, shows relatively mild frontal, parietal, and cingulate cortex hypometabolism.
We reviewed reports with ample numbers of cases having a dementia-predominant phenotype, published through March 2012. Reports focused on ALS with cognitive and behavioral data were also included. We identified nine recent publications meeting these criteria [20-28], and a summary of the core features associated with c9FTD/ALS is shown in Table Table11.
More than 250 subjects among more than 230 kindreds with sufficient cognitive/behavioral data are included in these reports to be summarized and reviewed for general consistencies [20-22,24-29]. This accumulation of hundreds of subjects is in itself striking given that these data have been published within seven months since the publication of the landmark papers on the C9ORF72 mutation [18,19]; similar data exist for FTD associated with mutations in the gene encoding MAPT among 134 kindreds since the original report on MAPT mutations in 1996  and in the gene encoding PGRN among 231 kindreds since the original reports on PGRN mutations in 2006 [2,3,30].
Among those series in which the frequency of the C9ORF72 mutation was assessed (some also compared this frequency with the frequency of mutations in MAPT and PGRN), the frequency was calculated as sporadic or familial or both; also, the frequency of FTD ± parkinsonism ± ALS was calculated [21,22,24-29]. Most reports state that the C9ORF72 mutation frequency is in the 7% to 12% range compared with the 6% to 10% range for MAPT and the 4% to 7% range for PGRN. These frequencies increase to 13% to 26% for C9ORF72, 11% to 22% for MAPT, and 6% to 22% for PGRN when the frequencies of mutations among familial FTD cases are considered. Importantly, despite the recruitment and analyses of familial FTD cases during at least the past 20 years among several teams focused on this issue, the frequency of familial cases without an identified genetic mechanism is in the 45% to 66% range, thereby providing ample reasons to continue research in familial FTD.
The male-to-female ratio on cumulative cases among FTD ± parkinsonism ± ALS suggests a slight male predominance (129:105 or 1.23:1). In different series, the mean/median age of onset is in the 52- to 65-year age range, and the range of age of onset is wide (33 to 78 years). Survival mean/median values are in the 5- to 9-year range, and the range of survival also is wide (1 to 22 years). The illustrative case above exemplifies the slow course and long survival of some individuals. In the reports in which this was assessed, those with FTD and concomitant ALS tended to have shorter survival, as one would expect.
The disorder of c9FTD/ALS is inherited in an autosomal dominant fashion with high but not complete penetrance, and sporadic cases have been identified in every report published to date. Many reports document families in which succeeding generations appear to have a younger age of onset; hence, these reports suggest genetic anticipation [21,25,29]. Given that c9FTD/ALS involves a polynucleotide repeat expansion mechanism, it stands to reason that anticipation could occur. The challenge among geneticists is to resolve the technical aspects of quantifying the number of repeats in this mutation but this has been difficult. One can easily hypothesize that, with increasing numbers of repeats, an earlier age of onset would occur, but this awaits confirmation.
Clearly, the predominant dementia phenotype is the classic bvFTD syndrome [31,32]. Many have some degree of parkinsonism, which is typically of the akinetic-rigid type without tremor and is levodopa-unresponsive . Others have elements or the full clinical picture of ALS. This phenotype has not yet been reported in c9FTD/ALS, in contrast to FTD with or without parkinsonism associated with MAPT and PGRN mutations, in which a primary parkinsonian phenotype can occur. Most series do not have any cases with a primary progressive aphasia (PPA) phenotype, although this has been encountered rarely in some series [25-28]. Only one case of the corticobasal syndrome phenotype  has been reported in c9FTD/ALS . Though rare, the amnestic presentation diagnosed clinically as probable Alzheimer's disease has been observed across many in the series [20,21,25,26], including one analysis focused on late-onset Alzheimer's disease . The phenotype of dementia with Lewy bodies was reported in a few cases in one series . These observations suggest that the C9ORF72 mutation can manifest as a variety of dementia phenotypes as well as pure ALS, but the vast majority have the core syndrome of bvFTD ± parkinsonism ± ALS.
The classic bvFTD phenotype involves executive dysfunction and word retrieval difficulties with relative sparing of memory and visuospatial functioning [31,32], as exemplified by our illustrative case. Degeneration of the dorsomedial and dorsolateral cortices and their afferent and efferent connections - two of the critical frontosubcortical neural networks involved in executive functioning, word retrieval, psychomotor speed, motivation, and so on - is the likely substrate underlying the typical bvFTD cognitive features. In some c9FTD/ALS cases, this classic phenotype is not always exhibited, owing mainly to memory being impaired [20,21,25-28]. Visuo-spatial dysfunction is present in a minority of cases [21,25-28]. In addition to bifrontal and cingulate cortex atrophy, parietal cortex atrophy is part of the signature pattern on MRI  and this likely explains visuospatial dysfunction, but memory impairment is harder to explain. The determination of whether memory is impaired varies on the basis of clinical evaluation, neuropsychological testing, and which tests are used. For example, one can consider the older and more simplistic rubric that memory impairment is due to an encoding versus retrieval deficit. A deficit in encoding implicates the mesial temporal lobe structures with or without other structures in the limbic system such as the medial thalamus, whereas a retrieval deficit implicates the frontosubcortical neural networks. Most cases of c9FTD/ALS have clinical, neuropsychological, and neuroimaging features implicating the frontosubcortical neural networks, and thus a retrieval deficit would be expected, and in one study in which neuropsychological tests were performed in many c9FTD/ALS subjects, performance on delayed recall measures was usually normal . Yet many cases exhibit poor performance on delayed recall measures as well as on recognition of stimuli [26-28], suggesting an encoding deficit, yet the medial temporal lobes tend to be relatively spared, according to neuroimaging studies conducted thus far [21,26,35]. However, pathologic studies show that hippocampal sclerosis is frequent and associated with those presenting with an amnestic disorder . This issue is reviewed in more detail in the section on 'Neuropathologic features and their clinical relevance'.
Another challenge is understanding the executive dysfunction in mutation carriers who have the bvFTD phenotype yet no apparent frontotemporal atrophy on MRI or hypometabolism on FDG-PET . The pathologic findings, however, provide evidence that frontal atrophy is indeed more frequent with this phenotype. One hypothesis is that the executive deficits are due, in part, to primary cerebellar dysfunction akin to the cerebellar cognitive affective syndrome [36-38]. All pathologic studies in c9FTD/ALS have shown widespread ubiquitin-positive inclusions in the cerebellum, and this could contribute to 'frontal' dysfunction (see section on 'Neuropathologic features and their clinical relevance'). Furthermore, while neuroimaging studies clearly include the cerebellum as part of the signature pattern of atrophy [26,35], cerebellar degeneration per se tends to be minimal on pathologic analyses, and other clinical features of cerebellar dysfunction, such as limb or truncal ataxia, limb dysmetria, ataxic dysarthria, and nystagmus, have not been appreciated in affected cases. Understanding the mechanism for executive dysfunction in c9FTD/ALS cases with minimal or no frontotemporal atrophy will require further study.
Language impairment is relatively common in c9FTD/ALS but is rarely the predominant phenotype; aphasia typically evolves as the illness progresses. When the primary progressive aphasia syndrome is the predominant phenotype, it is typically of the non-fluent/agrammatic type [25-28]. Non-fluent/agrammatic aphasia relates to degeneration of Broca's area or the insula in the dominant hemisphere or both, and in those with a predominant non-fluent/agrammatic PPA phenotype, neuroimaging studies demonstrate this topography of atrophy or hypometabolism [39-44]. However, such PPA phenotype cases in c9FTD/ALS have not been well characterized with detailed speech/language assessments and neuroimaging studies, and so this remains to be seen. Furthermore, symmetric neuroimaging abnormalities are the rule and asymmetric findings are the exception [21,26,35], and so these PPA cases could be the exceptions with focal/asymmetric dominant hemisphere degeneration. One might also predict that if a bilateral and relatively symmetric pattern of degeneration has ensued and if the key anterior language networks are affected, then a non-fluent/agrammatic phenotype could be present. Also, the dominant hemisphere supplementary motor area has recently been implicated in the primary progressive apraxia of speech phenotype [45,46], and this could easily be construed to represent non-fluent aphasia; mesial frontal atrophy/hypoperfusion/hypometabolism is part of the signature pattern of topography in c9FTD/ALS [21,26,35], and so this mechanism is quite plausible. This is yet another area worthy of further research.
The overwhelming majority of cases with a dementia syndrome-predominant phenotype as part of c9FTD/ALS manifest the full spectrum of the bvFTD features [31,32]: early behavioral disinhibition, early apathy or inertia, early loss of sympathy or empathy, and hyperorality and dietary changes. The dorsolateral prefrontal cortex, orbitofrontal cortex, and anterior cingulate cortex are typically affected, according to neuroimaging and neuropathologic studies [20,21,26,35], and this topography readily explains the full bvFTD spectrum of behavioral features. Yet there are those who do not have neuroimaging evidence of frontal atrophy or hypometabolism , and as noted above, perhaps the cerebellar degeneration contributes to these behavioral features similar to the hypothesis that such degeneration might explain executive dysfunction. These 'frontally impaired but frontally normal on neuroimaging' cases clearly deserve ample study, as understanding the neuroanatomic correlates of their impairment will not only aid in understanding the disease of c9FTD/ALS but also enhance our understanding of brain-behavior correlations in general.
A few investigators have observed that some c9FTD/ALS cases exhibit the most bizarre behavioral manifestations they have ever witnessed among all of the bvFTD patients they have cared for [21,28]. Psychotic features, obsessive-compulsive behaviors, odd ritualistic behaviors, and so on are often striking. A summary of observations by clinicians is presented in Table Table22.
Whereas the documentation of other clinical features varied across reports, many cases with frontal release signs, parkinsonism, upper or lower motor neuron dysfunction (or both) not fulfilling criteria for ALS, and the full ALS phenotype were observed. Limb apraxia was rarely documented.
Atypical features are already emerging. A very interesting (and, for many clinicians, somewhat frightening) finding is the identification of the C9ORF72 mutation in rare cases of the FTD phenocopy syndrome . The FTD phenocopy refers to those individuals who clearly exhibit cognitive and behavioral changes suggestive of bvFTD, but neuropsychological tests and neuroimaging studies tend to be more normal than not during the initial years of symptoms [48,49]. The 'typical' FTD phenocopy patient does not show progression on longitudinal clinical, neuropsychological, and neuroimaging evaluations, and such cases are now considered to usually have a non-degenerative substrate for their features. When first encountering patients who clearly have bvFTD features but no corroborating evidence of an underlying neurodegenerative disorder, the clinician is faced with the obvious challenge of establishing a confident diagnosis and predicting what the future holds. And since so few cases have come to autopsy, the underlying substrate for their symptoms has not been well characterized. The two cases recently reported with the FTD phenocopy associated with the C9ORF72 mutation are very intriguing , not only because such atypical FTD cases do have a neurodegenerative disorder underlying their symptoms but also because of the number of atypical FTD cases who have surely been suspected by seasoned clinicians to have a primary psychiatric disorder. Clinical testing is now commercially available for C9ORF72 mutation detection, and more FTD phenocopy and other atypical neurobehavioral syndromes will undoubtedly be identified with this mutation.
Neuropathologic studies in c9FTD/ALS have shown many consistent findings yet also some unexpected, variable, and curious findings. All cases studied to date - except one (see below) - have had TDP-43 pathology associated with frontal and variable parietal or temporal cortical atrophy (or both) and microscopic evidence of neurodegeneration [20,21,25-28,50-55]. Many have evidence of upper or lower motor neuron degeneration (or both) that may or may not have been appreciated antemortem, but this finding underscores the involvement of the brain and spinal cord motor systems in this disease and also emphasizes the overlapping spectrum of FTD and ALS. Degeneration of the substantia nigra is also common and likely explains the presence of parkinsonism in the significant minority of cases who have parkinsonism. A few cases have had coexisting Alzheimer's disease pathology. One case with an apparent hexanucleotide expansion has been described in association with corticobasal degeneration pathology ; hopefully, additional details will be presented in the future to better understand this single case with non-TDP pathology.
Unexpected findings in c9FTD/ALS are the variable histologic features across cases [20,21,25,27,51-53]. Earlier studies suggested that all chromosome 9-linked FTD/ALS cases had a moderate degree of cortical neurons with neuronal cytoplasmic inclusions and relatively few dystrophic neurites across all cortical layers (which is characteristic of Mackenzie type 3, Sampathu type 2, and harmonized type B FTLD-TDP pathology) [56,57], yet approximately half of c9FTD/ALS cases have had many neurons with neuronal cytoplasmic inclusions and many dystrophic neurites in the cortex, especially in layer 2 (which is characteristic of Mackenzie type 1, Sampathu type 3, and harmonized type A FTLD-TDP pathology and most often associated with mutations in PGRN) [20,21,57]. Why this variability exists is not understood, but this finding suggests that there is not a distinctive set of histologic features for c9FTD/ALS based on TDP-positive inclusions alone.
One of the most unexpected and still curious findings in c9FTD/ALS cases is the predominance of ubiquitin-positive inclusions in the cerebellum, which far exceeds the density of TDP-positive inclusions [20,21,50,51,53,58]. The ubiquitin-positive inclusions also stain positively for ubiquilin and p62 immunohistochemistry, suggesting a pathophysiological link between C9ORF72 expansions and ubiquilin proteins in ALS and FTLD-TDP [20,50,51,53,58]. Yet the degree of neuronal loss in cerebellar structures has been mild to negligible and this may explain why classic cerebellar signs such as ataxia, dysmetria, and nystagmus have not been appreciated or reported. However, the finding of ubiquitin-, ubiquilin-, and p62-positive inclusions in the cerebellum has been present in almost every case in which such immuno-histochemistry has been used. Hence, these cerebellar inclusions are now viewed as a highly sensitive and specific marker for the presence of the C9ORF72 mutation.
The cognitive and behavioral features and their known or presumed neuropathologic substrates are described above in the respective sections, but again, the typical cognitive features (executive dysfunction and word retrieval deficits) likely relate to degeneration in the dorsomedial and dorsolateral frontosubcortical networks, and the typical behavioral features (impaired social cognition, prominent apathy, and so on) likely relate to these and other frontosubcortical networks such as the orbitomedial frontal and anterior cingulate circuits. Furthermore, the von Economo neurons in the anterior cingulate and insular regions have been implicated in impaired social cognition [59-61]. These clinical-topography associations are very plausible when abnormalities on MRI, single-photon emission computed tomography, or PET correspond to the specific features that are present in individual cases.
The more challenging circumstance is when obvious cognitive or behavioral changes or both are present and the neuroimaging studies are normal regardless of whether any patient has an obvious neurologic cause or has the less obvious FTD phenocopy syndrome. Memory impairment is not typical of the bvFTD syndrome but is often present in c9FTD/ALS cases; as discussed above, this could relate to hippocampal sclerosis or a retrieval-based deficit due to frontosubcortical dysfunction. Also, even when hippocampal sclerosis is not present, an encoding deficit could relate to dysfunction associated with ubiquitin-, ubiquilin-, and p62-positive inclusions in the hippocampus . Dysfunction associated with these inclusions in the cerebellum as part of the cerebellar cognitive affective syndrome is also possible. This will be challenging to prove or disprove until radioligands that tag these key proteins are available for functional neuroimaging studies .
A summary of the salient features of the FTD-predominant phenotype of c9FTD/ALS due to the GGGGCC hexanucleotide repeat expansion in C9ORF72 is presented in Table Table33.
An important consideration for any clinician evaluating a patient for changes in cognition, behavior, or neuromuscular functioning is when to be suspicious of the mutation in C9ORF72. Clinical clues that should raise suspicion are listed in Table Table44.
With any discovery, 'one question answered poses ten new questions' and this is clearly the case in many aspects of c9FTD/ALS. A list of some issues worthy of further study is presented in Table Table5.5. Our hope is that the observations in this review based on what has been published thus far help steer investigators to answer these and other questions associated with this fascinating disorder.
ALS: amyotrophic lateral sclerosis; bvFTD: behavioral variant frontotemporal dementia; c9FTD/ALS: frontotemporal dementia or amyotrophic lateral sclerosis (or both) linked to chromosome 9; C9ORF72: (gene encoding the mutation in) chromosome 9 open reading frame 72; FDG-PET: flourodeoxyglucose positron emission tomography; FTD: frontotemporal dementia; FTD/ALS: frontotemporal dementia or amyotrophic lateral sclerosis or both; FTLD-MND: frontotemporal lobar degeneration with motor neuron disease; FUS: fused in sarcoma; GGGGCC: (the hexanucleotide expansion of ) guanine-guanine-guanine-guanine-cytosine-cytosine; MAPT: microtubule-associated protein tau; MRI: magnetic resonance imaging; PET: positron emission tomography; PGRN: progranulin; PPA: primary progressive aphasia; TARDBP: TAR DNA-binding protein.
This paper was supported by P50 AG016574. Ronald C Petersen is the principal investigator. BFB declares that he has no competing interests. He has served as an investigator for clinical trials sponsored by Cephalon, Inc. (Frazer, PA, USA), Allon Pharmaceuticals Inc. (Vancouver, BC, Canada), and GE Healthcare (Little Chalfont, Buckinghamshire, UK). He receives royalties from the publication of a book entitled the Behavioral Neurology of Dementia (Cambridge: Cambridge University Press; 2009). He has received honoraria from the American Academy of Neurology. NRG-R declares that he has no competing interests. He is on the scientific advisory board of Codman (part of DePuy Orthopaedics, Inc, Warsaw, IN, USA) and is chair of the data and safety monitoring board of Baxter (Deerfield, IL, USA) regarding an IGIV (immune globulin administered intravenously) trial in Alzheimer's disease, an editor for the Neurologist, and part of multicenter trials for Allon Pharmaceuticals Inc. (progressive supranuclear palsy), Janssen (Titusville, NJ, USA), Pfizer Inc (New York, NY, USA) (bapineuzumab for Alzheimer's disease), and Forest Laboratories, Inc. (New York, NY, USA) using memantine in frontotemporal dementia.
Both authors contributed to the analysis and views expressed in this review. BFB drafted the manuscript, and NRG-R revised it critically. Both authors read and approved the final manuscript.
This work was supported by the 'Mayo Alzheimer's Disease Research Center' (P50 AG016574), the 'Mayo Alzheimer's Disease Patient Registry' (UO1 AG006786), 'Identifying Mechanisms of Dementia: Role for MRI in the Era of Molecular Imaging' (RO1 AG011378), and the Robert H. and Clarice Smith and Abigail Van Buren Alzheimer's Disease Research Program of the Mayo Foundation. We thank our many collaborators across the Mayo Clinic sites in Rochester, MN; Jacksonville, FL; and Scottsdale, AZ. We thank Ian Mackenzie, Adam Boxer, and Bruce Miller for collaborating on the VSM-20 (Vancouver-San Francisco-Mayo Clinic family 20) kindred. We particularly thank the patients and their families for participating in aging and neurodegenerative disease research.