Heterogeneity within a large kindred with frontotemporal dementia: A novel progranulin mutation

balt4/znl-neurol/znl-neurol/znl02607/znl4553-07a eideg Sⴝ10 6/8/07 8:09 Art: WNL183201 Input-nlm

Heterogeneity within a large kindred with frontotemporal dementia A novel progranulin mutation

Fn1

A.C. Bruni, MD* P. Momeni, PhD* L. Bernardi, PhD C. Tomaino, PhD F. Frangipane, MD J. Elder T. Kawarai, MD C. Sato, BSc S. Pradella, MD Y. Wakutani, MD M. Anfossi, PhD M. Gallo, PhD S. Geracitano, PhD A. Costanzo, BTech N. Smirne, AS S.A.M. Curcio, PhD M. Mirabelli, PhD G. Puccio, MD R. Colao, MD R.G. Maletta, MD A. Kertesz, MD P. St. George-Hyslop, MD, FRCP(C) J. Hardy, PhD E. Rogaeva, PhD

Address correspondence and reprint requests to Dr. A.C. Bruni, Centro Regionale di Neurogenetica AS6, Viale A. Perugini 88046 Lamezia Terme, CZ, Italy [email protected]

Editorial, see 129

Background: Frontotemporal dementia (FTD) in several 17q21-linked families was recently explained by truncating mutations in the progranulin gene (GRN). Objective: To determine the

ABSTRACT

frequency of GRN mutations in a cohort of Caucasian patients with FTD without mutations in known FTD genes. Methods: GRN was sequenced in a series of 78 independent FTD patients including 23 familial subjects. A different Calabrian dataset (109 normal control subjects and 96 FTD patients) was used to establish the frequency of the GRN mutation. Results: A novel truncating GRN mutation (c.1145insA) was detected in a proband of an extended consanguineous Calabrian kindred. Segregation analysis of 70 family members revealed 19 heterozygous mutation carriers including 9 patients affected by FTD. The absence of homozygous carriers in a highly consanguineous kindred may indicate that the loss of both GRN alleles might lead to embryonic lethality. An extremely variable age at onset in the mutation carriers (more than five decades apart) is not explained by APOE genotypes or the H1/H2 MAPT haplotypes. Intriguingly, the mutation was excluded in four FTD patients belonging to branches with an autosomal dominant mode of inheritance of FTD, suggesting that another novel FTD gene accounts for the disease in the phenocopies. It is difficult to clinically distinguish phenocopies from GRN mutation carriers, except that language in mutation carriers was more severely compromised. Conclusion: The current results imply further genetic heterogeneity of frontotemporal dementia, as we detected only one GRN-linked family (about 1%). The value of discovering large kindred includes the possibility of a longitudinal study of GRN mutation carriers. NEUROLOGY 2007;69: 140–147

Frontotemporal dementia (FTD) is characterized by early behavioral, language and extrapyramidal changes.1 In about 20% of patients, FTD is compatible with autosomal dominant inheritance.2 The histopathology of about 60% FTD cases displays neuronal ubiquitinpositive inclusions1,3,4 consisting mainly of TAR DNA binding protein (TDP43).5 Defects in three known FTD genes are associated with a spectrum of brain neuropathology. The deposition of tau-associated neurofibrillary tangles and glial pathology play a crucial role in FTD with parkinsonism linked to chromosome 17q21 (FTDP17). About 100 but not all FTDP17 families are explained by mutations in the microtubule-associated protein tau (MAPT).6 The disease in the remaining 17q21-linked families was recently attributed to truncating mutations in the progranulin gene (GRN).7,8 Patients with GRN mutations have neuronal inclusions containing ubiquitinated TDP43.5 In contrast, the splicing mutation in the chromatin modifying protein 2B gene (CHMP2B) is responsible for FTD without distinct histopathology.9 Patients with GRN mutations demonstrate a highly variable age at onset.10 In addition, the phenotypic spectrum of GRN-linked families includes corticobasal syndrome.11 As the ex*These authors contributed equally to the work as co–first authors. From the Regional Neurogenetic Centre (A.C.B., L.B., C.T., F.F., M.A., M.G., S.G., A.C., N.S., S.A.M.C., M.M., G.P., R.C., R.G.M.), Lamezia Terme; Department of Neurology and Psychiatry (S.P.), University of Florence, Firenze, Italy; Department of Neurology (P.M.), Texas Tech University Health Sciences Center, Lubbock; Laboratory of Neurogenetics (J.E., J.H.), National Institute on Aging, Bethesda, MD; Centre for Research in Neurodegenerative Diseases (T.K., C.S., Y.W., P.S.G.-H., E.R.), Department of Medicine, University of Toronto, Toronto Western Hospital Research Institute (P.S.G.-H.), University Health Network, Department of Medicine (P.S.G.-H., E.R.), Division of Neurology, University of Toronto, and Department of Clinical Neurological Sciences (A.K.), St. Joseph’s Health Centre, University of Western Ontario, London, Canada. Supported by grants from the Canadian Institutes of Health Research, Howard Hughes Medical Institute, Canada Foundation for Innovation (P.H.), Japan–Canada and Canadian Institutes of Health Research Joint Health Research Program, Parkinson Society of Canada, W. Garfield Weston Fellows (E.R.), fellowship from the Japanese Society for the Promotion of Science, Japan (T.K.), and NIA/NIH Intramural Program (J.H.). A.C.B. and the team at the Regional Neurogenetic Centre were supported in part by grants from the Italian Ministry of Health (finalized projects no. 2002/156; no. 2003/42) and the Calabria Regional Health Department. Disclosure: The authors report no conflicts of interest.

140

Copyright © 2007 by AAN Enterprises, Inc.

• 10.1212/01.wnl.0000265220.64396.b4

balt4/znl-neurol/znl-neurol/znl02607/znl4553-07a eideg Sⴝ10 6/8/07 8:09 Art: WNL183201 Input-nlm Table 1

Characteristics of the frontotemporal dementia (FTD) datasets

Sample characteristics

Patients

Controls

B-family

FTD patients (patients with family history of FTD)

n ⫽ 78 (23)

n ⫽ 96 (42)

n ⫽ 109

n ⫽ 27

Ubiquitin-positive, tau-negative neuronal inclusion

4

1

Not applicable

Not available

Age at onset or age at time of examination, mean ⫹ SD; y

64.9 ⫾ 11.3

65.1 ⫾ 9.2

67.5 ⫾ 8.9

64.9 ⫾ 13.0

Age at onset or age at time of examination, range; y

37–84

45–83

51–83

35–87

Women, %

50

55

58

67

tended H1 MAPT haplotype was implicated in several tauopathies, including cortical basal degeneration,12,13 it is a good candidate for an age at onset modifier in the GRNlinked families. Another possible age at onset modifier is APOE because it is associated with Alzheimer disease.14 Here we determine the frequency of GRN mutations in a series of 78 FTD patients without MAPT and CHMP2B mutations15-17 and report a novel GRN mutation in a large Calabrian kindred.

T1

METHODS Subjects. All patients or their substitute decision makers provided written, informed consent to participate in this study and underwent a detailed clinical assessment involving clinical history, physical and laboratory examinations, and a standardized behavioral assessment (including morphologic and functional neuroimaging). The Lund–Manchester criteria were used to establish a diagnosis of FTD.18 The characteristics of the study participants are presented in table 1. GRN was sequenced in a series of 78 independent cases clinically diagnosed as having FTD, encompassing 55 sporadic and 23 familial patients. Brain autopsies were available for only four cases and demonstrated a pathology with ubiquitinpositive, tau-negative inclusions. The majority of the FTD samples (n ⫽ 55) were collected at the University of Toronto from patients recruited through various Canadian clinics, and the rest, including the proband of the Calabrian kindred (B-family), were recruited at the Regional Neurogenetics Centre (Calabria, southern Italy). The genealogic methods used to reconstruct the B-family have already been described.17 An independent previously published Calabrian case-control dataset collected at the Regional Neurogenetics Centre was used to establish the frequency of the novel GRN mutation.19 This cohort consisted of 203 unrelated individuals including 109 normal control subjects and 96 FTD patients (table 1).

Genetic analysis. Genomic DNA was extracted from whole

F1

Case-control FTD dataset

FTD patients sequenced for GRN mutations

blood using Qiagen kits. The entire open reading frame with the exon–intron boundaries of the GRN gene was sequenced in FTD patients as previously described.11 In families with more than one affected individual, only the proband was included in the initial analysis. The PCR products were sequenced on automated sequencers (ABI 3100; Applied Biosystems, Foster City, CA) using the ABI Prism Big Dye Terminator Cycle sequencing kit or with a Beckman CEQ8000 using the CEQ DTCS kit (Beckman Coulter, Fullerton, CA) as recommended by the

manufacturer. The frequency of the GRN mutation (c.1145insA) in an Italian case-control dataset was evaluated by a restriction assay. The 152-bp fragment in exon 9 was amplified using the forward (mismatched) primer 5=GATAATGTCAGCAGCTGTCCCTCCTCCGATACCTGCTGCCAAgTCA-3= and the reverse primer 5=-GAGGGCAGAAAGCAATAGG-3=. The PCR conditions were 94 °C for 5 minutes, followed by 35 cycles of 94 °C for 30 seconds, 58 °C for 30 seconds, and 72 °C for 30 seconds. The PCR reaction included 2 mM Mg and 1⫻ Q-solution provided by Qiagen Inc. The amplified fragment was digested for over 4 hours with 3 U of HincII at 37 °C, and the resulting restriction fragments were resolved on a 4% agarose gel. The mutant PCR product is cut into 106- and 46-bp fragments, and the wild-type product remains uncut. The APOE polymorphisms and the 238-bp insertion/deletion in intron 9 of MAPT gene defining the H1 and H2 haplotypes were genotyped in all members of the B-family as described previously.19

Statistical analysis. The effects of the APOE genotypes and MAPT haplotypes on the age at onset were evaluated with the nonparametric Mann–Whitney U test using the software StatView release 5.01 (SAS). Statistical significance was taken to be p ⬍ 0.05. Differences between the phenocopies and affected mutation carriers were performed using the ␹2 test, concerning clinical symptoms and neurologic signs, and by the Student two-tailed t test for the analysis of the age at onset and age at death (SPSS 11.5). RESULTS Genetic analysis. A mutation analysis of the GRN was performed on a cohort of 78 independent FTD patients, which identified several common polymorphisms including three novel intronic variations (rs9897526, rs25646, rs850713, G to T at ⫹46 bp from the first noncoding exon 1, G to A at ⫹7 bp from exon 2, G to A at ⫹7 bp from exon 7). The pathologic significance of the novel intronic variants is currently unknown (future family-based and case-control association studies should clarify the potential contribution of these variations as risk factors of FTD). The only definite pathologic GRN mutation was detected in the proband no. 5470 that belongs to the B-family (figure 1B). The proband is a heterozygous carrier of a novel single nucleotide insertion “A” in exon 9 at mRNA position 1145 (numbering according to GeneBank accession no. NM_002087.2 starting at the translation initiation codon). If translated, the c.1145insA mutation is preNeurology 69

July 10, 2007

141

balt4/znl-neurol/znl-neurol/znl02607/znl4553-07a eideg Sⴝ10 6/8/07 8:09 Art: WNL183201 Input-nlm Figure 1

Truncated pedigree structure of the B-family showing the inheritance of the disease with genotypes for the mutation c.1145insA in GRN

(A) Genomic DNA sequence fluorescent chromatograms around the GRN mutation (c.1145insA) observed in proband no. 5470. M ⫽ mutation; W ⫽ wild-type allele; double lines ⫽ consanguineous marriages; (⽧) ⫽ GRN, personal examination; (½) ⫽ phenocopies, ) ⫽ phenocopies. The gender of the individuals has been masked to personal examination; ( ) ⫽ affected by history; ( ) ⫽ proband; ( protect family confidentiality. (B) Genomic DNA sequence fluorescent chromatograms around the GRN mutation (c.1145insA) observed in proband no. 5470.

dicted to have dramatic consequences on the GRN protein, leading to a frame-shift and premature stop codon, resulting in the truncation of the protein at amino acid position 413 (p.Thr382AsnfsX31). Segregation analysis, using DNA samples from 70 members of the B-family, revealed that the c.1145insA mutation was present in 19 individuals including 9 cases affected with FTD and 10 currently asymptomatic relatives (table 2; figure 1A). Intriguingly, we detected four affected individuals in which the mutation was absent (phenocopies) in branches distant from the core of the Calabrian kindred (case nos. 5568, 8292, 9082, and 9085). Importantly, the c.1145insA mutation was not detected in 7 spouses of the B-family and 109 independent normal control subjects drawn from the same Calabrian population as the B-kindred. There is no evidence that the c.1145insA is a common founder mutation in the Italian population as we did not detect the mutation in any of the 96 independent FTD cases collected from the Calabrian population and 23 other FTD patients of Italian origin included in the cohort for the initial sequencing analysis of the GRN gene. We assessed the possibility that the H1/H2 MAPT haplotypes or APOE genotypes could ex-

T2

142

Neurology 69

July 10, 2007

plain the highly variable age at onset in individuals with the c.1145insA mutation (range 35 to 87 years). The GRN mutation occurred on the H2 MAPT haplotype as we revealed six mutation carriers homozygous for this haplotype (table 2). Thirteen GRN mutation carriers were heterozygous for the H1 haplotype previously associated with different tauopathies.20 However, the presence of the H1 haplotype was not associated with a decreased age at onset (mean 65.1 ⫾ 17.1 years, range 35 to 87 years) compared with the H2 homozygotes (mean 60.0 ⫾ 11.4 years, range 52 to 73 years). Hence, the MAPT haplotypes do not explain the very diverse age at onset in the B-family (p ⫽ 0.52). A similar result was obtained for the APOE gene (p ⫽ 0.30; table 2). The APOE ␧4 allele was present in four mutation carriers and was not associated with an earlier age at onset (range between 52 and below 70 years). Notably, the only affected GRN mutation carrier with both the H1 and APOE ␧4 alleles did not present with an earlier age at onset (68 years). Clinical features. Detailed clinical information on the B-family was published previously.17 In brief, this large Calabrian kindred has been genealogically

balt4/znl-neurol/znl-neurol/znl02607/znl4553-07a eideg Sⴝ10 6/8/07 8:09 Art: WNL183201 Input-nlm Table 2

AQ: 1

F2 F3

Age or age at onset (y) and GRN, MAPT, and APOE genotypes for key family members of B-kindred

ID no.

FTD status

Age: Current or at time of death,* y

Age at onset, y

c.1145insA

MAPT H1/H2 haplotype

APOE

1

Affected

56*

52

Mw

22

34

3

Affected

80*

68

Mw

12

34

4

Affected

90

87

Mw

12

33

47

Affected

73*

66

Mw

12

23

55

Affected

80*

73

Mw

12

33

359

Affected

59*

55

Mw

22

34

476

Affected

77*

73

Mw

22

33

5470

Affected

65*

62

Mw

12

33

5474

Affected

47

35

Mw

12

33

8292

Affected

82*

74

ww

11

34

9082

Affected

83

74

ww

12

33

9085

Affected

82*

79

ww

11

33

5568

Affected

77*

72

ww

11

33

36

Asymptomatic

53

—

Mw

22

33

46

Asymptomatic

70

—

Mw

22

34

65

Asymptomatic

51

—

Mw

12

33

66

Asymptomatic

36

—

Mw

12

33

74

Asymptomatic

46

—

Mw

12

33

364

Asymptomatic

47

—

Mw

12

33

367

Asymptomatic

41

—

Mw

22

33

589

Asymptomatic

44

—

Mw

12

33

5640

Asymptomatic

67

—

Mw

12

33

12550

Asymptomatic

61

—

Mw

12

33

FTD ⫽ frontotemporal dementia; M ⫽ mutation; w ⫽ wild-type allele.

reconstructed for 15 generations, back to the 16th century, and all 36 patients with FTD (16 men and 20 women) have been linked to the same ancestors who lived in the early 18th century. Autosomal dominant transmission of FTD is evident from the inspection of the genealogic tree simplified and updated in figure 1A). DNA samples were collected from 70 family members including 13 individuals affected with FTD, which were examined and diagnosed by an author and the clinical team at the Neurogenetic Regional Centre. Neuropathology was not available for the B-kindred owing to the refusal of the family to participate in such a study. The Calabrian kindred presented with an extremely variable age at onset ranging between 35 and 87 years. The mean age at onset was 64.6 ⫾ 13.7 years, mean age at death was 73.1 ⫾ 9.7 years (range 56 to 82 years), and mean duration was 5.7 ⫾ 3.0 years (range 3 to 12 years). Clinical features were roughly uniform within the kindred and met the Lund– Manchester criteria of FTD.18,21 In addition to the 19 GRN mutation carriers, we identified 4 affected individuals without a mutation in the GRN (figure 1A; table 2). These phenocopies

are descendents of distant branches from the core B-family. The phenocopies had a mean age at onset of 74.8 ⫾ 3.0 years, duration of 6.2 ⫾ 2.7 years, and death occurred at 81.0 ⫾ 2.7 years. Conversely, the affected GRN mutation carriers had a mean onset at age 63.4 ⫾ 14.9 years, duration of 6.2 ⫾ 3.6 years, and death occurred at 69.7 ⫾ 13.8 years. The only significant difference was an earlier age at death in the mutation carriers compared with phenocopies (p ⬍ 0.05). Information on the clinical symptoms and neurologic signs at onset and at a manifest stage (namely, a stage in which behavioral and cognitive symptoms and neurologic signs of FTD were clearly shown) was carefully reviewed in an attempt to clinically differentiate GRN mutation carriers from phenocopies (figures 2 and 3). Phenocopies carry cardiovascular risk factors, and the disease onset presented with a marked reduction of verbal initiative, loss of judgment, falls, and collapse episodes with normal neurologic examination. At the same stage, mutation carriers presented with an absence of insight, distractibility, disinhibition, spatial disorientation, and early incontinence; neurologic exNeurology 69

July 10, 2007

143

balt4/znl-neurol/znl-neurol/znl02607/znl4553-07a eideg Sⴝ10 6/8/07 8:09 Art: WNL183201 Input-nlm Figure 2

Clinical symptoms and neurologic signs at onset

amination showed pyramidal and extrapyramidal signs as well as primitive reflexes (figure 2). During the manifest stage, there were no specific differences in the symptoms and signs displayed by the two groups, except that language was compromised and progressed to a complete mutism only in GRN mutation carriers (figure 3). In addition, alteration of social behavior, somnolence, and time disorientation together with primitive reflexes were more prevalent among mutation carriers (figure 3). 144

Neurology 69

July 10, 2007

Screening for the GRN mutations in a series of 78 independent FTD cases led to the identification of a novel heterozygous truncating mutation (c.1145insA) in a large Italian kindred of Calabrian origin. The c.1145insA is not a common founder mutation, as it was excluded in 96 independent FTD patients from the Calabrian population. Our results imply further genetic heterogeneity of FTD, because we detected only one family in which FTD is caused by a GRN mutation. Notably, GRN

DISCUSSION

balt4/znl-neurol/znl-neurol/znl02607/znl4553-07a eideg Sⴝ10 6/8/07 8:09 Art: WNL183201 Input-nlm Figure 3

Clinical symptoms and neurologic signs at the manifest stage

mutations were excluded even in two extended previously published FTD families with ubiquitinpositive, tau-negative brain histopathology.22,23 Of the 78 independent FTD cases analyzed in the current study, only the proband of the B-family belongs to the kindred previously found to be possibly linked to the 17q21 locus.17 In our cohort, the estimated genetic contribution of GRN mutations in FTD is much lower (about 1%) than in the recently published series of 378 FTD patients (about 10%).10 Such a discrepancy is likely explained by the fact that the prior report estimated the frequency of GRN mutations based on a dataset enriched in pathologically confirmed cases with ubiquitin-

positive inclusions (about 30%), whereas the current cohort included only four such patients (about 5%). It is unlikely that the ongoing gene-dosage study of the GRN could significantly change the estimated mutation frequency in our dataset, as the prior report failed to detect any genomic rearrangements in a large FTD cohort.10 There are no doubts about the pathologic nature of the c.1145insA mutation. It segregates with the disease in 9 affected family members and is absent in 116 unrelated normal controls from the same area in Italy. Most likely the mutant transcript is destroyed by nonsense-mediated decay as it was established for several other truncating GRN mutations.7,8,10,11 Neurology 69

July 10, 2007

145

balt4/znl-neurol/znl-neurol/znl02607/znl4553-07a eideg Sⴝ10 6/8/07 8:09 Art: WNL183201 Input-nlm

However, a source of RNA was not available to confirm the haploinsufficiency mechanism. Despite the fact that the B-kindred is highly consanguineous with at least five marriages between first cousins, 17 the mutation analysis excluded the presence of homozygous mutation carriers. As GRN is a growth factor involved in the regulation of multiple processes, one might speculate that the loss of both GRN alleles could lead to embryonic lethality. The disease in the B-kindred presented with a phenotype indistinguishable from typical FTD.18 However, the family demonstrates a very variable age at onset (more than five decades apart). It is unlikely that environmental factors influenced the variability in age at onset, as all the FTD patients shared a similar environment. We found that the variability in onset is not explained by the APOE genotypes or the extended H1/H2 MAPT haplotypes. This conclusion is consistent with the prior study in which MAPT haplotypes showed no effect on age at onset in the carriers of different GRN mutations.10 It is tempting to speculate that GRN itself is responsible for the high variability in age at onset. Preliminary support for such a possibility came from the examination of the microsatellite markers harboring the GRN locus (D17S800 –3.5 Mb– GRN–2.4 Mb–D17S791) in three siblings carrying the c.1145insA mutation (the genotypes were obtained from the published linkage analysis).17 The siblings no. 1 and no. 359 had a very similar age at onset (ages 52 and 55) and inherited an identical normal parental allele in addition to the mutant allele. In contrast, the third sibling (no. 46), who remains asymptomatic at age 70, inherited a different normal parental allele compared with the two siblings affected with early-onset FTD. Future association studies should evaluate whether common GRN polymorphism(s) influence FTD age at onset and disease risk, especially through a lowered level of GRN expression. In addition, it would be important to evaluate whether different degrees of nonsensemediated decay in individual patients might contribute to the variability in age at onset. Intriguingly, the B-kindred displays two genetically distinct diseases, as the c.1145insA mutation was absent in 4 of 13 FTD patients available for study (figure 1A). The presence of the phenocopies is likely the result of the ascertainment of a very extended kindred segregating a relatively common and etiologically heterogeneous phenotype such as FTD in this Calabrian population and explains, indeed, the ambiguous support for linkage to chromosome 17 in our published analysis of the B-family.17 The disease in the phenocopies remains to be ex-

AQ: 2

146

Neurology 69

July 10, 2007

plained. These patients belong to family branches with at least three consecutive generations of FTD cases, suggesting that another autosomal dominant gene accounts for the FTD in the phenocopies. Our previous studies excluded the presence of CHMP2B and MAPT mutations in several affected members of the B-family including the phenocopies.15,17 In addition, we excluded the possibility of duplications of the MAPT locus in these individuals.16 Samples from the family branches related to the phenocopies should be included for a complete genome scan to identify a novel FTD gene. Intriguingly, it is difficult to clinically distinguish GRN mutation carriers from phenocopies (figures 2 and 3), and brain autopsy was not available for any of the family members. However, detailed analysis has shown that language disturbances evolved differently. Whereas the phenocopies showed reduced verbal initiative that remained constant during the course of the disease, language in mutation carriers deteriorated so that they eventually became completely mute. This observation is in agreement with the published report demonstrating that language dysfunction is as a common presenting clinical symptom in patients with different GRN mutations.10 Neuropsychological evaluation of a mutation carrier (no 4) and phenocopy (no. 5568) done 3 years after disease onset revealed that the phonologic verbal fluency and episodic memory of the mutation carrier were severely affected, whereas the phenocopy presented only with a moderate reduction in verbal initiative without memory disturbances. Extrapyramidal and pyramidal signs and primitive reflexes were observed at disease onset only in GRN mutation carriers; however, in the later stage of disease, extrapyramidal signs and primitive reflexes were also observed in phenocopies as well. Importantly, cardiovascular risk factors, collapse episodes, and falls were present only in phenocopies. Furthermore, in the late course of the disease, the GRN mutation carriers became somnolent, whereas the phenocopies became severely agitated. Importantly, the value of discovering large GRN-linked FTD families includes the possibility of a future longitudinal study. For example, the investigation of the 10 presymptomatic mutation carriers of the B-kindred could include testing the predictive value of neuroimaging techniques and potential biomarkers. ACKNOWLEDGMENT Research on the reported population has been possible thanks to V. Valenti (family doctor), F. Comito (lab technician), and S. Marzano (psychologist), who were the key persons involved in establishing cooperation with the kindred. The authors also thank M.G. Muraca, A.

balt4/znl-neurol/znl-neurol/znl02607/znl4553-07a eideg Sⴝ10 6/8/07 8:09 Art: WNL183201 Input-nlm Paonessa, and C. Calignano from the Association for Neurogenetics Research–ONLUS of Lamezia Terme for their assistance in studying the genealogies and maintaining the database.

11.

12. Received December 7, 2007. Accepted in final form February 28, 2007. 13. REFERENCES 1. Kertesz A. Frontotemporal dementia: one disease, or many?: probably one, possibly two. Alzheimer Dis 2005; 19(suppl 1):S19–S24. 2. Cruts M, Rademakers R, Gijselinck I, et al. Genomic architecture of human 17q21 linked to frontotemporal dementia uncovers a highly homologous family of low-copy repeats in the tau region. Hum Mol Genet 2005;14:1753– 1762. 3. Josephs KA, Holton JL, Rossor MN, et al. Frontotemporal lobar degeneration and ubiquitin immunohistochemistry. Neuropathol Appl Neurobiol 2004;30:369–373. 4. Ince PG, Morris JC. Demystifying lobar degenerations: tauopathies vs Gehrigopathies. Neurology 2006;66:8–9. 5. Neumann M, Sampathu DM, Kwong LK, et al. Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 2006;314:130–133. 6. 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;393:702–705. 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: 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: 920–924. 9. Skibinski G, Parkinson NJ, Brown JM, et al. Mutations in the endosomal ESCRTIII-complex subunit CHMP2B in frontotemporal dementia. Nat Genet 2005;37:806–808. 10. 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: 2988–3001.

14.

15.

16.

17.

18.

19.

20. 21.

22.

23.

Masellis M, Momeni P, Meschino W, et al. Novel splicing mutation in the progranulin gene causing familial corticobasal syndrome. Brain 2006;129:3115–3123. Rademakers R, Cruts M, van Broeckhoven C. The role of tau (MAPT) in frontotemporal dementia and related tauopathies. Hum Mutat 2004;24:277–295. Stefansson H, Helgason A, Thorleifsson G, et al. A common inversion under selection in Europeans. Nat Genet 2005;37:129–137. Saunders AM, Strittmatter WJ, Schmechel D, et al. Association of apolipoprotein E allele epsilon 4 with late-onset familial and sporadic Alzheimer’s disease. Neurology 1993;43:1467–1472. Momeni P, Rogaeva E, Van Deerlin V, et al. Genetic variability in CHMP2B and frontotemporal dementia. Neurodegen Dis 2006;3:129–133. Johnson J, Ostojic J, Lannfelt L, et al. No evidence for tau duplications in frontal temporal dementia families showing genetic linkage to the tau locus in which tau mutations have not been found. Neurosci Lett 2004;363:99–101. Curcio SA, Kawarai T, Paterson AD, et al. A large Calabrian kindred segregating frontotemporal dementia. J Neurol 2002;249:911–922. Brun A, Englund B, Gustafson L. Clinical and neuropathological criteria for frontotemporal dementia. The Lund and Manchester Groups. J Neurol Neurosurg Psychiatry 1994;57:416–418. Bernardi L, Maletta RG, Tomaino C, et al. The effects of APOE and tau gene variability on risk of frontotemporal dementia. Neurobiol Aging 2006;27:702–709. Hardy J, Orr H. The genetics of neurodegenerative diseases. J Neurochem 2006;97:1690–1699. Neary D, Snowden JS, Gustafson L, et al. Frontotemporal lobar degeneration: a consensus on clinical diagnostic criteria. Neurology 1998;51:1546–1554. Kertesz A, Kawarai T, Rogaeva E, et al. Familial frontotemporal dementia with ubiquitin-positive, tau-negative inclusions. Neurology 2000;54:818–827. Bruni AC, Kawarai T, Spillantini MG, et al. [Familial fronto-temporal dementia with brain stem ubiquitinpositive neuronal inclusions]. Rev Neurol (Paris) 2004; 160:1171–1179.

Neurology 69

July 10, 2007

147