C9ORF72 repeat expansions and other FTD gene mutations in a clinical AD patient series from Mayo Clinic

Am J Neurodegener Dis. 2012; 1(1): 107–118.

Published online 2012 May 16.

PMCID: PMC3560455

C9ORF72 repeat expansions and other FTD gene mutations in a clinical AD patient series from Mayo Clinic

Aleksandra Wojtas,¹ Kristin A Heggeli,² NiCole Finch,¹ Matt Baker,¹ Mariely DeJesus-Hernandez,¹ Steven G Younkin,¹ Dennis W Dickson,¹ Neill R Graff-Radford,² and Rosa Rademakers¹

¹Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA

²Department of Neurology, Mayo Clinic, Jacksonville, FL, USA

Address correspondence to: Dr. Rosa Rademakers, Department of Neuroscience, Mayo Clinic College of Medicine, 4500 San Pablo Road, Jacksonville, FL, USA. Phone: (904) 953-6279; Fax: (904) 953-7370, E-mail: Rademakers.rosa/at/mayo.edu

Received May 8, 2012; Accepted May 15, 2012.

Abstract

Alzheimer disease (AD) and frontotemporal dementia (FTD) are two frequent forms of primary neurodegenerative dementias with overlapping clinical symptoms. Pathogenic mutations of the amyloid precursor protein (APP) and presenilins 1 and 2 (PSEN1, PSEN2) genes have been linked to familial early-onset forms of AD; however, more recently mutations in the common FTD genes encoding the microtubule associated protein tau (MAPT), progranulin (GRN) and C9ORF72, have also been reported in clinically diagnosed AD patients. To access the contribution of mutations in a well-characterized series of patients, we systematically performed genetic analyses of these EOAD and FTD genes in a novel cohort of 227 unrelated probands clinically diagnosed as probable AD which were ascertained at Mayo Clinic Florida between 1997 and 2011. All patients showed first symptoms of dementia before 70 years. We identified 9 different pathogenic mutations in the EOAD genes in a total of 11 patients explaining 4.8% of the patient population. Two mutations were novel: PSEN1 p.Pro218Leu and PSEN2 p.Phe183Ser. Importantly, mutations were also identified in all FTD genes: one patient carried a MAPT p.R406W mutation, one patient carried the p.Arg198Glyfs19X loss-of-function mutation in GRN and two patients were found to carry expanded GGGGCC repeats in the non-coding region of C9ORF72. Together the FTD genes explained the disease in 1.8% of our probable AD population. The identification of mutations in all major FTD genes in this novel cohort of clinically diagnosed AD patients underlines the challenges associated with the differential diagnosis of AD and FTD resulting from overlapping symptomatology and has important implications for molecular diagnostic testing and genetic counseling of clinically diagnosed AD patients. Our findings suggest that in clinically diagnosed AD patients, genetic analyses should include not only the well-established EOAD genes APP, PSEN1 and PSEN2 but also genes that are usually associated with FTD. Finally, the overall low frequency of mutation carriers observed in our study (6.6%) suggests the involvement of other as yet unknown genetic factors associated with AD.

Keywords: Alzheimer’s disease, frontotemporal dementia, amyloid precursor protein, presenilin 1, presenilin 2, progranulin, microtubule associated protein tau, C9ORF72, mutation, diagnosis.

Introduction

Alzheimer’s disease (AD) is the most common type of neurodegenerative dementia, clinically characterized by progressive memory impairment and deficits in cognitive functions [1]. A definite diagnosis of AD can only be obtained at autopsy. In addition to overt neuronal loss, AD is pathologically characterized by extracellular deposition of β-amyloid (Aβ) in senile plaques and the formation of intracellular neurofibrillary tangles mainly composed of hyperphosphorylated microtubule associated protein tau. The distinction between the rare early-onset (presenile, EOAD) and common late-onset (senile, LOAD) form of AD is based on the age when first clinical symptoms appear, and usually 65 years is used as an arbitrary cut-off age. EOAD patients are clinically and pathologically identical to LOAD patients, although the disease progression may be more rapid and the brain pathology more pronounced in EOAD patients.

AD is a genetically complex disorder. In the last two decades, pathogenic mutations leading to autosomal dominant EOAD have been identified in the Aβ precursor protein (APP) gene and the presenilins 1 and 2 (PSEN1, PSEN2) genes [2-5]. Studies of cellular and mouse models have shown that mutations in these genes cause an increased production of the neurotoxic Aβ₄₂ [6], indicating that unbalanced APP processing might be the primary event leading to neurodegenerative brain pathology in AD patients carrying these mutations. In addition to these causal genes, the ε4 allele of the apolipoprotein E (APOE) gene has been established as a major risk factor for both familial and sporadic EOAD and LOAD patients [7-9]. More recently, genetic studies of AD have focused on the identification of common variants associated with risk for LOAD through genome-wide association studies. These studies have identified several new genes that show significant association with LOAD, including CLU, BIN1, PICALM and ABCA7 among others, albeit each with only a small effect size [10-14].

The clinical symptoms of AD display a substantial overlap with symptoms observed in frontotemporal dementia (FTD), the second most common form of presenile dementia after AD [15,16]. FTD is clinically associated with behavior/personality changes and language disturbances [17,18]. The most common neuropathology associated with FTD is frontotemporal lobar degeneration (FTLD) with ubiquitin and TAR DNA-binding protein 43 (TDP-43) positive inclusions (FTLD-TDP) [19]. In recent years, significant progress has been made in the identification of causal FTD genes and mutations in the microtubule associated protein tau (MAPT), progranulin (GRN) and chromosome 9 open reading frame 72 (C9ORF72), now explain at least 20-30% of the familial and 5-10% of all sporadic FTD patients [20-26].

Due to the heterogeneity and wide range of clinical presentation of both AD and FTD, these disorders can share common features [27], particularly in patients with an early disease onset. Therefore, despite our increased understanding of clinical and pathological aspects of AD and FTD, the distinction between these presenile dementias is still difficult and may lead to a clinical pathological mismatch, that is, patients presenting with an amnestic syndrome may have TDP-43 or tau pathology and those presenting with behavior symptoms may have Alzheimer pathology, predominantly in the frontal lobes.

In this study, we genetically characterize a newly ascertained cohort of 227 clinical probable AD patients seen at Mayo Clinic, all with first symptoms of dementia before 70 years of age, for mutations in the common AD and FTD genes. We report mutations in all known AD and FTD genes, providing important implications for molecular diagnostic testing and genetic counseling of clinically diagnosed AD patients.

Materials and methods

Subjects

Our study cohort consisted of 227 unrelated EOAD patients (40.1% males and 59.9% females) from a clinical case series diagnosed at the Department of Neurology at Mayo Clinic Florida between 1997 and 2011. The majority of individuals tested in this study were Caucasian (90%), 21 individuals (9%) were African American and 2 (1%) were Asian. For all patients the diagnosis of probable AD was established according to the NINCDS-ADRDA criteria [28]. Autopsy was performed in 9 patients, confirming the diagnosis of AD in all. The onset of dementia was before 70 years of age in all patients, with a mean age at onset of 59.8 ± 7.0 years (range 34-69 years). In 142 patients (63% of the cohort), the onset of dementia was before the age of 65. A positive family history defined as having at least one affected first- or second degree relative with dementia was found in 128 patients (56%). For genetic studies, a total of 641 healthy controls collected at the Department of Neurology at Mayo Clinic Florida were also available. All subjects agreed to participate in the study and biological samples were obtained after written informed consent.

Sequencing analysis

Genomic DNA was isolated from blood samples using standard procedures. For each patient, PCR was performed for exon 16 and 17 of APP, exons 3-12 of PSEN1 and exons 3-12 of PSEN2 (primer sequences available upon request). PCR reactions were performed using 50 ng genomic DNA, 10x PCR Buffer (Quiagen) containing 15mM MgCl₂, 5mM dNTPs, 10 mM of each primer and 1U Taq polymerase (Apex). Each PCR product was purified using the AMPure system (Agencourt Bioscience Corporation, Beverly, MA, USA) and sequenced using the same forward and reverse primers with Big Dye terminator v3.1 Cycle Sequencing kit (Applied Biosystems, Foster City, CA, USA). Sequencing products were purified using the CleanSEQ system (Agencourt Bioscience Corporation) and run on an ABI 3730 Genetic Analyzer (Applied Biosystems). The sequences were analyzed using Sequencher software (Gene Codes, Ann Arbor, MI, USA). Sequencing analyses of PSEN2 exon 6 was also performed in all control individuals to exclude the presence of the novel c.548T>C (p.Phe183Ser) in our control population.

Genotyping analysis

APOE genotypes were determined with predesigned TaqMan SNP genotyping assays for rs7412 and rs429358 (Applied Biosystems, Foster City, CA, USA) and analyzed on an ABI 7900HT Fast Real Time PCR system using Sequence Detection System 2.2.2 software (Applied Biosystems). The presence of the c.1216C>T (p.Arg406Trp) mutation in the MAPT gene was determined using a custom designed TaqMan SNP genotyping assay and confirmed for one heterozygous individual using PCR and sequencing analysis of MAPT exon 13. A custom designed TaqMan SNP genotyping assays was also used to study the presence of the novel mutation c.653C>T (p.Pro218Leu) in exon 7 of PSEN1 in control individuals. Details on all custom and pre-designed Taqman assays are summarized in Table 1.

Table 1

TaqMan genotyping assays used to genotype APOE, MAPT, and PSEN1

APP copy-number analysis

To detect genomic APP copy-number mutations, real-time PCR analysis was performed with a made to order TaqMan assay (Hs01547105_cn, Applied Biosystems) and analyzed on ABI7900HT Fast Real Time PCR system using SDS 2.2.2 software (ΔΔct method). Following manufacturer’s protocol, 20ng genomic DNA from each patient was run in duplicate and normalized to the Copy Number Reference Assay RNase P (cat: 4403326, Applied Biosystems). Two previously identified patients, each carrying an APP duplication were included as a positive controls.

Screening for GGGGCC repeat expansions in C9ORF72

The GGGGCC hexanucleotide repeat expansion in C9ORF72 was detected using a two-step PCR based protocol, as previously described [22]. Briefly, the hexanucleotide repeat was amplified in all samples using one fluorescently labeled PCR primer. Next, fragment length analysis was performed on an automated ABI3730 DNA analyzer using GeneMapper software (Applied Biosystems). All patients that appeared homozygous in this assay were next analyzed using a repeat primed PCR method where characteristic stutter amplification pattern on electropherogram was considered evidence of a pathogenic C9ORF72 expansion.

GRN expression analyses

Plasma samples were available for 196 patients (86% of the cohort). GRN levels in 72 of these patients were analyzed and described previously [29]. For the remaining samples GRN expression levels were determined using the human Progranulin ELISA kit (Adipogen Inc., Seoul, Korea) using a 1:100 dilution of the plasma samples in 1x diluent following manufacturer’s instructions. To increase accuracy all samples were analyzed twice in two independent experiments. Recombinant human GRN provided with the ELISA kit was used as a standard.

Results

Mutation analyses of EOAD genes

In the 227 clinical AD patients we identified 9 different pathogenic missense mutations in APP, PSEN1 and PSEN2 genes in a total of 11 patients (Table 2). In APP, we observed the known p.Thr714Ile mutation in exon 17, previously reported in an Austrian family [30], in one patient. No duplications of the APP gene were found. In PSEN1, we identified 4 known missense mutations (p.Asn135Ser, p.Met146Leu, p.Gly206Ala, p.Ile238Met) and 1 novel mutation (p.Pro218Leu), in a total of 7 affected individuals. All mutations were identified in a single patient except p.Gly206Ala which was detected in 3 unrelated patients. In PSEN2 we found 3 missense mutations, two known (p.Ser130Leu, p.Met174Val) and one novel (p.Phe183Ser) in one patient each. The presence of the two novel mutations (PSEN1 p.Pro218Leu and PSEN2 p.Phe183Ser) was subsequently excluded in 641 healthy control individuals ascertained at Mayo Clinic. Both novel mutations are located in highly conserved residues of the PSEN1 and PSEN2 proteins, respectively (Figure 1). Moreover, protein sequence alignment of the two presenilins showed that amino acid residue Phe183 in PSEN2 corresponds to Phe177 in PSEN1. This codon in PSEN1 was previously reported to carry a pathogenic p.Phe177Ser mutation [31], further supporting the pathogenic character of this novel PSEN2 mutation (Figure 1). In addition to the pathogenic missense mutations, we identified four coding variants in exon 4 of PSEN2, all encoding amino acid changes in the poorly conserved N-terminal domain: 1 known variant of unknown significance (p.Arg62His) in 4 patients and 3 novel variants (p.Glu54Asp, p.Arg62Gly and p.Gly70Arg) in one patient each (Table 3). We also observed the common non-pathogenic polymorphism, PSEN1 p.Glu318Gly, in 8 patients (3.5% of the population).

Table 2

Pathogenic mutations identified in EOAD and FTD genes in this study

Figure 1

Evolutionary sequence conservation of novel PSEN2 mutation p.Phe183Ser and homology with PSEN1. ClustalW alignment for the part of PSEN2 with the novel p.F183S mutation. Shown are human PSEN2 (NP_036618.2), chimpanzee PSEN2 (XP_001142009.2), cow PSEN2 (more ...)

Table 3

Coding sequence variants in EOAD genes with unknown significance

APOE genotyping

In our series, 95 (42.4%) patients carried one APOE ε4 allele and 48 (21.4%) patients were homozygote for APOE ε4 (Table 4). The frequency of ε4/ε4 homozygotes increased with increasing age at onset. Although we did not perform a classical case-control association study, these frequencies are comparable to other AD patient series and confirm that APOE ε4 is a major risk factor in our series [9,32].

Table 4

APOE genotyping results in clinical AD patient series.

Mutation analyses of FTD genes

To determine the contribution of FTD gene mutations to disease in our clinical AD cohort, we further performed mutation analyses of the common FTD genes GRN, MAPT and C9ORF72 and identified 4 clinical probable AD patients carrying pathogenic mutations in FTD genes. The presence of pathogenic GRN mutations or deletions was determined using a GRN ELISA in plasma samples in 196 patients. Reduced levels of GRN (74 ng/ml) were observed in one patient, whereas GRN levels in the other AD patients were within the normal range. Sequencing analyses had previously confirmed the presence of a pathogenic loss-of-function mutation c.592_593delAG (p.Arg198Glyfs19X) in this patient [29]. In MAPT, we identified one patient carrying the c.1216C>T (p.Arg406Trp) missense mutation in exon 13. Finally, we analyzed our cohort for the presence of repeat expansions in C9ORF72. Out of the 227 patients, 91 were homozygous in our initial fluorescent PCR assay and were therefore analyzed using our C9ORF72 repeat-primed PCR assay. Using this assay, two patients were found to carry the characteristic stutter pattern indicative of a pathogenic repeat expansion (Figure 2). Based on the repeat-primed PCR assay, patient 7391 is likely to carry a relatively small repeat expansion of about 60 repeats in this particular DNA sample extracted from blood cells, whereas the stutter pattern of patient 9979 is comparable to all previously published patients, known to carry 700-1600 copies of the GGGGCC repeat.

Figure 2

C9ORF72 repeat-primed PCR assay in clinical AD patients. PCR products of C9ORF72 repeat-primed PCR reactions separated on an ABI3730 DNA Analyzer and visualized by GENEMAPPER software. Electropherograms are zoomed to 4,000 relative fluorescence units (more ...)

Clinical characteristics of mutation carriers

The clinical characteristics of the 15 clinical probable AD patients with pathogenic mutations identified in this study are summarized in Table 5. There was significant difference in age at onset between patients with APP and PSEN mutations (mean age 49.4 ± 8.1 years) and patients with mutations in FTD genes (mean age 62.3 ± 8.7 years). Among all mutations carriers, 10 patients reported at least one first-degree relative with dementia, 4 patients were sporadic and one patient was adopted. The initial symptom always included memory loss which is why the clinical diagnosis of probable AD was made. None of the patients carrying mutations that typically cause FTD (MAPT, GRN, C9ORF72) presented with personality change or aphasia. Interestingly, 4 of the PSEN1 patients had a focal onset, two with language difficulty and two with visual impairment. In the Alzheimer disease Mutation Database (www.molgen.ua. ac.be/ADMutations) [33] only one PSEN1 mutation is reported to have progressive non-fluent aphasia and none with the so called visual variant of AD [34]. Two of the patients were Hispanic and carried the known p.Gly206Ala mutation which was previously reported as a founder mutation in the Caribbean Hispanic population, suggesting these patients may be part of this extensive founder family [35].

Table 5

Clinical characteristics of EOAD and FTD gene mutation carriers

Discussion

We report on the genetic characterization of a consecutive cohort of 227 clinical AD patients with an onset of dementia before 70 years of age ascertained at Mayo Clinic Florida. Despite the high proportion of AD patients with an early age at onset (63% with onset before 65 years) and a positive family history in more than half of the patients (56%), only 4.8% of our study cohort (11 patients) carried pathogenic mutations in the APP and PSEN genes. This low mutation frequency is similar to studies performed in the Danish population [36]; however other groups reported mutation frequencies of 22% [31] or even 71% [37]. The autosomal dominant pattern of inheritance in a large proportion of the patients included in the latter studies is likely to explain the significantly higher mutation frequency in these cohorts.

Two novel EOAD mutations were reported in this study. PSEN1 p.Pro218Leu was identified in a familial AD patient with onset age at 55 years. This is the first mutation at PSEN1 codon 218; however, several pathogenic mutations have been reported at the flanking codons 217 and 219, supporting the pathogenic nature of this mutation (www.molgen.ua.ac.be/ADMutations) [33]. We also observed a novel mutation in PSEN2. Since its discovery in 1995 as a causal EOAD gene, only 13 pathogenic PSEN2 mutations have been reported in a total of 22 families. We identified a p.Phe183Ser mutation in exon 6 of PSEN2 in an EOAD patient with first symptoms at 46 years. Unfortunately, since this patient was adopted no information on family history could be provided and no samples for segregation studies could be obtained. However, the strong conservation of this amino acid and the fact that the corresponding amino acid in PSEN1 has previously been shown to carry the same pathogenic mutation (p.Phe177Ser) provides strong support for its pathogenic nature (Figure 1). In contrast to p.Phe183Ser, the pathogenic nature of 4 coding variants found in exon 4 of PSEN2 in this study remains less clear. Most of the patients carrying these variants (86%) were homo- or heterozygote for APOE ε4 allele. What is more, one patient carrying PSEN2 p.Arg62His also carried the PSEN1 p.Gly206Ala mutation which is a relatively common pathogenic mutation. Due to the fact that N-terminal domain of PSEN2 is a non-conserved region among mammalian species, it is more likely that the observed sequence variations are polymorphisms associated with increased risk of AD, rather than pathogenic mutations [38].

Based on previous findings that AD and FTD often share features that may lead to clinical misdiagnosis, we also determined the presence of common FTD gene mutations in our cohort of patients diagnosed as probable AD. For the MAPT gene, we specifically focused our analysis on the p.Arg406Trp mutation, previously reported to present with clinical AD in several families [39-42]. This mutation was identified in one AD patient (0.4%) with a strong family history of dementia. Using a GRN ELISA assay we further identified one AD patient (0.4%) with low plasma GRN levels which was found to carry the c.592_593delAG (p.Arg198Glyfs19X) mutation in GRN. This finding confirms previous studies reporting GRN loss-of-function mutations in clinically diagnosed AD patients [43-47]. Finally, we identified two unrelated patients carrying an expansion of the GGGGCC hexanucleotide repeat in the non-coding region of the newly discovered gene C9ORF72. Repeat-primed PCR analyses using DNA extracted from blood showed a predominant population of cells with approximately ~60 repeats for one patient, and a typical amplification pattern suggesting hundreds to even thousands of GGGGCC repeats for the other patient. The minimal repeat-size required for pathogenicity has not yet been established [48]; however, the maximum length observed in healthy control individuals is currently around 30 repeats, suggesting that both patients carry pathogenic repeats. Moreover, based on other non-coding repeat expansion disorders it is expected that repeat lengths may vary among different tissues within the same individual, and the repeat length in brain tissue may be significantly longer in both patients [49-51].

Recent reports showed high frequencies of C9ORF72 repeat expansions in amyotrophic lateral sclerosis (ALS) and FTD patients, constituting approximately 40% and 25% of all ALS and FTD familial forms, respectively [22,25,48,52]. In our clinical AD study cohort, the proportion of C9ORF72 expanded repeat carriers (0.9%) is comparable to that recently published by Majounie et al. (2012) [53], which reported C9ORF72 repeat expansions in 6 out of 771 clinical AD patients. In their study, pathological examination in two repeat carriers showed FTLD-TDP pathology, suggesting that that these subjects had amnestic FTD that was misdiagnosed as probable AD. Autopsy confirmation was not available for the two C9ORF72 repeat expansion carriers observed in our study; however, in a recent clinicopathological study of FTLD-TDP patients carrying C9ORF72 repeat expansions from the Mayo Clinic brain bank, several patients were found to carry an ante-mortem diagnosis of Alzheimer-type dementia supporting the idea that misdiagnosis may be a consistent feature across probable AD populations [54]. Interestingly, despite the fact that we included a large proportion of young AD patients in our analyses, both C9ORF72 repeat expansion carriers were among the oldest patients included in our study with onset ages of 68 and 69 years, respectively. Majounie et al. studied AD patients with onset ages ranging from 60-97 years and only identified expansion carriers with onset ages between 61-71 years, suggesting that this age range may be a characteristic feature of C9ORF72 repeat expansion carriers with a predominant amnestic syndrome.

In summary, in addition to mutations in the known EOAD genes, we identified pathogenic mutations in all common genes related to FTD (GRN, MAPT and C9ORF72) in our cohort of patients diagnosed with clinical probable AD. Based on these findings, we believe that AD and FTD can be easily and frequently misdiagnosed as a result of overlapping clinical symptoms. Another reason of misdiagnosis is that the clinical presentation of AD and FTD may be atypical, especially in patients with an early disease onset. Our findings suggest that in clinically diagnosed AD patients, genetic analyses should include not only the well-established AD genes such as APP, PSEN1 and PSEN2 but also genes that are usually associated with FTD. Finally, we emphasize the fact that the low overall frequency of mutation carriers in our study cohort indicates that further genetic factors associated with EOAD must exist. Next-generation technologies such as exome-sequencing and whole-genome sequencing in specific AD families or extended series of well-characterized unrelated AD patients are likely to uncover novel AD genes in the near future.

Acknowledgements

This work was funded by the US National Institutes of Health (grants P50 AG016574, R01 AG026251, R01 AG18023 and R01 NS065782), the ALS Therapy Alliance, the Robert and Clarice Smith and Abigail Van Buren Alzheimer's Disease Research Program and the Consortium for Frontotemporal Dementia Research.

Conflict of interest

Rosa Rademakers and Mariely DeJesus-Hernandez have a patent pending on the discovery of the hexanucleotide repeat expansion in the C9ORF72 gene.

References

1. Bertram L, Lill CM, Tanzi RE. The genetics of Alzheimer disease: back to the future. Neuron. 2010;68:270–281. [PubMed]

2. Goate A, Chartier-Harlin MC, Mullan M, Brown J, Crawford F, Fidani L, Giuffra L, Haynes A, Irving N, James L, Mant R, Newton P, Rooke K, Roques P, Talbot C, Pericak-Vance M, Roses A, Williamson R, Rossor M, Owen M, Hardy J. Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease. Nature. 1991;349:704–706. [PubMed]

3. Levy-Lahad E, Wasco W, Poorkaj P, Romano DM, Oshima J, Pettingell WH, Yu CE, Jondro PD, Schmidt SD, Wang K, et al. Candidate gene for the chromosome 1 familial Alzheimer's disease locus. Science. 1995;269:973–977. [PubMed]

4. Rogaev EI, Sherrington R, Rogaeva EA, Levesque G, Ikeda M, Liang Y, Chi H, Lin C, Holman K, Tsuda T, et al. Familial Alzheimer's disease in kindreds with missense mutations in a gene on chromosome 1 related to the Alzheimer's disease type 3 gene. Nature. 1995;376:775–778. [PubMed]

5. Sherrington R, Rogaev EI, Liang Y, Rogaeva EA, Levesque G, Ikeda M, Chi H, Lin C, Li G, Holman K, Tsuda T, Mar L, Foncin JF, Bruni AC, Montesi MP, Sorbi S, Rainero I, Pinessi L, Nee L, Chumakov I, Pollen D, Brookes A, Sanseau P, Polinsky RJ, Wasco W, Da Silva HA, Haines JL, Perkicak-Vance MA, Tanzi RE, Roses AD, Fraser PE, Rommens JM, St George-Hyslop PH. Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease. Nature. 1995;375:754–760. [PubMed]

6. Theuns J, Van Broeckhoven C. Transcriptional regulation of Alzheimer's disease genes: implications for susceptibility. Hum Mol Genet. 2000;9:2383–2394. [PubMed]

7. Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small GW, Roses AD, Haines JL, Pericak-Vance MA. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science. 1993;261:921–923. [PubMed]

8. Strittmatter WJ, Saunders AM, Schmechel D, Pericak-Vance M, Enghild J, Salvesen GS, Roses AD. Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease. Proc Natl Acad Sci U S A. 1993;90:1977–1981. [PubMed]

9. van Duijn CM, de Knijff P, Cruts M, Wehnert A, Havekes LM, Hofman A, Van Broeckhoven C. Apolipoprotein E4 allele in a population-based study of early-onset Alzheimer's disease. Nat Genet. 1994;7:74–78. [PubMed]

10. Harold D, Abraham R, Hollingworth P, Sims R, Gerrish A, Hamshere ML, Pahwa JS, Moskvina V, Dowzell K, Williams A, Jones N, Thomas C, Stretton A, Morgan AR, Lovestone S, Powell J, Proitsi P, Lupton MK, Brayne C, Rubinsztein DC, Gill M, Lawlor B, Lynch A, Morgan K, Brown KS, Passmore PA, Craig D, McGuinness B, Todd S, Holmes C, Mann D, Smith AD, Love S, Kehoe PG, Hardy J, Mead S, Fox N, Rossor M, Collinge J, Maier W, Jessen F, Schurmann B, van den Bussche H, Heuser I, Kornhuber J, Wiltfang J, Dichgans M, Frolich L, Hampel H, Hull M, Rujescu D, Goate AM, Kauwe JS, Cruchaga C, Nowotny P, Morris JC, Mayo K, Sleegers K, Bettens K, Engelborghs S, De Deyn PP, Van Broeckhoven C, Livingston G, Bass NJ, Gurling H, McQuillin A, Gwilliam R, Deloukas P, Al- Chalabi A, Shaw CE, Tsolaki M, Singleton AB, Guerreiro R, Muhleisen TW, Nothen MM, Moebus S, Jockel KH, Klopp N, Wichmann HE, Carrasquillo MM, Pankratz VS, Younkin SG, Holmans PA, O'Donovan M, Owen MJ, Williams J. Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease. Nat Genet. 2009;41:1088–1093. [PMC free article] [PubMed]

11. Hollingworth P, Harold D, Sims R, Gerrish A, Lambert JC, Carrasquillo MM, Abraham R, Hamshere ML, Pahwa JS, Moskvina V, Dowzell K, Jones N, Stretton A, Thomas C, Richards A, Ivanov D, Widdowson C, Chapman J, Lovestone S, Powell J, Proitsi P, Lupton MK, Brayne C, Rubinsztein DC, Gill M, Lawlor B, Lynch A, Brown KS, Passmore PA, Craig D, McGuinness B, Todd S, Holmes C, Mann D, Smith AD, Beaumont H, Warden D, Wilcock G, Love S, Kehoe PG, Hooper NM, Vardy ER, Hardy J, Mead S, Fox NC, Rossor M, Collinge J, Maier W, Jessen F, Ruther E, Schurmann B, Heun R, Kolsch H, van den Bussche H, Heuser I, Kornhuber J, Wiltfang J, Dichgans M, Frolich L, Hampel H, Gallacher J, Hull M, Rujescu D, Giegling I, Goate AM, Kauwe JS, Cruchaga C, Nowotny P, Morris JC, Mayo K, Sleegers K, Bettens K, Engelborghs S, De Deyn PP, Van Broeckhoven C, Livingston G, Bass NJ, Gurling H, McQuillin A, Gwilliam R, Deloukas P, Al-Chalabi A, Shaw CE, Tsolaki M, Singleton AB, Guerreiro R, Muhleisen TW, Nothen MM, Moebus S, Jockel KH, Klopp N, Wichmann HE, Pankratz VS, Sando SB, Aasly JO, Barcikowska M, Wszolek ZK, Dickson DW, Graff-Radford NR, Petersen RC, van Duijn CM, Breteler MM, Ikram MA, DeStefano AL, Fitzpatrick AL, Lopez O, Launer LJ, Seshadri S, Berr C, Campion D, Epelbaum J, Dartigues JF, Tzourio C, Alperovitch A, Lathrop M, Feulner TM, Friedrich P, Riehle C, Krawczak M, Schreiber S, Mayhaus M, Nicolhaus S, Wagenpfeil S, Steinberg S, Stefansson H, Stefansson K, Snaedal J, Bjornsson S, Jonsson PV, Chouraki V, Genier-Boley B, Hiltunen M, Soininen H, Combarros O, Zelenika D, Delepine M, Bullido MJ, Pasquier F, Mateo I, Frank-Garcia A, Porcellini E, Hanon O, Coto E, Alvarez V, Bosco P, Siciliano G, Mancuso M, Panza F, Solfrizzi V, Nacmias B, Sorbi S, Bossu P, Piccardi P, Arosio B, Annoni G, Seripa D, Pilotto A, Scarpini E, Galimberti D, Brice A, Hannequin D, Licastro F, Jones L, Holmans PA, Jonsson T, Riemenschneider M, Morgan K, Younkin SG, Owen MJ, O'Donovan M, Amouyel P, Williams J. Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer's disease. Nat Genet. 2011;43:429–435. [PMC free article] [PubMed]

12. Lambert JC, Heath S, Even G, Campion D, Sleegers K, Hiltunen M, Combarros O, Zelenika D, Bullido MJ, Tavernier B, Letenneur L, Bettens K, Berr C, Pasquier F, Fievet N, Barberger-Gateau P, Engelborghs S, De Deyn P, Mateo I, Franck A, Helisalmi S, Porcellini E, Hanon O, de Pancorbo MM, Lendon C, Dufouil C, Jaillard C, Leveillard T, Alvarez V, Bosco P, Mancuso M, Panza F, Nacmias B, Bossu P, Piccardi P, Annoni G, Seripa D, Galimberti D, Hannequin D, Licastro F, Soininen H, Ritchie K, Blanche H, Dartigues JF, Tzourio C, Gut I, Van Broeckhoven C, Alperovitch A, Lathrop M, Amouyel P. Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer's disease. Nat Genet. 2009;41:1094–1099. [PubMed]

13. Naj AC, Jun G, Beecham GW, Wang LS, Vardarajan BN, Buros J, Gallins PJ, Buxbaum JD, Jarvik GP, Crane PK, Larson EB, Bird TD, Boeve BF, Graff-Radford NR, De Jager PL, Evans D, Schneider JA, Carrasquillo MM, Ertekin-Taner N, Younkin SG, Cruchaga C, Kauwe JS, Nowotny P, Kramer P, Hardy J, Huentelman MJ, Myers AJ, Barmada MM, Demirci FY, Baldwin CT, Green RC, Rogaeva E, St George-Hyslop P, Arnold SE, Barber R, Beach T, Bigio EH, Bowen JD, Boxer A, Burke JR, Cairns NJ, Carlson CS, Carney RM, Carroll SL, Chui HC, Clark DG, Corneveaux J, Cotman CW, Cummings JL, DeCarli C, DeKosky ST, Diaz-Arrastia R, Dick M, Dickson DW, Ellis WG, Faber KM, Fallon KB, Farlow MR, Ferris S, Frosch MP, Galasko DR, Ganguli M, Gearing M, Geschwind DH, Ghetti B, Gilbert JR, Gilman S, Giordani B, Glass JD, Growdon JH, Hamilton RL, Harrell LE, Head E, Honig LS, Hulette CM, Hyman BT, Jicha GA, Jin LW, Johnson N, Karlawish J, Karydas A, Kaye JA, Kim R, Koo EH, Kowall NW, Lah JJ, Levey AI, Lieberman AP, Lopez OL, Mack WJ, Marson DC, Martiniuk F, Mash DC, Masliah E, McCormick WC, McCurry SM, McDavid AN, McKee AC, Mesulam M, Miller BL, Miller CA, Miller JW, Parisi JE, Perl DP, Peskind E, Petersen RC, Poon WW, Quinn JF, Rajbhandary RA, Raskind M, Reisberg B, Ringman JM, Roberson ED, Rosenberg RN, Sano M, Schneider LS, Seeley W, Shelanski ML, Slifer MA, Smith CD, Sonnen JA, Spina S, Stern RA, Tanzi RE, Trojanowski JQ, Troncoso JC, Van Deerlin VM, Vinters HV, Vonsattel JP, Weintraub S, Welsh-Bohmer KA, Williamson J, Woltjer RL, Cantwell LB, Dombroski BA, Beekly D, Lunetta KL, Martin ER, Kamboh MI, Saykin AJ, Reiman EM, Bennett DA, Morris JC, Montine TJ, Goate AM, Blacker D, Tsuang DW, Hakonarson H, Kukull WA, Foroud TM, Haines JL, Mayeux R, Pericak-Vance MA, Farrer LA, Schellenberg GD. Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer's disease. Nat Genet. 2011;43:436–441. [PMC free article] [PubMed]

14. Seshadri S, Fitzpatrick AL, Ikram MA, DeStefano AL, Gudnason V, Boada M, Bis JC, Smith AV, Carassquillo MM, Lambert JC, Harold D, Schrijvers EM, Ramirez-Lorca R, Debette S, Longstreth WT Jr, Janssens AC, Pankratz VS, Dartigues JF, Hollingworth P, Aspelund T, Hernandez I, Beiser A, Kuller LH, Koudstaal PJ, Dickson DW, Tzourio C, Abraham R, Antunez C, Du Y, Rotter JI, Aulchenko YS, Harris TB, Petersen RC, Berr C, Owen MJ, Lopez-Arrieta J, Varadarajan BN, Becker JT, Rivadeneira F, Nalls MA, Graff-Radford NR, Campion D, Auerbach S, Rice K, Hofman A, Jonsson PV, Schmidt H, Lathrop M, Mosley TH, Au R, Psaty BM, Uitterlinden AG, Farrer LA, Lumley T, Ruiz A, Williams J, Amouyel P, Younkin SG, Wolf PA, Launer LJ, Lopez OL, van Duijn CM, Breteler MM. Genome-wide analysis of genetic loci associated with Alzheimer disease. JAMA. 2010;303:1832–1840. [PMC free article] [PubMed]

15. McNeill R, Sare GM, Manoharan M, Testa HJ, Mann DM, Neary D, Snowden JS, Varma AR. Accuracy of single-photon emission computed tomography in differentiating frontotemporal dementia from Alzheimer's disease. J Neurol Neurosurg Psychiatry. 2007;78:350–355. [PMC free article] [PubMed]

16. Johnson KA, Dickerson BC. A tale of two tracers: The age of wisdom for dementia diagnosis? Neurology. 2011;77:2008–2009. [PubMed]

17. Rademakers R, Hutton M. The genetics of frontotemporal lobar degeneration. Curr Neurol Neurosci Rep. 2007;7:434–442. [PubMed]

18. Graff-Radford NR, Woodruff BK. Frontotemporal dementia. Semin Neurol. 2007;27:48–57. [PubMed]

19. Mackenzie IR, Neumann M, Bigio EH, Cairns NJ, Alafuzoff I, Kril J, Kovacs GG, Ghetti B, Halliday G, Holm IE, Ince PG, Kamphorst W, Revesz T, Rozemuller AJ, Kumar-Singh S, Akiyama H, Baborie A, Spina S, Dickson DW, Trojanowski JQ, Mann DM. Nomenclature for neuropathologic subtypes of frontotemporal lobar degeneration: consensus recommendations. Acta Neuropathol. 2009;117:15–18. [PMC free article] [PubMed]

20. Baker M, Mackenzie IR, Pickering-Brown SM, Gass J, Rademakers R, Lindholm C, Snowden J, Adamson J, Sadovnick AD, Rollinson S, Cannon A, Dwosh E, Neary D, Melquist S, Richardson A, Dickson D, Berger Z, Eriksen J, Robinson T, Zehr C, Dickey CA, Crook R, McGowan E, Mann D, Boeve B, Feldman H, Hutton M. Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17. Nature. 2006;442:916–919. [PubMed]

21. Cruts M, Gijselinck I, van der Zee J, Engelborghs S, Wils H, Pirici D, Rademakers R, Vandenberghe R, Dermaut B, Martin JJ, van Duijn C, Peeters K, Sciot R, Santens P, De Pooter T, Mattheijssens M, Van den Broeck M, Cuijt I, Vennekens K, De Deyn PP, Kumar-Singh S, Van Broeckhoven C. Null mutations in progranulin cause ubiquitin-positive frontotemporal dementia linked to chromosome 17q21. Nature. 2006;442:920–924. [PubMed]

22. DeJesus-Hernandez M, Mackenzie IR, Boeve BF, Boxer AL, Baker M, Rutherford NJ, Nicholson AM, Finch NA, Flynn H, Adamson J, Kouri N, Wojtas A, Sengdy P, Hsiung GY, Karydas A, Seeley WW, Josephs KA, Coppola G, Geschwind DH, Wszolek ZK, Feldman H, Knopman DS, Petersen RC, Miller BL, Dickson DW, Boylan KB, Graff-Radford NR, Rademakers R. Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron. 2011;72:245–256. [PMC free article] [PubMed]

23. Hutton M, Lendon CL, Rizzu P, Baker M, Froelich S, Houlden H, Pickering-Brown S, Chakraverty S, Isaacs A, Grover A, Hackett J, Adamson J, Lincoln S, Dickson D, Davies P, Petersen RC, Stevens M, de Graaff E, Wauters E, van Baren J, Hillebrand M, Joosse M, Kwon JM, Nowotny P, Che LK, Norton J, Morris JC, Reed LA, Trojanowski J, Basun H, Lannfelt L, Neystat M, Fahn S, Dark F, Tannenberg T, Dodd PR, Hayward N, Kwok JB, Schofield PR, Andreadis A, Snowden J, Craufurd D, Neary D, Owen F, Oostra BA, Hardy J, Goate A, van Swieten J, Mann D, Lynch T, Heutink P. Association of missense and 5'-splice-site mutations in tau with the inherited dementia FTDP-17. Nature. 1998;393:702–705. [PubMed]

24. Poorkaj P, Bird TD, Wijsman E, Nemens E, Garruto RM, Anderson L, Andreadis A, Wiederholt WC, Raskind M, Schellenberg GD. Tau is a candidate gene for chromosome 17 frontotemporal dementia. Ann Neurol. 1998;43:815–825. [PubMed]

25. Renton AE, Majounie E, Waite A, Simon-Sanchez J, Rollinson S, Gibbs JR, Schymick JC, Laaksovirta H, van Swieten JC, Myllykangas L, Kalimo H, Paetau A, Abramzon Y, Remes AM, Kaganovich A, Scholz SW, Duckworth J, Ding J, Harmer DW, Hernandez DG, Johnson JO, Mok K, Ryten M, Trabzuni D, Guerreiro RJ, Orrell RW, Neal J, Murray A, Pearson J, Jansen IE, Sondervan D, Seelaar H, Blake D, Young K, Halliwell N, Callister JB, Toulson G, Richardson A, Gerhard A, Snowden J, Mann D, Neary D, Nalls MA, Peuralinna T, Jansson L, Isoviita VM, Kaivorinne AL, Holtta-Vuori M, Ikonen E, Sulkava R, Benatar M, Wuu J, Chio A, Restagno G, Borghero G, Sabatelli M, Heckerman D, Rogaeva E, Zinman L, Rothstein JD, Sendtner M, Drepper C, Eichler EE, Alkan C, Abdullaev Z, Pack SD, Dutra A, Pak E, Hardy J, Singleton A, Williams NM, Heutink P, Pickering-Brown S, Morris HR, Tienari PJ, Traynor BJ. A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron. 2011;72:257–268. [PMC free article] [PubMed]

26. Spillantini MG, Murrell JR, Goedert M, Farlow MR, Klug A, Ghetti B. Mutation in the tau gene in familial multiple system tauopathy with presenile dementia. Proc Natl Acad Sci U S A. 1998;95:7737–7741. [PubMed]

27. van der Zee J, Sleegers K, Van Broeckhoven C. Invited article: the Alzheimer disease-frontotemporal lobar degeneration spectrum. Neurology. 2008;71:1191–1197. [PubMed]

28. McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM. Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease. Neurology. 1984;34:939–944. [PubMed]

29. Finch N, Baker M, Crook R, Swanson K, Kuntz K, Surtees R, Bisceglio G, Rovelet-Lecrux A, Boeve B, Petersen RC, Dickson DW, Younkin SG, Deramecourt V, Crook J, Graff-Radford NR, Rademakers R. Plasma progranulin levels predict progranulin mutation status in frontotemporal dementia patients and asymptomatic family members. Brain. 2009;132:583–591. [PMC free article] [PubMed]

30. Kumar-Singh S, De Jonghe C, Cruts M, Kleinert R, Wang R, Mercken M, De Strooper B, Vanderstichele H, Lofgren A, Vanderhoeven I, Backhovens H, Vanmechelen E, Kroisel PM, Van Broeckhoven C. Nonfibrillar diffuse amyloid deposition due to a gamma(42)-secretase site mutation points to an essential role for N-truncated A beta(42) in Alzheimer's disease. Hum Mol Genet. 2000;9:2589–2598. [PubMed]

31. Rogaeva EA, Fafel KC, Song YQ, Medeiros H, Sato C, Liang Y, Richard E, Rogaev EI, Frommelt P, Sadovnick AD, Meschino W, Rockwood K, Boss MA, Mayeux R, St George-Hyslop P. Screening for PS1 mutations in a referral-based series of AD cases: 21 novel mutations. Neurology. 2001;57:621–625. [PubMed]

32. Farrer LA, Cupples LA, Haines JL, Hyman B, Kukull WA, Mayeux R, Myers RH, Pericak-Vance MA, Risch N, van Duijn CM. Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A meta-analysis. APOE and Alzheimer Disease Meta Analysis Consortium. JAMA. 1997;278:1349–1356. [PubMed]

33. Cruts M, Van Broeckhoven C. Presenilin mutations in Alzheimer's disease. Hum Mutat. 1998;11:183–190. [PubMed]

34. Tang-Wai DF, Graff-Radford NR, Boeve BF, Dickson DW, Parisi JE, Crook R, Caselli RJ, Knopman DS, Petersen RC. Clinical, genetic, and neuropathologic characteristics of posterior cortical atrophy. Neurology. 2004;63:1168–1174. [PubMed]

35. Athan ES, Williamson J, Ciappa A, Santana V, Romas SN, Lee JH, Rondon H, Lantigua RA, Medrano M, Torres M, Arawaka S, Rogaeva E, Song YQ, Sato C, Kawarai T, Fafel KC, Boss MA, Seltzer WK, Stern Y, St George-Hyslop P, Tycko B, Mayeux R. A founder mutation in presenilin 1 causing early-onset Alzheimer disease in unrelated Caribbean Hispanic families. JAMA : the journal of the American Medical Association. 2001;286:2257–2263. [PubMed]

36. Lindquist SG, Schwartz M, Batbayli M, Waldemar G, Nielsen JE. Genetic testing in familial AD and FTD: mutation and phenotype spectrum in a Danish cohort. Clin Genet. 2009;76:205–209. [PubMed]

37. Campion D, Dumanchin C, Hannequin D, Dubois B, Belliard S, Puel M, Thomas-Anterion C, Michon A, Martin C, Charbonnier F, Raux G, Camuzat A, Penet C, Mesnage V, Martinez M, Clerget-Darpoux F, Brice A, Frebourg T. Early-onset autosomal dominant Alzheimer disease: prevalence, genetic heterogeneity, and mutation spectrum. Am J Hum Genet. 1999;65:664–670. [PubMed]

38. Cruts M, van Duijn CM, Backhovens H, Van den Broeck M, Wehnert A, Serneels S, Sherrington R, Hutton M, Hardy J, St George-Hyslop PH, Hofman A, Van Broeckhoven C. Estimation of the genetic contribution of presenilin-1 and -2 mutations in a population-based study of presenile Alzheimer disease. Hum Mol Genet. 1998;7:43–51. [PubMed]

39. Lindquist SG, Holm IE, Schwartz M, Law I, Stokholm J, Batbayli M, Waldemar G, Nielsen JE. Alzheimer disease-like clinical phenotype in a family with FTDP-17 caused by a MAPT R406W mutation. Eur J Neurol. 2008;15:377–385. [PubMed]

40. Rademakers R, Dermaut B, Peeters K, Cruts M, Heutink P, Goate A, Van Broeckhoven C. Tau (MAPT) mutation Arg406Trp presenting clinically with Alzheimer disease does not share a common founder in Western Europe. Hum Mutat. 2003;22:409–411. [PubMed]

41. Reed LA, Grabowski TJ, Schmidt ML, Morris JC, Goate A, Solodkin A, Van Hoesen GW, Schelper RL, Talbot CJ, Wragg MA, Trojanowski JQ. Autosomal dominant dementia with widespread neurofibrillary tangles. Ann Neurol. 1997;42:564–572. [PubMed]

42. van Swieten JC, Stevens M, Rosso SM, Rizzu P, Joosse M, de Koning I, Kamphorst W, Ravid R, Spillantini MG, Niermeijer , Heutink P. Phenotypic variation in hereditary frontotemporal dementia with tau mutations. Ann Neurol. 1999;46:617–626. [PubMed]

43. Brouwers N, Nuytemans K, van der Zee J, Gijselinck I, Engelborghs S, Theuns J, Kumar-Singh S, Pickut BA, Pals P, Dermaut B, Bogaerts V, De Pooter T, Serneels S, Van den Broeck M, Cuijt I, Mattheijssens M, Peeters K, Sciot R, Martin JJ, Cras P, Santens P, Vandenberghe R, De Deyn PP, Cruts M, Van Broeckhoven C, Sleegers K. Alzheimer and Parkinson diagnoses in progranulin null mutation carriers in an extended founder family. Arch Neurol. 2007;64:1436–1446. [PubMed]

44. Kelley BJ, Haidar W, Boeve BF, Baker M, Graff-Radford NR, Krefft T, Frank AR, Jack CR Jr, Shiung M, Knopman DS, Josephs KA, Parashos SA, Rademakers R, Hutton M, Pickering-Brown S, Adamson J, Kuntz KM, Dickson DW, Parisi JE, Smith GE, Ivnik RJ, Petersen RC. Prominent phenotypic variability associated with mutations in Progranulin. Neurobiol Aging. 2009;30:739–751. [PMC free article] [PubMed]

45. Kelley BJ, Haidar W, Boeve BF, Baker M, Shiung M, Knopman DS, Rademakers R, Hutton M, Adamson J, Kuntz KM, Dickson DW, Parisi JE, Smith GE, Petersen RC. Alzheimer disease-like phenotype associated with the c. 154delA mutation in progranulin. Arch Neurol. 2010;67:171–177. [PMC free article] [PubMed]

46. Rademakers R, Baker M, Gass J, Adamson J, Huey ED, Momeni P, Spina S, Coppola G, Karydas AM, Stewart H, Johnson N, Hsiung GY, Kelley B, Kuntz K, Steinbart E, Wood EM, Yu CE, Josephs K, Sorenson E, Womack KB, Weintraub S, Pickering-Brown SM, Schofield PR, Brooks WS, Van Deerlin VM, Snowden J, Clark CM, Kertesz A, Boylan K, Ghetti B, Neary D, Schellenberg GD, Beach TG, Mesulam M, Mann D, Grafman J, Mackenzie IR, Feldman H, Bird T, Petersen R, Knopman D, Boeve B, Geschwind DH, Miller B, Wszolek Z, Lippa C, Bigio EH, Dickson D, Graff-Radford N, Hutton M. Phenotypic variability associated with progranulin haploinsufficiency in patients with the common 1477C-->T (Arg493X) mutation: an international initiative. Lancet Neurol. 2007;6:857–868. [PubMed]

47. Yu CE, Bird TD, Bekris LM, Montine TJ, Leverenz JB, Steinbart E, Galloway NM, Feldman H, Woltjer R, Miller CA, Wood EM, Grossman M, McCluskey L, Clark CM, Neumann M, Danek A, Galasko DR, Arnold SE, Chen-Plotkin A, Karydas A, Miller BL, Trojanowski JQ, Lee VM, Schellenberg GD, Van Deerlin VM. The spectrum of mutations in progranulin: a collaborative study screening 545 cases of neurodegeneration. Arch Neurol. 2010;67:161–170. [PMC free article] [PubMed]

48. Rademakers R. C9orf72 repeat expansions in patients with ALS and FTD. Lancet Neurol. 2012;11:297–298. [PubMed]

49. Lavedan C, Hofmann-Radvanyi H, Shelbourne P, Rabes JP, Duros C, Savoy D, Dehaupas I, Luce S, Johnson K, Junien C. Myotonic dystrophy: size- and sex-dependent dynamics of CTG meiotic instability, and somatic mosaicism. American journal of human genetics. 1993;52:875–883. [PubMed]

50. Matsuura T, Fang P, Lin X, Khajavi M, Tsuji K, Rasmussen A, Grewal RP, Achari M, Alonso ME, Pulst SM, Zoghbi HY, Nelson DL, Roa BB, Ashizawa T. Somatic and germline instability of the ATTCT repeat in spinocerebellar ataxia type 10. American journal of human genetics. 2004;74:1216–1224. [PubMed]

51. Moseley ML, Schut LJ, Bird TD, Koob MD, Day JW, Ranum LP. SCA8 CTG repeat: en masse contractions in sperm and intergenerational sequence changes may play a role in reduced penetrance. Human molecular genetics. 2000;9:2125–2130. [PubMed]

52. Majounie E, Renton AE, Mok K, Dopper EG, Waite A, Rollinson S, Chio A, Restagno G, Nicolaou N, Simon-Sanchez J, van Swieten JC, Abramzon Y, Johnson JO, Sendtner M, Pamphlett R, Orrell RW, Mead S, Sidle KC, Houlden H, Rohrer JD, Morrison KE, Pall H, Talbot K, Ansorge O, Hernandez DG, Arepalli S, Sabatelli M, Mora G, Corbo M, Giannini F, Calvo A, Englund E, Borghero G, Floris GL, Remes AM, Laaksovirta H, McCluskey L, Trojanowski JQ, Van Deerlin VM, Schellenberg GD, Nalls MA, Drory VE, Lu CS, Yeh TH, Ishiura H, Takahashi Y, Tsuji S, Le Ber I, Brice A, Drepper C, Williams N, Kirby J, Shaw P, Hardy J, Tienari PJ, Heutink P, Morris HR, Pickering-Brown S, Traynor BJ. Frequency of the C9orf72 hexanucleotide repeat expansion in patients with amyotrophic lateral sclerosis and frontotemporal dementia: a cross-sectional study. Lancet Neurol. 2012;11:323–330. [PMC free article] [PubMed]

53. Majounie E, Abramzon Y, Renton AE, Perry R, Bassett SS, Pletnikova O, Troncoso JC, Hardy J, Singleton AB, Traynor BJ. Repeat expansion in C9ORF72 in Alzheimer's disease. N Engl J Med. 2012;366:283–284. [PMC free article] [PubMed]

54. Murray ME, DeJesus-Hernandez M, Rutherford NJ, Baker M, Duara R, Graff-Radford NR, Wszolek ZK, Ferman TJ, Josephs KA, Boylan KB, Rademakers R, Dickson DW. Clinical and neuropathologic heterogeneity of c9FTD/ALS associated with hexanucleotide repeat expansion in C9ORF72. Acta Neuropathol. 2011;122:673–690. [PMC free article] [PubMed]

Articles from American Journal of Neurodegenerative Disease are provided here courtesy of
e-Century Publishing Corporation