Research
Original Investigation
Development and Validation of Pedigree Classification Criteria
for Frontotemporal Lobar Degeneration
Elisabeth M. Wood, MS; Dana Falcone, MS; EunRan Suh, PhD; David J. Irwin, MD; Alice S. Chen-Plotkin, MD;
Edward B. Lee, PhD; Sharon X. Xie, PhD; Vivianna M. Van Deerlin, MD, PhD; Murray Grossman, MD
IMPORTANCE A significant portion of frontotemporal lobar degeneration (FTLD) is due to
Supplemental content at
jamaneurology.com
inherited gene mutations, and we are unaware of a large sequential series that includes a
recently discovered inherited cause of FTLD. There is also great need to develop clinical tools
and approaches that will assist clinicians in the identification and counseling of patients with
FTLD and their families regarding the likelihood of an identifiable genetic cause.
OBJECTIVES To ascertain the frequency of inherited FTLD and develop validated pedigree
classification criteria for FTLD that provide a standardized means to evaluate pedigree
information and insight into the likelihood of mutation-positive genetic test results for
C9orf72, MAPT, and GRN.
DESIGN Information about pedigrees and DNA was collected from 306 serially assessed
patients with a clinical diagnosis of FTLD. This information included gene test results for
C9orf72, MAPT, and GRN. Pedigree classification criteria were developed based on a literature
review of FTLD genetics and pedigree tools and then refined by reviewing mutation-positive
and -negative pedigrees to determine differentiating characteristics.
SETTING Academic medical center.
PARTICIPANTS Patients with FTLD.
MAIN OUTCOMES AND MEASURES Familial risk.
RESULTS The rate of C9orf72, MAPT, or GRN mutation–positive FTLD in this series was 15.4%.
Categories designating the risk level for hereditary cause were termed high, medium, low,
apparent sporadic, and unknown significance. Thirty-nine pedigrees (12.7%) met criteria for
high, 31 (10.1%) for medium, 46 (15.0%) for low, 91 (29.7%) for apparent sporadic, and 99
(32.4%) for unknown significance. The mutation-detection rates were as follows: high, 64.1%;
medium, 29%; low, 10.9%; apparent sporadic, 1.1%; and unknown significance, 7.1%.
Mutation-detection rates differed significantly between the high and other categories.
CONCLUSIONS AND RELEVANCE Mutation rates are high in FTLD spectrum disorders, and the
proposed criteria provide a validated standard for the classification of FTLD pedigrees. The
combination of pedigree criteria and mutation-detection rates has important implications for
genetic counseling and testing in clinical settings.
JAMA Neurol. 2013;70(11):1411-1417. doi:10.1001/jamaneurol.2013.3956
Published online September 30, 2013.
Author Affiliations: Department of
Pathology and Laboratory Medicine,
Center for Neurodegenerative
Disease Research, Perelman School of
Medicine at the University of
Pennsylvania, Philadelphia (Wood,
Falcone, Suh, Irwin, Lee, Van Deerlin);
Department of Neurology and Penn
Frontotemporal Degeneration Center,
Perelman School of Medicine at the
University of Pennsylvania,
Philadelphia (Irwin, Chen-Plotkin,
Grossman); Department of
Biostatistics and Epidemiology,
Perelman School of Medicine at the
University of Pennsylvania,
Philadelphia (Xie).
Corresponding Author: Elisabeth M.
Wood, MS, Department of Pathology
and Laboratory Medicine, Center for
Neurodegenerative Disease
Research, University of Pennsylvania,
3600 Spruce St, 3 Maloney Bldg,
Philadelphia, PA 19104 (mccarty
@upenn.edu).
1411
Downloaded From: http://archneur.jamanetwork.com/ by a University of Pennsylvania User on 11/26/2013
Research Original Investigation
F
rontotemporal lobar degeneration (FTLD) is the second most common type of presenile dementia. Although most FTLD is sporadic, up to 50% of FTLD may
be familial, and an estimated 15% to 40% is due to singlegene mutations.1-5 Mutations in MAPT, GRN, and C9orf72 account for most hereditary FTLD cases.1,2,5-11 Genetic mutations in VCP, CHMP2B, TARDBP, FUS, and PSEN1 have been
documented in rare clinical cases.12-18
Previous studies have used a variety of definitions to describe a positive family history. Chow et al19 used the report
of FTLD disorders in first-degree relatives (FDRs) or seconddegree relatives (SDRs). An epidemiologic survey used dementia before the age of 80 years in at least one FDR.20 Goldman
et al3 used 4 descriptive categories: (1) autosomal dominant,
(2) family aggregation, (3) a single-affected FDR with dementia or amyotrophic lateral sclerosis (ALS), and (4) noncontributory or unknown family history. A follow-up study21 split Goldman category 3 (single-affected FDR) according to the FDR's
age at onset. Two positive family history classes were distinguished in another study11 as (1) autosomal dominant and (2)
1 or more affected individuals within 1 generation or different
family branches.
We are unaware of a validated family history classification
system specific to FTLD that can be used in a clinical setting.
The Goldman criteria, arguably the most cited in FTLD research, was not specifically designed for clinical use and was
first published before the discovery of GRN and C9orf72 mutations in FTLD. This is particularly important given that, although most GRN and C9orf72 mutations are found in familial
kindreds, these mutations have been reported in patients with
no family history of disease.1,2,22-24 We established criteria for
inheritability specifically for FTLD using a serially assessed clinic
population and validated the criteria with genetic testing in the
entire cohort for the 3 most common FTLD-associated genes.
Methods
Frontotemporal Lobar Degeneration
Development of Family History Criteria
Family history criteria were initially developed based on a literature review of FTLD genetics and previously published pedigree classifications in adult-onset hereditary conditions.29-33
The initial criteria were reviewed by geneticists, neurologists, and genetic counselors and applied to an original cohort of 194 probands with FTLD. This original cohort was tested
for C9orf72, MAPT, and GRN mutations. To refine the initial
criteria, mutation-positive and -negative cases were reviewed, focusing on incorrectly categorized cases. Uninformative criteria providing little insight into mutation probability were eliminated, and new criteria improving categorization
of mutation status were added. The original cohort was recategorized using these revised criteria, and we tested the revised criteria in a replication cohort of 112 serially recruited
pedigrees of FTLD probands.
Two certified genetic counselors (E.M.W. and D.F.) independently reviewed each pedigree in both cohorts and assigned them to a family history category. Concordance for category assignment was evaluated. Modified Goldman scores
were also assigned.21
Genetic Testing
Genomic DNA was extracted from blood or brain tissue in all
members of the cohort using commercially available
reagents following manufacturer recommendations. DNA
sequencing of the entire coding region of GRN and targeted
regions of MAPT (exons 1 and 9-13) was performed by Beckman Coulter Genomics, as previously described.34,35 Data
were analyzed with Mutation Surveyor software (Soft Genetics). C9orf72 hexanucleotide repeat expansions (defined as
>30 repeats) were tested with repeat-primed polymerase
chain reaction and fragment analysis, as previously
described.36 Genetic analysis was limited to C9orf72, GRN,
and MAPT because these genes are responsible for most
hereditary FTD. Only mutations of known or predicted
pathogenic status were considered mutation positive.
Patients
All patients with a clinical diagnosis of an FTLD spectrum disorder (behavioral variant frontotemporal dementia [FTD], primary progressive aphasia, corticobasal syndrome, progressive supranuclear palsy, ALS with comorbid behavioral variant
FTD or primary progressive aphasia, and excluding patients
with ALS without dementia) were serially recruited during 8
years into an institutional review board–approved genetic research study at the University of Pennsylvania. Patients met
published criteria for FTLD spectrum disorders.4,25-28 Recruitment included collection of a DNA sample and a 3-generation
pedigree. All pedigrees were collected by a certified genetic
counselor with experience in the field of neurodegenerative
disease. Only patients originating from the Department of Neurology at the University of Pennsylvania were included in the
present analysis to provide a nonbiased representation of an
FTLD clinical population because outside referrals to the research study were often made based on a strong family history. Participants of all races and ethnicities were included because no data suggest that ancestry affects FTLD frequency.
1412
Results
Family History Criteria
The criteria are divided into 4 categories that indicated the likelihood of a pathogenic mutation: high, medium, low, and apparent sporadic (Table 1). A fifth category of unknown significance was used to capture pedigrees with information that was
too limited or uncertain for categorization. The criteria are
based primarily on the number of affected FDRs and SDRs with
an FTLD spectrum disorder or another neurodegenerative
disease.
Classification of Pedigrees Using Proposed Criteria
The total cohort (original and replication) consisted of 306 pedigrees, each having a proband with a diagnosis of an FTLD spectrum disorder. Demographic and clinical features of probands are summarized in Table 2 according to family history
classification. Concordance rate between the 2 raters was
90.7%. Nonconsensus occurred only in low, apparent spo-
JAMA Neurology November 2013 Volume 70, Number 11
Downloaded From: http://archneur.jamanetwork.com/ by a University of Pennsylvania User on 11/26/2013
jamaneurology.com
Frontotemporal Lobar Degeneration
radic, and unknown significance cases; classification in the high
and medium categories was 100% concordant. Nonconsensus was typically due to dementia symptoms with no medical diagnosis in key relatives.
Original Investigation Research
Table 1. Criteria for FTLD Spectrum Disorder Pedigree Categorization
Family History
Category
High
jamaneurology.com
≥1 FDR with FTLD or ALS
1 SDR with FTLD or ALS and ≥1 FDR or SDR with FTLD,
ALS, PD, AD, or dementia NOS
Genetic Testing
Probands were tested for C9orf72, GRN, and MAPT mutations
(n = 306). Mutation-detection rates for original and replication cohorts are listed in Table 3. Details on specific GRN and
MAPT mutations are provided in eTable 1 in the Supplement.
The Fisher exact tests comparing mutation-detection rates in
the 2 cohorts were not statistically different (P = .23).
Matched demographics and mutation-detection rates of
original and replication cohorts allowed us to combine these
and provide an overall detection rate in our series. Of 306
clinical FTLD probands tested, pathogenic mutations were
found in 47 (15.4%), including 25 C9orf72 (8.2%), 12 GRN
(3.9%), and 10 MAPT (3.3%) (Table 4). The mutationdetection rate was highest in the high category, with a rate
of 64.1%. This decreased to a rate of 29.0% in the medium
category, 10.9% in the low category, and 1.1% in the apparent sporadic category. The Fisher exact tests found statistically different mutation-detection rates between high and
each of the other categories, including medium (P = .004),
and between apparent sporadic and low (P = .02). The statistical difference did not reach significance between medium
and low (P = .07) and between apparent sporadic and
unknown significance (P = .07). Most mutations (n = 45)
were found in probands of white race with non-Hispanic
ethnicity; 1 MAPT mutation was found in a proband of African American race, and 1 MAPT mutation was found in a
proband of Hispanic ethnicity.
Because clinical diagnosis in FTLD can be faulty, we
reexamined our findings after having considered the results
of our autopsy cohort. Of 306 probands, 90 were known to
be deceased, and of these 60 had autopsy results (19.6% of
the cohort; see eTable 2 in the Supplement). Of this autopsyonly cohort, 14 (23.3%) had non-FTLD disease (primarily
Alzheimer disease). We repeated our analysis after removing these 14 non-FTLD cases and found absolutely no
changes to our findings.
We applied the modified Goldman criteria, arguably the
most comparable FTLD pedigree classification system to the
new criteria proposed herein, to our cohort. We found similar mutation-detection rates as a previously published
cohort37 (Table 5). Our criteria for the high category identified 25 (53.2%) of our 47 mutation cases, whereas the Goldman 1 criteria identified only 8 (17.0%) of these cases. Using
the McNemar test, the above 2 percentages are significantly
different (53.2% vs 17%, McNemar χ 21 = 15.06, P < .001). Conversely, our criteria for the apparently sporadic category
included only 1 mutation case (2.1%), whereas the Goldman
4 criteria identified 7 (14.9%). Using the McNemar test, the
above 2 percentages are significantly different (2.1% vs
14.9%, McNemar's χ 21 = 4.17, P = .04). These observations are
consistent with the possibility that the proposed criteria
may have better specificity and sensitivity for categorizing
the likelihood of a known FTLD genetic cause.
Criteriaa
2 FDRs with PD, AD, or dementia NOS with onset
at ≤65 years
Medium
1 SDR with FTLD or ALS
1 FDR with PD, AD, or dementia NOS with onset
at ≤65 years
≥3 FDRs or SDRs with PD, AD, or dementia NOS
Low
1 FDR with PD, AD, or dementia NOS with onset
at >65 years
Apparent
sporadic
≤2 SDRs with PD, AD, or dementia NOS
at any age of onset
No other affected FDRs or SDRs
Unknown
significance
Small family size (eg, only child, lack of SDRs)
Lack of information regarding key relatives due to adoption, early death from an unrelated cause, diagnosis or
clinical details not well documented, or no diagnosis but
family reports FTLD spectrum disorder symptoms
Abbreviations: AD, Alzheimer disease; ALS, amyotrophic lateral sclerosis;
FDR, first-degree relative; FTLD, frontotemporal lobar degeneration; NOS, not
otherwise specified; PD, Parkinson disease; SDR, second-degree relative.
a
Only 1 criteria point needs to be met to be classified in that category. All
criteria points refer to FDRs or SDRs of the proband. FTLD spectrum disorders
include FTLD, primary progressive aphasia, corticobasal syndrome,
progressive supranuclear palsy, FTD with ALS, and ALS with dementia.
Pathologic disorders include FTLD with ubiquitin-positive but τ- and
α-synuclein-negative inclusions, dementia lacking distinctive histopathology,
tangle predominant senile dementia, Pick disease, corticobasal degeneration,
progressive supranuclear palsy, neuronal intermediate filament disease, and
FTLD with motor neuron disease. We included PD with or without dementia
because of reports of parkinsonism in families with C9orf72, MAPT, and/or GRN
mutations and families providing a history of parkinsonism without possible
verification.
Discussion
This study ascertained mutation rate and developed family history categorization criteria to guide clinical assessment of the
likelihood of FTLD pathogenic gene mutations in a large, serially ascertained clinical cohort. Clinical genetic testing is available for FTLD-associated genes, but it is not economically feasible to test every individual with FTLD in a communitybased population. Given previous reports that C9orf72
expansions have been found in nonfamilial cases, decisions
about genetic testing would particularly benefit from criteria
that assess familial risk.1,2,23,24 We found an overall mutation
rate of 15.4% and that individuals in the high likelihood group
had more than twice the mutation rate as those in the medium group and almost 6 times the mutation rate as those in
the low group. We conclude that mutation rate is high in FTLD
and that our criteria are reasonably effective at detecting these
cases.
Previous studies3-5 have estimated that 10% to 15% of FTLD
cases are hereditary with autosomal dominant inheritance, and
an additional 25% to 30% of cases of FTD are considered familial. Classic autosomal dominant inheritance typically relies on observing the phenotype in multiple generations, clear
transmission of the disease from affected parent to affected
JAMA Neurology November 2013 Volume 70, Number 11
Downloaded From: http://archneur.jamanetwork.com/ by a University of Pennsylvania User on 11/26/2013
1413
Research Original Investigation
Frontotemporal Lobar Degeneration
Table 2. Demographic and Clinical Characteristics of Probands for the Original, Replication, and Combined Cohorts by Categorya
Combined Cohort
Original
Cohort
Characteristic
Replication
Cohort
High
Medium
Low
Apparent
Sporadic
Unknown
Significance
No. of males/females
106/88
63/49
19/20
16/15
30/16
50/41
54/45
Age at onset, median (range), y
59 (30-80)
60 (33-80)
56 (31-74)
57 (33-71)
61 (37-79)
58 (30-80)
61 (38-80)
185
106
38
29
41
88
95
9
6
1
2
5
3
4
bvFTD
81
34
15
12
20
36
32
SD
21
16
5
5
3
10
14
PNFA
11
10
2
1
4
2
12
LPA
13
4
1
3
2
4
7
CBS
46
21
10
9
6
23
19
8
16
1
1
4
9
9
14
11
5
0
7
7
6
Ethnicity, No.
White
Race other than white
FTLD clinical diagnosis, No.
PSP
FTLD with ALS
Abbreviations: ALS, amyotrophic lateral sclerosis; bvFTD, behavioral variant
frontotemporal dementia; CBS, corticobasal syndrome; FTLD, frontotemporal
lobar degeneration; LPA, logopenic progressive aphasia; PNFA, progressive
nonfluent aphasia; PSP, progressive supranuclear palsy; SD, semantic dementia.
a
Demographic characteristics of original cohort and replication cohorts were
not significantly different.
Table 3. Summary of Pedigree Classification and Mutation-Detection Rates
Original Cohort
Category
No. With
Mutation/
Total No. of
Pedigrees
High
Detection
Rate, %
Detection
Rate, %
Combined Cohorts
Total No.
With Mutation/
Total No. of
Pedigrees
Detection
Rate,a %
Distribution
of Mutation
Positive Cases, %
(n = 47)
19/30
63.3
6/9
66.7
25/39
64.1
53.2
6/20
30.0
3/11
27.3
9/31
29.0
19.1
Low
3/24
12.5
2/22
9.1
5/46
10.9
10.6
Apparent sporadic
0/55
0
1/36
2.8
1/91
1.1
2.1
Unknown significance
3/65
4.6
4/34
11.8
7/99
7.1
14.9
31/194
16.0
16/112
14.3
47/306
15.4
Medium
Total
a
Replication Cohort
No. With
Mutation/
Total No. of
Pedigrees
Fisher exact P values comparing categories: high vs medium: P = .004; medium vs low: P = .07; low vs sporadic: P = .02; and sporadic vs unknown: P = .07.
Table 4. Detection Rate by Gene for the Combined Cohort
Probands, No. (%)
Cohort
C9orf 72 Expansion
GRN Mutation
7
5
Medium (n = 31)
2
3
4
Low (n = 46)
4
1
0
Apparent sporadic (n = 91)
1
0
0
Unknown significance (n = 99)
5
1
1
Total cohort (n = 306)
25 (8.2)
12 (3.9)
High and medium (n = 70)
15 (21.4)
10 (14.3)
9 (12.9)
Only mutation-positive cases (n = 47)
25 (53.2)
12 (25.5)
10 (21.3)
offspring with equal risk among both sexes, whereas familial
reflects that there is more than 1 family member with a certain phenotype.38 The criteria presented in this study reflect
these rates, with approximately 13% categorized as high likelihood and approximately 25% categorized as medium and low
likelihood. Unlike previous criteria, the classic description of
autosomal dominant inheritance is not required to meet the
1414
MAPT Mutation
13
High (n = 39)
10 (3.3)
criteria for the high category. This is because reduced penetrance, older age at onset, and death before symptom onset
can hide a classic autosomal dominant condition, as reported
in FTLD.32,33 Furthermore, variable clinical phenotypes within
families and misdiagnosis of relatives in previous generations challenge pedigree interpretation.32 We also address the
broad definition of familial by providing a structured ap-
JAMA Neurology November 2013 Volume 70, Number 11
Downloaded From: http://archneur.jamanetwork.com/ by a University of Pennsylvania User on 11/26/2013
jamaneurology.com
Frontotemporal Lobar Degeneration
Original Investigation Research
Table 5. Modified Goldman Scores for Study Cohort
Modified
Goldman
Score
Total No. With Mutation/
Total No. of Pedigrees
(N=47/306)
Detection Rate, %
Distribution of
Mutation-Positive Cases, %
(n = 47)
1
8/9
88.9
17.0
2
24/59
40.7
51.1
3
4/10
40.0
8.5
3.5
4/40
10
4
7/188
a
3.7
proach to assess families with more than 1 affected individual. By incorporating not only essential clinical information, such as diagnoses and ages at onset in affected relatives,
but also potential room for error, such as misdiagnoses in relatives, the proposed FTLD-specific pedigree criteria may prove
beneficial in the clinical setting compared with more classic
descriptions of hereditary disease.
Although the highest mutation-detection rate was seen in
the high category, mutations are not exclusive to those family histories that meet the criteria for the high category. In addition, not all families who meet the criteria for the high category have an identifiable genetic cause. In our series, 53.2%
of mutation-positive probands were categorized as high, and
72.3% were categorized as high or medium, suggesting that our
criteria are reasonably successful at identifying those at risk
for an inherited form of FTLD. Explaining a negative test result to a family with a strong history of FTLD spectrum disorders requires clear genetic counseling because it is important
to understand that family history alone assigns an increased
risk. Families with a strong family history who test negative
for C9orf72, GRN, and MAPT may benefit from additional clinical genetic testing and involvement in genetic research. Rare
FTLD genes, such as VCP, TARDBP, and CHMP2B, and genetic causes of other neurodegenerative diseases, such as
PSEN1 for early-onset Alzheimer disease, should be considered. Finally, unidentified genes likely contribute to the development of FTLD.
With a mutation-detection rate of 10.9%, most families in
the low category will not have a mutation. However, the risk
is still significant when compared with the 1.1% of the apparent sporadic group. C9orf72 was responsible for 4 of 5 autosomal dominant mutations in the low category and the singlemutation–positive apparent sporadic case. This finding is
consistent with prior reports of C9orf72 expansion in sporadic families. These findings suggest that it will be important to inform patients and families about C9orf72 even when
family history does not indicate a hereditary risk and for clinicians to exercise clinical judgment regarding genetic testing in patients who meet the criteria for the low or apparent
sporadic category.
The category of unknown significance poses a genetic risk
assessment challenge. An unknown significance category was
necessary because some patients do not know medical family history information. Because relatives may have died of unrelated causes before exhibiting symptoms, a complete 3-generation pedigree is vital for providing the most accurate
categorization. In this series, 32.4% of pedigrees were classijamaneurology.com
8.5
14.9
a
Fisher exact P values comparing
categories in Goldman-modified
criteria: 1 vs 2: P = .01; 2 vs 3:
P > .99; 3 vs 3.5: P = .04; and 3.5 vs
4: P = .11.
fied as unknown significance. Many were classified as unknown because of limited information about SDRs and thus
could not be categorized definitively as apparent sporadic. In
reviewing the 7 mutation-positive unknown significance pedigrees, it was noted that 4 were classified because of family stories that suggested the possibility of relatives with FTLD-like
symptoms, and 2 were from FTLD with ALS probands who
knew little about their family history. Clinicians may need to
provide additional case-by-case insight to help guide genetic
testing decisions in pedigrees of unknown significance.
Clinical factors, such as early age at onset or a diagnosis of
FTLD with ALS, may influence a clinician’s decision to recommend genetic testing. Earlier versions of the criteria included
early age at onset (<45 years) as a criterion. However, we found
that age at onset alone did not predict C9orf72, GRN, or MAPT
mutation. Fourteen individuals in our cohort had age at onset
before 45 years, and 5 of these (mutation rate, 35.7%) were mutation positive. All 5 mutation-positive cases were categorized
as high (n = 2) or medium (n = 3) because of family history. Conversely, the clinical diagnosis of combined FTLD with ALS is
likely reason enough to recommend testing of C9orf72. Of 25
FTLD with ALS probands, 7 tested positive for C9orf72 (mutation rate, 28.0%); 3 were categorized as high, 1 as low, 1 as the
sole mutation-positive apparent sporadic case, and 2 as unknown significance. In addition, because mutations were found
in multiple races and ethnicities, all pedigrees should be evaluated without race or ethnicity factoring into the criteria.
Although the purpose of the criteria is to help identify the
likelihood of a gene mutation, none of the proposed criteria guarantee genetic status. A previous study22 reported a 3.2% rate of
GRN mutations in apparently sporadic FTLD cases, but only
FDRs were used in that study to ascertain FTLD family history.
Using our criteria, which consider both FDRs and SDRs, we found
no GRN mutations in cases that met the criteria for the apparent sporadic category, and the single GRN-positive case in unknown significance was categorized as such because of familyreported information that questioned the neurologic health of
an SDR. On the basis of our analysis, genetic risk in FTLD cannot be determined only by FDRs; classification of apparently
sporadic FTLD must include information on SDRs.
Strengths of our study include the large number of serially analyzed pedigrees, review of each pedigree independently by 2 genetic counselors (E.M.W. and D.F.), and ascertainment of genetic status in the entire cohort. A selection bias
toward individuals with a strong family history is unlikely because all individuals with an FTLD spectrum disorder seen serially by a University of Pennsylvania neurologist were inJAMA Neurology November 2013 Volume 70, Number 11
Downloaded From: http://archneur.jamanetwork.com/ by a University of Pennsylvania User on 11/26/2013
1415
Research Original Investigation
Frontotemporal Lobar Degeneration
vited to participate, and individuals referred by neurologists
outside the University of Pennsylvania system because of a
positive family history were excluded. Some probands in our
clinical cohort do not have FTLD because the clinical diagnosis of FTLD has a reported accuracy of approximately 80%.39,40
Although this study focuses on a clinical approach to assessing risk, in which the patient’s condition would be unknown,
consideration of autopsy-based diagnosis did not change our
findings. In addition, pedigrees were collected during 10 years,
ARTICLE INFORMATION
Accepted for Publication: June 19, 2013.
Published Online: September 30, 2013.
doi:10.1001/jamaneurol.2013.3956.
Author Contributions:
Study concept and design: Wood, Falcone, Van
Deerlin, Grossman.
Acquisition of data: Wood, Falcone, Suh, Irwin, Lee,
Van Deerlin, Grossman.
Analysis and interpretation of data: All authors.
Drafting of the manuscript: Wood, Falcone, Van
Deerlin, Grossman.
Critical revision of the manuscript for important
intellectual content: Wood, Suh, Irwin,
Chen-Plotkin, Lee, Xie, Van Deerlin, Grossman.
Statistical analysis: Wood, Xie, Grossman.
Obtained funding: Van Deerlin, Grossman.
Study supervision: Van Deerlin, Grossman.
Conflict of Interest Disclosures: None reported.
Funding/Support: This research was funded by
grants T32-AG00025 (Dr Irwin), AG033101 (Dr
Chen-Plotkin), and AG017586, AG032953,
AG10124, and NS044266 from the National
Institutes of Health, the ALS Association, and the
Wyncote Foundation. Dr Irwin is also supported by
the Penn Institute for Translational Medicine and
Therapeutics fellowship. Dr Chen-Plotkin is also
supported by the Burroughs Wellcome Fund and
the Doris Duke Clinician Scientist Development
Award.
Role of the Sponsor: The funding institutions had
no role in the design and conduct of the study;
collection, management, analysis, and
interpretation of the data; and preparation, review,
or approval of the manuscript; and decision to
submit the manuscript for publication.
Additional Contributions: The following University
of Pennsylvania physicians contributed through
clinical evaluation and referral of cases: Steven
Arnold, MD, Jason Karlawish, MD, Anjan Chatterjee,
MD, Geoffrey Aguirre, MD, and Branch Coslett, MD;
there was no financial compensation provided. The
authors thank the patients and families who made
this research possible.
REFERENCES
1. 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.
2. 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.
3. Goldman JS, Farmer JM, Wood EM, et al.
Comparison of family histories in FTLD subtypes
1416
and some older pedigrees did not contain as detailed information as currently collected. Therefore, many of these pedigrees had to be classified as unknown significance. Because
families were ascertained at a tertiary referral clinic, the cohort may not be representative of the population as a whole.
With these caveats in mind, the criteria developed here seem
to provide a high detection rate for known genetic causes of
FTLD and thus are likely to offer useful information to help
guide genetic testing decisions by clinicians.
and related tauopathies. Neurology.
2005;65(11):1817-1819.
4. McKhann GM, Albert MS, Grossman M, Miller B,
Dickson D, Trojanowski JQ; Work Group on
Frontotemporal Dementia and Pick’s Disease.
Clinical and pathological diagnosis of
frontotemporal dementia: report of the Work
Group on Frontotemporal Dementia and Pick’s
Disease. Arch Neurol. 2001;58(11):1803-1809.
5. Rohrer JD, Guerreiro R, Vandrovcova J, et al. The
heritability and genetics of frontotemporal lobar
degeneration. Neurology. 2009;73(18):1451-1456.
6. 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. JAMA Neurol. 2013;70(3):365-373.
7. Baker M, Mackenzie IR, Pickering-Brown SM,
et al. Mutations in progranulin cause tau-negative
frontotemporal dementia linked to chromosome 17.
Nature. 2006;442(7105):916-919.
8. 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.
9. Hutton M, Lendon CL, Rizzu P, et al. Association
of missense and 5′-splice-site mutations in tau with
the inherited dementia FTDP-17. Nature.
1998;393(6686):702-705.
10. Poorkaj P, Bird TD, Wijsman E, et al. Tau is a
candidate gene for chromosome 17 frontotemporal
dementia. Ann Neurol. 1998;43(6):815-825.
11. Seelaar H, Kamphorst W, Rosso SM, et al.
Distinct genetic forms of frontotemporal dementia.
Neurology. 2008;71(16):1220-1226.
12. Skibinski G, Parkinson NJ, Brown JM, et al.
Mutations in the endosomal ESCRTIII-complex
subunit CHMP2B in frontotemporal dementia. Nat
Genet. 2005;37(8):806-808.
13. Borroni B, Bonvicini C, Alberici A, et al. Mutation
within TARDBP leads to frontotemporal dementia
without motor neuron disease. Hum Mutat.
2009;30(11):974-983.
14. Kovacs GG, Murrell JR, Horvath S, et al. TARDBP
variation associated with frontotemporal dementia,
supranuclear gaze palsy, and chorea. Mov Disord.
2009;24(12):1843-1847.
15. Van Langenhove T, van der Zee J, Sleegers K,
et al. Genetic contribution of FUS to frontotemporal
lobar degeneration. Neurology. 2010;74(5):
366-371.
16. Watts GD, Wymer J, Kovach MJ, et al. Inclusion
body myopathy associated with Paget disease of
bone and frontotemporal dementia is caused by
mutant valosin-containing protein. Nat Genet.
2004;36(4):377-381.
JAMA Neurology November 2013 Volume 70, Number 11
Downloaded From: http://archneur.jamanetwork.com/ by a University of Pennsylvania User on 11/26/2013
17. Raux G, Gantier R, Thomas-Anterion C, et al.
Dementia with prominent frontotemporal features
associated with L113P presenilin 1 mutation.
Neurology. 2000;55(10):1577-1578.
18. Tang-Wai D, Lewis P, Boeve B, et al. Familial
frontotemporal dementia associated with a novel
presenilin-1 mutation. Dement Geriatr Cogn Disord.
2002;14(1):13-21.
19. Chow TW, Miller BL, Hayashi VN, Geschwind
DH. Inheritance of frontotemporal dementia. Arch
Neurol. 1999;56(7):817-822.
20. Stevens M, van Duijn CM, Kamphorst W, et al.
Familial aggregation in frontotemporal dementia.
Neurology. 1998;50(6):1541-1545.
21. 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.
22. Le Ber I, van der Zee J, Hannequin D, et al;
French Research Network on FTD/FTD-MND.
Progranulin null mutations in both sporadic and
familial frontotemporal dementia. Hum Mutat.
2007;28(9):846-855.
23. Majounie E, Renton AE, Mok K, et al;
Chromosome 9-ALS/FTD Consortium; French
research network on FTLD/FTLD/ALS; ITALSGEN
Consortium. Frequency of the C9orf72
hexanucleotide repeat expansion in patients with
amyotrophic lateral sclerosis and frontotemporal
dementia: a cross-sectional study. Lancet Neurol.
2012;11(4):323-330.
24. Irwin DJ, McMillan CT, Brettschneider J, et al.
Cognitive decline and reduced survival in C9orf72
expansion frontotemporal degeneration and
amyotrophic lateral sclerosis. J Neurol Neurosurg
Psychiatry. 2013;84(2):163-169.
25. 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.
26. Gorno-Tempini ML, Hillis AE, Weintraub S, et al.
Classification of primary progressive aphasia and its
variants. Neurology. 2011;76(11):1006-1014.
27. 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.
28. Strong MJ, Grace GM, Freedman M, et al.
Consensus criteria for the diagnosis of
frontotemporal cognitive and behavioural
syndromes in amyotrophic lateral sclerosis.
Amyotroph Lateral Scler. 2009;10(3):131-146.
29. Trepanier A, Ahrens M, McKinnon W, et al;
National Society of Genetic Counselors. Genetic
jamaneurology.com
Frontotemporal Lobar Degeneration
cancer risk assessment and counseling:
recommendations of the national society of genetic
counselors. J Genet Couns. 2004;13(2):83-114.
30. Hoskins KF, Stopfer JE, Calzone KA, et al.
Assessment and counseling for women with a
family history of breast cancer: a guide for
clinicians. JAMA. 1995;273(7):577-585.
31. Hampel H, Sweet K, Westman JA, Offit K, Eng C.
Referral for cancer genetics consultation: a review
and compilation of risk assessment criteria. J Med
Genet. 2004;41(2):81-91.
32. Goldman JS, Farmer JM, Van Deerlin VM,
Wilhelmsen KC, Miller BL, Grossman M.
Frontotemporal dementia: genetics and genetic
counseling dilemmas. Neurologist.
2004;10(5):227-234.
jamaneurology.com
Original Investigation Research
33. Gass J, Cannon A, Mackenzie IR, et al.
Mutations in progranulin are a major cause of
ubiquitin-positive frontotemporal lobar
degeneration. Hum Mol Genet. 2006;15(20):29883001.
34. Yu CE, Bird TD, Bekris LM, et al. The spectrum
of mutations in progranulin: a collaborative study
screening 545 cases of neurodegeneration. Arch
Neurol. 2010;67(2):161-170.
35. Van Deerlin VM, Gill LH, Farmer JM,
Trojanowski JQ, Lee VM. Familial frontotemporal
dementia: from gene discovery to clinical molecular
diagnostics. Clin Chem. 2003;49(10):1717-1725.
36. Brettschneider J, Van Deerlin VM, Robinson JL,
et al. Pattern of ubiquilin pathology in ALS and
FTLD indicates presence of C9ORF72
hexanucleotide expansion. Acta Neuropathol.
2012;123(6):825-839.
37. 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.
38. Illustrated Glossary. 1993. www.ncbi.nlm.nih
.gov/books/NBK5191/. Accessed February 7, 2013.
39. Grossman M. Primary progressive aphasia:
clinicopathological correlations. Nat Rev Neurol.
2010;6(2):88-97.
40. Knopman DS, Boeve BF, Parisi JE, et al.
Antemortem diagnosis of frontotemporal lobar
degeneration. Ann Neurol. 2005;57(4):480-488.
JAMA Neurology November 2013 Volume 70, Number 11
Downloaded From: http://archneur.jamanetwork.com/ by a University of Pennsylvania User on 11/26/2013
1417