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Original Contribution |

Distinct Clinical Characteristics of C9orf72 Expansion Carriers Compared With GRN, MAPT, and Nonmutation Carriers in a Flanders-Belgian FTLD Cohort FREE

Tim Van Langenhove, MD; Julie van der Zee, PhD; Ilse Gijselinck, PhD; Sebastiaan Engelborghs, MD, PhD; Rik Vandenberghe, MD, PhD; Mathieu Vandenbulcke, MD, PhD; Jan De Bleecker, MD, PhD; Anne Sieben, MD; Jan Versijpt, MD, PhD; Adrian Ivanoiu, MD, PhD; Olivier Deryck, MD; Christiana Willems, MD; Lubina Dillen, PhD; Stéphanie Philtjens, MSc; Githa Maes, MPharm; Veerle Bäumer, BSc; Marleen Van Den Broeck, BSc; Maria Mattheijssens, BSN; Karin Peeters, BSN; Jean-Jacques Martin, MD, PhD; Alex Michotte, MD; Patrick Santens, MD, PhD; Peter De Jonghe, MD, PhD; Patrick Cras, MD, PhD; Peter P. De Deyn, MD, PhD; Marc Cruts, PhD; Christine Van Broeckhoven, PhD, DSc
[+] Author Affiliations

Author Affiliations: VIB–Department of Molecular Genetics, Neurodegenerative Brain Diseases Group (Drs Van Langenhove, van der Zee, Gijselinck, Sieben, Dillen, Martin, Cruts, and Van Broeckhoven, and Mss Philtjens, Van Den Broeck, Mattheijssens, Maes, Bäumer, and Peeters); Institute Born-Bunge, University of Antwerp (Drs Van Langenhove, van der Zee, Gijselinck, Engelborghs, Sieben, Dillen, Martin, De Jonghe, Cras, De Deyn, Cruts, and Van Broeckhoven, and Mss Philtjens, Van Den Broeck, Mattheijssens, Maes, Bäumer, and Peeters); Department of Neurology, Hospital Network Antwerp (ZNA) Middelheim (Drs Engelborghs and De Deyn); Department of Molecular Genetics, Neurogenetics Group (Dr De Jonghe), Antwerp; Department of Neurology, Antwerp University Hospital, Edegem (Drs Van Langenhove, De Jonghe, and Cras); Memory Clinic, Hospital Network Antwerp (ZNA) Hoge Beuken, Hoboken (Drs Engelborghs and De Deyn); Department of Neurology, Laboratory for Cognitive Neurology, University of Leuven and University Hospitals Leuven Gasthuisberg (Dr Vandenberghe); Department of Psychiatry, Brain and Emotion Laboratory Leuven, University of Leuven and University Hospitals Leuven Gasthuisberg (Dr Vandenbulcke), Leuven; Department of Neurology, University Hospital Ghent and University of Ghent, Ghent (Drs De Bleecker, Sieben, and Santens); Department of Neurology, University Hospital Brussel (Drs Versijpt and Michotte); Department of Neurology, Saint-Luc University Hospital and Institute of Neuroscience, Université Catholique de Louvain (Dr Ivanoiu), Brussels; Department of Neurology, AZ Sint-Jan Brugge, Brugge (Dr Deryck); Department of Neurology, Jessa Hospital, Hasselt (Dr Willems), Belgium; and Alzheimer Research Center, University Medical Center Groningen, Groningen, the Netherlands (Dr De Deyn).


JAMA Neurol. 2013;70(3):365-373. doi:10.1001/2013.jamaneurol.181.
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Objective To characterize patients with frontotemporal lobar degeneration (FTLD) with a repeat expansion mutation in the gene C9orf72, and to determine whether there are differences in the clinical presentation compared with FTLD carriers of a mutation in GRN or MAPT or with patients with FTLD without mutation.

Design Patient series.

Setting Dementia clinics in Flanders, Belgium.

Patients Two hundred seventy-five genetically and phenotypically thoroughly characterized patients with FTLD.

Main Outcome Measures Clinical and demographic characteristics of 26 C9orf72 expansion carriers compared with patients with a GRN or MAPT mutation, as well as patients with familial and sporadic FTLD without mutation.

Results C9orf72 expansion carriers developed FTLD at an early age (average, 55.3 years; range, 42-69 years), significantly earlier than in GRN mutation carriers or patients with FTLD without mutation. Mean survival (6.2 years; range, 1.5-17.0 years) was similar to other patient groups. Most developed behavioral variant frontotemporal dementia (85%), with disinhibited behavior as the prominent feature. Concomitant amyotrophic lateral sclerosis is a strong distinguishing feature for C9orf72 -associated FTLD. However, in most patients (73%), amyotrophic lateral sclerosis symptoms were absent. Compared with C9orf72 expansion carriers, nonfluent aphasia and limb apraxia were significantly more common in GRN mutation carriers.

Conclusions C9orf72 -associated FTLD most often presents with early-onset behavioral variant frontotemporal dementia with disinhibition as the prominent feature, with or without amyotrophic lateral sclerosis. Based on the observed genotype-phenotype correlations between the different FTLD syndromes and different genetic causes, we propose a decision tree to guide clinical genetic testing in patients clinically diagnosed as having FTLD.

Figures in this Article

Frontotemporal lobar degeneration (FTLD) is a collective term for a group of neurodegenerative disorders with predominant atrophy of the frontal and/or the temporal lobes of the brain. Despite similar gross pathologic features, FTLD is markedly heterogeneous in clinical presentation, microscopic characteristics, and underlying genetic causes. Clinically, FTLD presents with either changes in personality and social conduct (behavioral variant frontotemporal dementia [bvFTD]) or with language problems (primary progressive aphasias including semantic dementia [SD] and progressive nonfluent aphasia [PNFA]).13 The pathology of FTLD can, in turn, be subdivided according to the identity of the major inclusion protein that is found in protein depositions in degenerating neurons, those being TAR DNA-binding protein 43 (TDP-43; pathologic subclass, FTLD-TDP), tau (FTLD-tau), and FUS (FTLD-FUS).4

Approximately 10% to 15% of patients with FTLD also develop amyotrophic lateral sclerosis (ALS), characterized by progressive muscle weakness, atrophy, and spasticity.5 Furthermore, TDP-43 and FUS are also key pathologic proteins in ALS, suggesting that FTLD and ALS represent a continuum of neurodegenerative diseases and share common pathogenic mechanisms.6 Frontotemporal lobar degeneration also shows clinical overlap with the atypical parkinsonian disorders corticobasal syndrome (CBS) and progressive supranuclear palsy (PSP).7

As much as 40% of patients with FTLD report a first-degree relative with a similar neurodegenerative disorder. Despite the progress in identification of causal genes for FTLD (GRN, MAPT, and rarely VCP and CHMP2B), a significant fraction of familial FTLD remained unexplained, particularly among patients who had a familial history of both FTLD and ALS. Very recently, we and others810 independently demonstrated that a pathologic expansion of a hexanucleotide repeat GGGGCC, located within the regulatory region of C9orf72 is at the basis of chromosome 9p–linked FTLD and ALS. Extensive screenings for this expansion mutation have now been performed in several large patient cohorts of different geographic background, which revealed a C9orf72 expansion in 7% to 9% of all patients with FTLD (12%-18% of familial FTLD) and in 7% to 11% of all patients with ALS (24%-38% of familial ALS).819 In nearly all patients with FTLD, the associated molecular pathology was characterized by cellular inclusion bodies of TDP-43. However, the observed TDP-43 load was variable, and ubiquitin-positive, TDP-43–negative inclusions were also observed, suggesting that other unidentified proteins were also accumulating.9,20,21 The exact length of the pathogenic repeat expansion in C9orf72 has proven difficult to determine but was in 1 family roughly estimated at 700 to 1600 repeat units.8

Here, we describe the detailed clinical characteristics of a large number of C9orf72 expansion carriers. Genotype-phenotype correlations were performed to investigate whether C9orf72 expansion carriers showed distinctive phenotypic features compared with GRN or MAPT mutation carriers or patients with FTLD with no mutation in any of the known FTLD genes. The results of these detailed comparative clinical genetic studies may guide neurology practice in the diagnosis and prognosis of these patients.

STUDY POPULATION

Patients with FTLD (n = 275) were recruited from 1998 as part of an ongoing multicenter collaboration of specialized memory clinics in Flanders, Belgium.9 Index patients were evaluated using a standard protocol, which included a detailed clinical and family history, neurologic examination, neuropsychologic testing, biochemical analyses, and neuroimaging. Additional relatives of mutation carriers of whom detailed neurologic records were available were included in the current study. The diagnosis of FTLD was made according to the international consensus criteria.1 A small number of patients (n = 8) had symptoms of different FTLD subtypes at presentation (denoted as mixed FTLD). Diagnosis of FTLD-ALS was made for 20 patients who also met the criteria for clinical possible ALS according to the revised El Escorial criteria.22 Ten patients with prominent behavioral changes and/or speech impairment received a clinical diagnosis of CBS23 and 4 of PSP.24 Brain autopsy was performed for 4 C9orf72 expansion carriers, as published.9 All data records, medical records, neuroimaging studies, and autopsy reports were reviewed, and the demographic, clinical, and pathologic characteristics of each patient were summarized in a standardized format.

For molecular genetic studies, index patients and relatives were contacted by trained research nurses. Detailed information on family history of dementia was gathered, and additional patients and unaffected family members were asked to participate in genetic studies.

All participants or their legal guardian gave written informed consent for participation in the clinical and genetic studies, as well as for brain autopsy if appropriate. The clinical study protocol and the informed consent forms for patient ascertainment were approved by the local ethics committees of the collaborating medical centers. The genetic and pathologic study protocols and informed consent forms were approved by the ethics committee of the University Hospital of Antwerp and the University of Antwerp, Belgium.

MUTATION ANALYSIS

All patients in this cohort were analyzed for mutations in the 5 known FTLD genes (ie, C9orf72, GRN, MAPT, VCP, and CHMP2B). Genomic DNA was isolated from whole blood using standard protocols. Patients were analyzed for the C9orf72 repeat expansion by a repeat-primed polymerase chain reaction, as described.9 Sequencing of GRN, MAPT, VCP, and CHMP2B was performed as described.2528 Mutation carriers were included in the clinical analysis if DNA was available for testing or if we could show segregation of the mutation to their offspring. Genetic and clinical characteristics of GRN, MAPT, VCP, and CHMP2B mutation carriers are summarized in the eTable.

STATISTICAL ANALYSIS

Average age at onset was compared using an independent-sample t test and median age at onset using a Mann-Whitney U test. Disease durations were analyzed using Cox regression, with sex and age at onset as covariables, as well as censoring at the time of last contact. Clinical characteristics were compared using a Fisher exact test.

DEMOGRAPHIC CHARACTERISTICS

Demographic data of 26 C9orf72 expansion carriers and patients with and without mutations in GRN or MAPT are summarized in Table 1. The mean age at onset of FTLD in C9orf72 expansion carriers was 55.3 years (range, 42-69 years). The age at onset was significantly earlier compared with patients with a GRN mutation (59.6 years; P = .03), as well as patients with sporadic FTLD (63.1 years; P < .001) and familial FTLD without a mutation (63.9 years; P < .001). We produced a liability risk curve by using age at onset or age at last evaluation of all expansion carriers in the C9orf72 families (n = 51), which showed that 47% of the expansion carriers were affected by the age of 60 years, whereas 91% were affected by the age of 70 years (Figure 1). Notably, 3 expansion carriers are still asymptomatic at ages older than 70 years (1 at age 73 years and 2 at age 76 years). The average duration of survival in 17 C9orf72 expansion carriers who died during follow-up was 6.2 years (range, 1.5-17.0 years), which was similar to that observed in the other patient groups. Once the first symptoms of ALS appeared, patients survived on average 1.8 years (range, 1.0-3.2 years). Thirteen index patients with a C9orf72 expansion mutation had a familial history compatible with autosomal dominant inheritance, while 4 had at least 1 affected relative but the criteria used for autosomal dominant inheritance were not met (Figure 2). Three expansion carriers had no familial history of the disease. In 64% of the C9orf72 families, the disease presentation included both FTLD and ALS phenotypes, while in the remainder, this was FTLD only.

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Figure 1. Liability risk curve for C9orf72 expansion carriers. The age-related penetrance of a C9orf72 expansion is shown using the age at onset or age at last evaluation for 42 affected and 9 unaffected expansion carriers.

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Figure 2. Gene mutation frequencies in the Flanders-Belgian frontotemporal lobar degeneration cohort. Indicated by F-AD, familial consistent with autosomal dominant means there were at least 3 affected individuals with dementia or amyotrophic lateral sclerosis in the pedigree in 2 or more generations. Familial (F) patients are those with at least 1 affected relative but the criteria used for F-AD were not met. Sporadic (S) patients are those patients without known affected relatives. MUT− indicates mutation negative.

Table Graphic Jump LocationTable 1. Characteristics of C9orf72 Expansion Carriers Compared With Other Patients With FTLD With and Without Mutations
BEHAVIORAL AND LANGUAGE DYSFUNCTION

Twenty-two C9orf72 expansion carriers (85%) were diagnosed as having bvFTD (Tables 2, 3, 4, and 5). Details on the behavioral, cognitive, and clinical characteristics are further shown in Tables 2-4. Social inappropriate, disinhibited behavior, with or without restlessness and hyperactivity, were the presenting and most prominent symptoms in most patients. Apathetic forms of bvFTD without disinhibition were infrequent (14%). Other frequent features of patients with bvFTD with a C9orf72 expansion included compulsive or stereotyped behavior and impaired insight. Psychotic features were recorded in 12%. Memory impairment was also a relatively frequent complaint (42%); however, an early isolated episodic memory disorder, typical for Alzheimer disease, did not occur. Neuropsychologic evaluation usually demonstrated remarkable impairment on frontal executive tasks. In 2 patients, the initial symptoms consisted mainly of nonfluent speech and agrammatism with spared single-word comprehension consistent with the diagnosis of PNFA. In contrast, the third patient was diagnosed as having SD; her initial symptoms consisted of severe anomia, with comprehension deficits, surface dyslexia, spared sentence repetition, and fluent speech, although decreased in output. Behavioral abnormalities were absent at the time of diagnosis for 2 of the patients with primary progressive aphasia, while mild rigidity in thoughts was reported in the third. Some patients developed overlapping symptoms of different FTLD subtypes during their disease course (Tables 2-4). The patient with SD initially presenting with anomia developed typical symptoms of bvFTD 3 years after onset. Another patient (DR489.1; Tables 2-4) presented with both prominent behavioral changes; effortful, halting speech; and impaired language comprehension.

Table Graphic Jump LocationTable 2. Clinical Phenotypes and Demographic Characteristics of Patients With C9orf72 Repeat Expansion
Table Graphic Jump LocationTable 3. Detailed Behavioral and Clinical Characteristics of Patients With C9orf72 Repeat Expansion
Table Graphic Jump LocationTable 4. Imaging and Other Investigation Findings in Patients With C9orf72 Repeat Expansion
Table Graphic Jump LocationTable 5. Clinical Characteristics of FTLD Groups With and Without a Mutation in C9orf72, GRN, or MAPT
MOTOR NEURON DISEASE

Seven C9orf72 expansion carriers with FTLD (27%) also developed signs of motor neuron disease in 2 or more anatomical regions (Tables 2-4). Nearly all patients with FTLD-ALS (86%) developed signs of both upper and lower motor neuron disease during the disease course, with one showing a lower motor neuron–predominant picture. Bulbar involvement at onset was seen in 5 patients with FTLD-ALS. In 4 patients, FTLD and ALS symptoms developed nearly simultaneously. In 3 other patients with FTLD-ALS, the maximum interval between onset of FTLD and ALS symptoms was 2.5 years. In the 19 patients with FTLD without ALS, neurologic examination results at onset were usually unremarkable, except for occasional frontal release signs or repetitive movements. Eight C9orf72 expansion carriers without ALS with disease duration of 5 years or more were evaluated. Signs of parkinsonism, mostly consisting of bradykinesia and rigidity, were found in 4 patients. However, signs of lower motor neuron disease were not reported in these patients.

IMAGING AND OTHER INVESTIGATION FINDINGS

Functional neuroimaging was performed in 18 C9orf72 expansion carriers, consisting of single-photon emission computed tomography in 13 individuals and positron emission tomography with 18fluorodeoxyglucose in 5 individuals. Predominant hypoperfusion or glucose hypometabolism in the frontal and/or temporal regions was detected on visual inspection in 89% (Tables 2-4). One patient with bvFTD had normal single-photon emission computed tomography results 3 years after clinical onset, and another had hypoperfusion in the superior part of the parietal lobes and left anterior temporal lobe. Magnetic resonance imaging or computed tomographic imaging showed some degree of frontal and/or temporal lobe atrophy, but the topographic pattern was generally less specific than functional imaging abnormalities. Levels of β-amyloid, total tau, and phospho-tau181P were normal in the cerebrospinal fluid of 5 C9orf72 mutation carriers. Nerve conduction studies and electromyography were performed in 5 patients with FTLD-ALS and confirmed the clinical diagnosis in all. Two patients with FTLD without clinical symptoms of ALS, of which 1 reported swallowing difficulties 3 years after onset of FTLD, had normal electromyography results. The diagnosis of FTLD was confirmed in 4 autopsied patients with bvFTD with the C9orf72 expansion (Tables 2-4).9 In 1 patient, DR29.1, the lower brainstem and spinal cord were also examined. No neuronal loss, ubiquitin-positive inclusions, or TDP-43–positive inclusions were observed in these regions.

GENOTYPE-PHENOTYPE CORRELATIONS IN FTLD

The C9orf72 expansion mutation accounted for most of the patients with familial FTLD-ALS (88%; Table 5). Amyotrophic lateral sclerosis was not found in GRN or MAPT mutation carriers and occurred less frequently in patients with unresolved familial FTLD (1%, <  .001) and sporadic FTLD (8%; P = .01). In contrast, GRN mutation carriers more often presented with PNFA (41%) compared with C9orf72 expansion carriers (8%; P = .009) and patients without mutation (14% of familial FTLD, P = .01; 14% of sporadic FTLD, P = .003). Of the 23 index patients with familial PNFA in the study population, 48% had a mutation in GRN. Furthermore, 1 patient with PNFA had concomitant CBS symptoms at onset, with severe limb apraxia and asymmetrical parkinsonism; 4 other GRN mutation carriers developed limb apraxia in a later phase of the disease. Together, 19% of GRN mutation carriers developed limb apraxia compared with none of the C9orf72 mutation carriers (P = .05), 3% of the patients with familial FTLD (P = .04), and 6% of those with sporadic FTLD (P = .03). The frequency of GRN mutations in familial FTLD with limb apraxia was 63%. All 8 studied MAPT mutation carriers had bvFTD presentations. One carrier of a p.R406W mutation in MAPT also developed vertical gaze palsy with postural instability, and parkinsonism 12 years after bvFTD onset, meeting the criteria for diagnosis of PSP.

To date, a pathogenic hexanucleotide repeat expansion in C9orf72 is the most frequent genetic cause of FTLD in the Flanders-Belgian cohort, with mutation frequencies of 8% overall and 17% in familial patients.9 In the present study, we studied in detail the clinical features of C9orf72 expansion carriers and compared the data with other patient groups with FTLD with a mutation in GRN or MAPT or without, with the aim of identifying noticeable relationships between genes and clinical phenotype.

C9orf72 expansion carriers often develop FTLD at a young age (average, 55.3 years), earlier than in GRN mutation carriers or patients without a mutation. However, the age at onset is highly variable, and some mutation carriers live up to 75 years without significant signs of disease. By the age of 70 years, nearly 90% of C9orf72 expansion carriers were affected. The mean disease survival in C9orf72 expansion carriers (6.2 years) was similar to that in the other patient groups but was also highly variable (range, 1.5-17.0 years). Amyotrophic lateral sclerosis is a negative prognostic factor; once first signs of ALS developed, patients survived on average 1.8 years. The wide variability in age at onset and disease duration suggests that other modifying factors are also important for the clinical expression of a C9orf72 expansion mutation.

Most C9orf72 expansion carriers had a positive family history of disease, but in agreement with other studies, C9orf72 expansions were also observed in a minor percentage of patients with sporadic FTLD (2%-5%).8,9,11,17,18 It is likely that in some of these patients with sporadic FTLD, the positive familial history was obscured by nonpenetrance of the mutation in parents, given that expansion carriers can remain asymptomatic until advanced age. Notably, all 3 sporadic C9orf72 expansion carriers had developed disease at a young age (42, 49, and 58 years).

In most of the C9orf72 expansion carriers (85%), the phenotype of dementia was consistent with bvFTD. In more detail, expansion carriers with bvFTD often presented with inappropriate behavior and agitation. This is in contrast to patients with bvFTD with a GRN mutation, in whom apathy dominates the clinical picture.29,30 One study reported that 38% of patients with FTLD with a C9orf72 expansion mutation had severe psychotic features compared with 4% in patients without mutation, suggesting that this is a distinct clinical feature of C9orf72 -associated FTLD.18 In contrast, we observed delusions or hallucinations in 12% of the C9orf72 expansion carriers, with a comparable frequency in the other patient groups. Similar low frequencies of hallucinations or delusions in C9orf72 expansion carriers were also reported in other FTLD cohorts.16,17

A few C9orf72 expansion carriers presented with isolated language dysfunction (12%), consistent with PNFA in 2 patients and SD in 1 patient. This is similar to the proportion of primary progressive aphasia phenotypes that have been reported in other FTLD cohorts (0%-34%).11,1518 The isolated language dysfunction in the patient with SD was followed by the development of typical symptoms of bvFTD after 3 years, which possibly reflects the diffuse spread of atrophy in the frontotemporal regions once the C9orf72 -associated disease progresses.

Despite C9orf72 being a major causal gene for ALS, ALS was absent in most of the Flanders-Belgian C9orf72 patients (27% had ALS). No signs of lower motor neuron disease were present on neurologic examination in several patients who were followed up for multiple years. Pathologic examination results of the brainstem and spinal cord in 1 of the patients we examined, as well as in other series of autopsied C9orf72 expansion carriers, support this observation.11,17,19 Parkinsonism, usually characterized by an akinetic-rigid syndrome later in the disease course, occurred in a similar proportion of C9orf72 expansion carriers as in other patient groups, precluding clinical differentiation. It is notable that when ALS complicated FTLD (n = 7), this was usually early in the disease course, with a maximum delay of 2.5 years. However, this finding needs confirmation by other, longitudinal studies.

Mutations in known FTLD genes now account for 34% of the familial FTLD cases and 88% of the familial FTLD-ALS cases in the Flanders-Belgian cohort. In patients with sporadic FTLD and those with FTLD-ALS, who constitute the majority, mutations can be observed in 3% and 0%, respectively. Taken together, this indicates that other genes remain to be discovered that contribute to the FTLD-ALS disease spectrum.

Frontotemporal lobar degeneration is a clinically and genetically heterogeneous disorder. Although differentiation at the individual patient level is still challenging, we found notable differences in the presenting phenotype associated with mutations in the 3 major FTLD genes. Based on these genotype-phenotype correlations combined with the observed mutation frequencies of the different FTLD-associated genes in the Flanders-Belgian FTLD cohort, we propose a decision tree on the basis of which the FTLD genes can be tested in a clinical genetic diagnostic setting (Figure 3).

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Figure 3. Decision tree for clinical genetic testing of patients clinically diagnosed as having frontotemporal lobar degeneration. +ALS indicates concomitant amyotrophic lateral sclerosis; bvFTD, behavioral variant frontotemporal dementia; +CBS, concomitant corticobasal degeneration syndrome; +PDB/IBM, concomitant Paget disease of the bone/inclusion body myopathy; PNFA, progressive nonfluent aphasia; +PSP, concomitant progressive supranuclear palsy syndrome; SD, semantic dementia. Dotted lines indicate rare genetic causes.

C9orf72 testing has priority in most patients with FTLD. To date, C9orf72 expansion mutations are the only known genetic cause of FTLD-ALS and are the most frequent cause of bvFTD without ALS in the Flanders-Belgian cohort. In contrast, familial occurrence of PNFA, limb apraxia, and a CBS-like phenotype are more often associated with a GRN mutation, in line with previous reports.29,30 The few MAPT mutation carriers in the Flanders-Belgian cohort complicated statistically robust comparison. Nonetheless, all MAPT mutation carriers presented with bvFTD, which is in keeping with results from literature.29,31MAPT mutations have also been associated with parkinsonism-predominant syndromes.31,32 In the Flanders-Belgian cohort, 1 carrier of the p.R406W mutation in MAPT developed 12 years after bvFTD onset the cardinal clinical signs of PSP. So far, CBS or PSP phenotypes have not been associated with C9orf72 expansion mutations, except for dystonic hand posturing being reported in 1 patient.15 In the unusual case of FTLD or FTLD-ALS families also segregating inclusion body myopathy and/or Paget disease of the bone,26VCP testing should be prioritized.

In conclusion, patients with the C9orf72 repeat mutation usually have an early onset, a familial history of FTLD and/or ALS, present with bvFTD (with disinhibition as the prominent feature), and more often develop ALS compared with other patient groups with FTLD. Yet, C9orf72 expansion mutations also account for a small percentage of patients with FTLD with language difficulties at onset and patients without a familial history of the disease. Furthermore, we report genotype-phenotype correlations in FTLD that may provide important insights that are of particular relevance in the context of molecular diagnostics of FTLD.

Correspondence: Christine Van Broeckhoven, PhD, DSc, VIB–Department of Molecular Genetics, Neurodegenerative Brain Diseases Group, University of Antwerp–CDE, Universiteitsplein 1, B-2610 Antwerp, Belgium (christine.vanbroeckhoven@molgen.vib-ua.be).

Accepted for Publication: August 6, 2012.

Published Online: January 21, 2013. doi:10.1001/2013.jamaneurol.181

Author Contributions:Study concept and design: Van Langenhove, van der Zee, De Deyn, Cruts, and Van Broeckhoven. Acquisition of data: Van Langenhove, van der Zee, Gijselinck, Engelborghs, Vandenberghe, Vandenbulcke, De Bleecker, Versijpt, Ivanoiu, Deryck, Willems, Dillen, Philtjens, Maes, Bäumer, Van Den Broeck, Mattheijssens, Peeters, Martin, Michotte, Santens, De Jonghe, Cras, De Deyn, and Cruts. Analysis and interpretation of data: Van Langenhove, van der Zee, Gijselinck, Vandenberghe, Vandenbulcke, Sieben, Versijpt, Ivanoiu, Deryck, Philtjens, Van Den Broeck, Peeters, Cras, Cruts, and Van Broeckhoven. Drafting of the manuscript: Van Langenhove, van der Zee, Vandenbulcke, Sieben, Ivanoiu, Deryck, Dillen, Maes, Bäumer, Van Den Broeck, Mattheijssens, Peeters, Cruts, and Van Broeckhoven. Critical revision of the manuscript for important intellectual content: Van Langenhove, van der Zee, Gijselinck, Engelborghs, Vandenberghe, Vandenbulcke, De Bleecker, Versijpt, Ivanoiu, Deryck, Willems, Philtjens, Martin, Michotte, Santens, De Jonghe, Cras, De Deyn, Cruts, and Van Broeckhoven. Statistical analysis: Van Langenhove, van der Zee, and Gijselinck. Obtained funding: van der Zee, Vandenberghe, De Deyn, Cruts, and Van Broeckhoven. Administrative, technical, and material support: van der Zee, Gijselinck, De Bleecker, Versijpt, Dillen, Philtjens, Maes, Bäumer, Van Den Broeck, Mattheijssens, and Peeters. Study supervision: van der Zee, Vandenberghe, De Bleecker, Sieben, Versijpt, Ivanoiu, Martin, Cras, De Deyn, and Van Broeckhoven.

Conflict of Interest Disclosures: None reported.

Funding/Support: This study was funded in part by the Interuniversity Attraction Poles program P6/43 of the Belgian Science Policy Office; the Foundation for Alzheimer Research (SAO/FRMA); the Medical Foundation Queen Elisabeth; the Methusalem Excellence Program of the Flemish government; the Research Foundation Flanders (FWO); the Agency for Innovation by Science and Technology Flanders (IWT); and the Special Research Fund of the University of Antwerp, Belgium. The study was performed in the frame of the international consortium of the Centers of Excellence in Neurodegenerative Brain Diseases (CoEN) supported by the Flemish government. The IWT provided a PhD fellowship to Dr Van Langenhove and the FWO a PhD fellowship to Ms Philtjens, postdoctoral fellowships to Drs van der Zee and Gijselinck, and senior clinical investigator mandates to Drs Sieben and Vandenberghe.

Additional Contributions: We thank the participants of this study for their generous cooperation. We further acknowledge the contribution of the personnel of the Genetic Service Facility (http://www.vibgeneticservicefacility.be/), the Diagnostic Service Facility (http://www.molgen.ua.ac.be/DNADiagnostics/), and the Antwerp Biobank, as well as the staff of the many neurologic centers that are part of the Belgian Neurology (BELNEU) consortium and have contributed to the sampling and clinical diagnoses of the participants of this study.

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Renton AE, Majounie E, Waite A,  et al; ITALSGEN Consortium.  A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD.  Neuron. 2011;72(2):257-268
PubMed   |  Link to Article
Boeve BF, Boylan KB, Graff-Radford NR,  et al.  Characterization of frontotemporal dementia and/or amyotrophic lateral sclerosis associated with the GGGGCC repeat expansion in C9ORF72.  Brain. 2012;135(pt 3):765-783
PubMed   |  Link to Article
Byrne S, Elamin M, Bede P,  et al.  Cognitive and clinical characteristics of patients with amyotrophic lateral sclerosis carrying a C9orf72 repeat expansion: a population-based cohort study.  Lancet Neurol. 2012;11(3):232-240
PubMed   |  Link to Article
Chiò A, Borghero G, Restagno G,  et al; ITALSGEN consortium.  Clinical characteristics of patients with familial amyotrophic lateral sclerosis carrying the pathogenic GGGGCC hexanucleotide repeat expansion of C9ORF72.  Brain. 2012;135(pt 3):784-793
PubMed   |  Link to Article
Cooper-Knock J, Hewitt C, Highley JR,  et al.  Clinico-pathological features in amyotrophic lateral sclerosis with expansions in C9ORF72.  Brain. 2012;135(pt 3):751-764
PubMed   |  Link to Article
Hsiung GY, DeJesus-Hernandez M, Feldman HH,  et al.  Clinical and pathological features of familial frontotemporal dementia caused by C9ORF72 mutation on chromosome 9p.  Brain. 2012;135(pt 3):709-722
PubMed   |  Link to Article
Mahoney CJ, Beck J, Rohrer JD,  et al.  Frontotemporal dementia with the C9ORF72 hexanucleotide repeat expansion: clinical, neuroanatomical and neuropathological features.  Brain. 2012;135(pt 3):736-750
PubMed   |  Link to Article
Simón-Sánchez J, Dopper EG, Cohn-Hokke PE,  et al.  The clinical and pathological phenotype of C9ORF72 hexanucleotide repeat expansions.  Brain. 2012;135(pt 3):723-735
PubMed   |  Link to Article
Snowden JS, Rollinson S, Thompson JC,  et al.  Distinct clinical and pathological characteristics of frontotemporal dementia associated with C9ORF72 mutations.  Brain. 2012;135(pt 3):693-708
PubMed   |  Link to Article
Stewart H, Rutherford NJ, Briemberg H,  et al.  Clinical and pathological features of amyotrophic lateral sclerosis caused by mutation in the C9ORF72 gene on chromosome 9p.  Acta Neuropathol. 2012;123(3):409-417
PubMed   |  Link to Article
Al-Sarraj S, King A, Troakes C,  et al.  p62 positive, TDP-43 negative, neuronal cytoplasmic and intranuclear inclusions in the cerebellum and hippocampus define the pathology of C9orf72-linked FTLD and MND/ALS.  Acta Neuropathol. 2011;122(6):691-702
PubMed   |  Link to Article
Murray ME, DeJesus-Hernandez M, Rutherford NJ,  et al.  Clinical and neuropathologic heterogeneity of c9FTD/ALS associated with hexanucleotide repeat expansion in C9ORF72.  Acta Neuropathol. 2011;122(6):673-690
PubMed   |  Link to Article
Brooks BR, Miller RG, Swash M, Munsat TL.World Federation of Neurology Research Group on Motor Neuron Diseases.  El Escorial revisited: revised criteria for the diagnosis of amyotrophic lateral sclerosis.  Amyotroph Lateral Scler Other Motor Neuron Disord. 2000;1(5):293-299
PubMed   |  Link to Article
Boeve BF, Lang AE, Litvan I. Corticobasal degeneration and its relationship to progressive supranuclear palsy and frontotemporal dementia.  Ann Neurol. 2003;54:(suppl 5)  S15-S19
PubMed   |  Link to Article
Litvan I, Agid Y, Calne D,  et al.  Clinical research criteria for the diagnosis of progressive supranuclear palsy (Steele-Richardson-Olszewski syndrome): report of the NINDS-SPSP international workshop.  Neurology. 1996;47(1):1-9
PubMed   |  Link to Article
Cruts M, Gijselinck I, van der Zee J,  et al.  Null mutations in progranulin cause ubiquitin-positive frontotemporal dementia linked to chromosome 17q21.  Nature. 2006;442(7105):920-924
PubMed   |  Link to Article
van der Zee J, Pirici D, Van Langenhove T,  et al.  Clinical heterogeneity in 3 unrelated families linked to VCP p.Arg159His.  Neurology. 2009;73(8):626-632
PubMed   |  Link to Article
van der Zee J, Rademakers R, Engelborghs S,  et al.  A Belgian ancestral haplotype harbours a highly prevalent mutation for 17q21-linked tau-negative FTLD.  Brain. 2006;129(pt 4):841-852
PubMed   |  Link to Article
van der Zee J, Urwin H, Engelborghs S,  et al.  CHMP2B C-truncating mutations in frontotemporal lobar degeneration are associated with an aberrant endosomal phenotype in vitro.  Hum Mol Genet. 2008;17(2):313-322
PubMed   |  Link to Article
Pickering-Brown SM, Rollinson S, Du Plessis D,  et al.  Frequency and clinical characteristics of progranulin mutation carriers in the Manchester frontotemporal lobar degeneration cohort: comparison with patients with MAPT and no known mutations.  Brain. 2008;131(pt 3):721-731
PubMed   |  Link to Article
Beck J, Rohrer JD, Campbell T,  et al.  A distinct clinical, neuropsychological and radiological phenotype is associated with progranulin gene mutations in a large UK series.  Brain. 2008;131(pt 3):706-720
PubMed   |  Link to Article
Spina S, Farlow MR, Unverzagt FW,  et al.  The tauopathy associated with mutation +3 in intron 10 of tau: characterization of the MSTD family.  Brain. 2008;131(pt 1):72-89
PubMed
Bugiani O, Murrell JR, Giaccone G,  et al.  Frontotemporal dementia and corticobasal degeneration in a family with a P301S mutation in tau.  J Neuropathol Exp Neurol. 1999;58(6):667-677
PubMed   |  Link to Article

Figures

Place holder to copy figure label and caption
Graphic Jump Location

Figure 1. Liability risk curve for C9orf72 expansion carriers. The age-related penetrance of a C9orf72 expansion is shown using the age at onset or age at last evaluation for 42 affected and 9 unaffected expansion carriers.

Place holder to copy figure label and caption
Graphic Jump Location

Figure 2. Gene mutation frequencies in the Flanders-Belgian frontotemporal lobar degeneration cohort. Indicated by F-AD, familial consistent with autosomal dominant means there were at least 3 affected individuals with dementia or amyotrophic lateral sclerosis in the pedigree in 2 or more generations. Familial (F) patients are those with at least 1 affected relative but the criteria used for F-AD were not met. Sporadic (S) patients are those patients without known affected relatives. MUT− indicates mutation negative.

Place holder to copy figure label and caption
Graphic Jump Location

Figure 3. Decision tree for clinical genetic testing of patients clinically diagnosed as having frontotemporal lobar degeneration. +ALS indicates concomitant amyotrophic lateral sclerosis; bvFTD, behavioral variant frontotemporal dementia; +CBS, concomitant corticobasal degeneration syndrome; +PDB/IBM, concomitant Paget disease of the bone/inclusion body myopathy; PNFA, progressive nonfluent aphasia; +PSP, concomitant progressive supranuclear palsy syndrome; SD, semantic dementia. Dotted lines indicate rare genetic causes.

Tables

Table Graphic Jump LocationTable 1. Characteristics of C9orf72 Expansion Carriers Compared With Other Patients With FTLD With and Without Mutations
Table Graphic Jump LocationTable 2. Clinical Phenotypes and Demographic Characteristics of Patients With C9orf72 Repeat Expansion
Table Graphic Jump LocationTable 3. Detailed Behavioral and Clinical Characteristics of Patients With C9orf72 Repeat Expansion
Table Graphic Jump LocationTable 4. Imaging and Other Investigation Findings in Patients With C9orf72 Repeat Expansion
Table Graphic Jump LocationTable 5. Clinical Characteristics of FTLD Groups With and Without a Mutation in C9orf72, GRN, or MAPT

References

Neary D, Snowden JS, Gustafson L,  et al.  Frontotemporal lobar degeneration: a consensus on clinical diagnostic criteria.  Neurology. 1998;51(6):1546-1554
PubMed   |  Link to Article
Rascovsky K, Hodges JR, Knopman D,  et al.  Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia.  Brain. 2011;134(pt 9):2456-2477
PubMed   |  Link to Article
Gorno-Tempini ML, Hillis AE, Weintraub S,  et al.  Classification of primary progressive aphasia and its variants.  Neurology. 2011;76(11):1006-1014
PubMed   |  Link to Article
Mackenzie IRA, Neumann M, Bigio EH,  et al.  Nomenclature and nosology for neuropathologic subtypes of frontotemporal lobar degeneration: an update.  Acta Neuropathol. 2010;119(1):1-4
PubMed   |  Link to Article
Lomen-Hoerth C, Anderson T, Miller B. The overlap of amyotrophic lateral sclerosis and frontotemporal dementia.  Neurology. 2002;59(7):1077-1079
PubMed   |  Link to Article
van Langenhove T, van der Zee J, van Broeckhoven C. The molecular basis of the frontotemporal lobar degeneration-amyotrophic lateral sclerosis spectrum [published online March 16, 2012].  Ann Med
PubMed  |  Link to Article
Kertesz A, Munoz D. Relationship between frontotemporal dementia and corticobasal degeneration/progressive supranuclear palsy.  Dement Geriatr Cogn Disord. 2004;17(4):282-286
PubMed   |  Link to Article
DeJesus-Hernandez M, Mackenzie IR, Boeve BF,  et al.  Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS.  Neuron. 2011;72(2):245-256
PubMed   |  Link to Article
Gijselinck I, Van Langenhove T, van der Zee J,  et al.  A C9orf72 promoter repeat expansion in a Flanders-Belgian cohort with disorders of the frontotemporal lobar degeneration-amyotrophic lateral sclerosis spectrum: a gene identification study.  Lancet Neurol. 2012;11(1):54-65
PubMed   |  Link to Article
Renton AE, Majounie E, Waite A,  et al; ITALSGEN Consortium.  A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD.  Neuron. 2011;72(2):257-268
PubMed   |  Link to Article
Boeve BF, Boylan KB, Graff-Radford NR,  et al.  Characterization of frontotemporal dementia and/or amyotrophic lateral sclerosis associated with the GGGGCC repeat expansion in C9ORF72.  Brain. 2012;135(pt 3):765-783
PubMed   |  Link to Article
Byrne S, Elamin M, Bede P,  et al.  Cognitive and clinical characteristics of patients with amyotrophic lateral sclerosis carrying a C9orf72 repeat expansion: a population-based cohort study.  Lancet Neurol. 2012;11(3):232-240
PubMed   |  Link to Article
Chiò A, Borghero G, Restagno G,  et al; ITALSGEN consortium.  Clinical characteristics of patients with familial amyotrophic lateral sclerosis carrying the pathogenic GGGGCC hexanucleotide repeat expansion of C9ORF72.  Brain. 2012;135(pt 3):784-793
PubMed   |  Link to Article
Cooper-Knock J, Hewitt C, Highley JR,  et al.  Clinico-pathological features in amyotrophic lateral sclerosis with expansions in C9ORF72.  Brain. 2012;135(pt 3):751-764
PubMed   |  Link to Article
Hsiung GY, DeJesus-Hernandez M, Feldman HH,  et al.  Clinical and pathological features of familial frontotemporal dementia caused by C9ORF72 mutation on chromosome 9p.  Brain. 2012;135(pt 3):709-722
PubMed   |  Link to Article
Mahoney CJ, Beck J, Rohrer JD,  et al.  Frontotemporal dementia with the C9ORF72 hexanucleotide repeat expansion: clinical, neuroanatomical and neuropathological features.  Brain. 2012;135(pt 3):736-750
PubMed   |  Link to Article
Simón-Sánchez J, Dopper EG, Cohn-Hokke PE,  et al.  The clinical and pathological phenotype of C9ORF72 hexanucleotide repeat expansions.  Brain. 2012;135(pt 3):723-735
PubMed   |  Link to Article
Snowden JS, Rollinson S, Thompson JC,  et al.  Distinct clinical and pathological characteristics of frontotemporal dementia associated with C9ORF72 mutations.  Brain. 2012;135(pt 3):693-708
PubMed   |  Link to Article
Stewart H, Rutherford NJ, Briemberg H,  et al.  Clinical and pathological features of amyotrophic lateral sclerosis caused by mutation in the C9ORF72 gene on chromosome 9p.  Acta Neuropathol. 2012;123(3):409-417
PubMed   |  Link to Article
Al-Sarraj S, King A, Troakes C,  et al.  p62 positive, TDP-43 negative, neuronal cytoplasmic and intranuclear inclusions in the cerebellum and hippocampus define the pathology of C9orf72-linked FTLD and MND/ALS.  Acta Neuropathol. 2011;122(6):691-702
PubMed   |  Link to Article
Murray ME, DeJesus-Hernandez M, Rutherford NJ,  et al.  Clinical and neuropathologic heterogeneity of c9FTD/ALS associated with hexanucleotide repeat expansion in C9ORF72.  Acta Neuropathol. 2011;122(6):673-690
PubMed   |  Link to Article
Brooks BR, Miller RG, Swash M, Munsat TL.World Federation of Neurology Research Group on Motor Neuron Diseases.  El Escorial revisited: revised criteria for the diagnosis of amyotrophic lateral sclerosis.  Amyotroph Lateral Scler Other Motor Neuron Disord. 2000;1(5):293-299
PubMed   |  Link to Article
Boeve BF, Lang AE, Litvan I. Corticobasal degeneration and its relationship to progressive supranuclear palsy and frontotemporal dementia.  Ann Neurol. 2003;54:(suppl 5)  S15-S19
PubMed   |  Link to Article
Litvan I, Agid Y, Calne D,  et al.  Clinical research criteria for the diagnosis of progressive supranuclear palsy (Steele-Richardson-Olszewski syndrome): report of the NINDS-SPSP international workshop.  Neurology. 1996;47(1):1-9
PubMed   |  Link to Article
Cruts M, Gijselinck I, van der Zee J,  et al.  Null mutations in progranulin cause ubiquitin-positive frontotemporal dementia linked to chromosome 17q21.  Nature. 2006;442(7105):920-924
PubMed   |  Link to Article
van der Zee J, Pirici D, Van Langenhove T,  et al.  Clinical heterogeneity in 3 unrelated families linked to VCP p.Arg159His.  Neurology. 2009;73(8):626-632
PubMed   |  Link to Article
van der Zee J, Rademakers R, Engelborghs S,  et al.  A Belgian ancestral haplotype harbours a highly prevalent mutation for 17q21-linked tau-negative FTLD.  Brain. 2006;129(pt 4):841-852
PubMed   |  Link to Article
van der Zee J, Urwin H, Engelborghs S,  et al.  CHMP2B C-truncating mutations in frontotemporal lobar degeneration are associated with an aberrant endosomal phenotype in vitro.  Hum Mol Genet. 2008;17(2):313-322
PubMed   |  Link to Article
Pickering-Brown SM, Rollinson S, Du Plessis D,  et al.  Frequency and clinical characteristics of progranulin mutation carriers in the Manchester frontotemporal lobar degeneration cohort: comparison with patients with MAPT and no known mutations.  Brain. 2008;131(pt 3):721-731
PubMed   |  Link to Article
Beck J, Rohrer JD, Campbell T,  et al.  A distinct clinical, neuropsychological and radiological phenotype is associated with progranulin gene mutations in a large UK series.  Brain. 2008;131(pt 3):706-720
PubMed   |  Link to Article
Spina S, Farlow MR, Unverzagt FW,  et al.  The tauopathy associated with mutation +3 in intron 10 of tau: characterization of the MSTD family.  Brain. 2008;131(pt 1):72-89
PubMed
Bugiani O, Murrell JR, Giaccone G,  et al.  Frontotemporal dementia and corticobasal degeneration in a family with a P301S mutation in tau.  J Neuropathol Exp Neurol. 1999;58(6):667-677
PubMed   |  Link to Article

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Supplemental Content

Van Langenhove T, van der Zee J, Gijselinck I, et al. Distinct clinical characteristics of C9orf72 expansion carriers compared with GRN, MAPT, and nonmutation carriers in a Flanders-Belgian FTLD cohort [published online January 21, 2013]. JAMA Neurology. doi:10.1001/2013.jamaneurol.181.

eTable. Phenotype of FTLD carriers of a mutation in known FTLD genes GRN, MAPT, VCP, and CHMP2B

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