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doi101093brainawl029 Brain (2006) 129 841ndash852

A Belgian ancestral haplotype harbours a highlyprevalent mutation for 17q21-linkedtau-negative FTLD

Julie van der Zee1 Rosa Rademakers1 Sebastiaan Engelborghs26 Ilse Gijselinck1 Veerle Bogaerts1

Rik Vandenberghe5 Patrick Santens4 Jo Caekebeke7 Tim De Pooter1 Karin Peeters1 Ursula Lubke3

Marleen Van den Broeck1 Jean-Jacques Martin3 Marc Cruts1 Peter P De Deyn26

Christine Van Broeckhoven1 and Bart Dermaut14

1Neurodegenerative Brain Diseases Group Department of Molecular Genetics Flanders Interuniversity Institute forBiotechnology 2Laboratory of Neurochemistry and Behavior 3Laboratory of Neuropathology Institute Born-BungeUniversity of Antwerp 4Department of Neurology Ghent University Hospital University of Ghent 5Department ofNeurology University Hospital Gasthuisberg Catholic University of Leuven 6Department of Neurology and MemoryClinic Middelheim General Hospital Antwerp and 7Department of Neurology OLV Hospital Aalst Belgium

Correspondence to Prof Dr Christine Van Broeckhoven Neurodegenerative Brain Diseases Group VIB8 Department ofMolecular Genetics University of Antwerp Building V Room 010 Universiteitsplein 1 BE-2610 Antwerpen BelgiumE-mail christinevanbroeckhovenuaacbe

Among patients with frontotemporal lobar degeneration (FTLD) the respective frequencies of dominant17q21-linked tau-negative FTLD (with unidentified molecular defect) and 17q21-linked tau-positive FTLD(due to MAPT mutations) remain unknown Here in a series of 98 genealogically unrelated Belgian FTLDpatients we identified an ancestral 8 cM MAPT containing haplotype in two patients belonging to multiplexfamilies DR2 and DR8 without demonstrableMAPTmutations in which FTLDwas conclusively linked to 17q21[maximum summed log of the odds (LOD) score of 528 at D17S931] Interestingly the same DR2ndashDR8ancestral haplotype was observed in five additional familial FTLD patients indicative of a founder effect Inthe FTLD series the DR2ndashDR8 ancestral haplotype explained 7 (7 out of 98) of FTLD and 17 (7 out of 42) offamilial FTLD andwas seven timesmore frequent thanMAPTmutations (1 out of 98 or 1) Clinically DR2ndashDR8haplotype carriers presented with FTLD often characterized by language impairment and in one carrier theneuropathological diagnosis was FTLD with rare tau-negative ubiquitin-positive inclusions Together theseresults strongly suggest that the DR2ndashDR8 founder haplotype at 17q21 harbours a tau-negative FTLD causingmutation that is a much more frequent cause of FTLD in Belgium than MAPT mutations

Keywords founder mutation frontotemporal lobar degeneration ubiquitin-positive 17q21 tau-negative

Abbreviations FTLD = frontotemporal lobar degeneration FTDU = FTLD with tau-negative and ubiquitin-positiveinclusions DLDH dementia lacking distinctive histopathology LOD = log of the odds

Received September 5 2005 Revised January 11 2006 Accepted January 16 2006 Advance Access publication February 22 2006

IntroductionIn the age group below 65 years frontotemporal lobar

degeneration (FTLD) [MIM 600274] comprises 12ndash20 of

demented patients and is the second-most common form of

neurodegenerative presenile dementia after Alzheimerrsquos

disease (AD) [MIM 104300] (Neary et al 1998 Ratnavalli

et al 2002 Harvey et al 2003) Clinically FTLD is

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characterized by progressive degeneration of frontal andor

temporal brain regions leading to behavioural and personality

disturbances including disinhibition perseveration and emo-

tional blunting often accompanied by progressive language

dysfunctions and eventually evolves into general cognitive

impairment (Neary et al 1998)

A positive family history of dementia is present in 38ndash50

of FTLD patients and in the majority of the families the

disease is inherited in an autosomal dominant manner

(Stevens et al 1998 Chow et al 1999 Poorkaj et al

2001a Rosso et al 2003) Linkage studies have identified

FTLD loci on chromosomes 3 [MIM 600795] (Brown et al

1995) 9 [MIM 105550] (Hosler et al 2000) and 17 (Foster

et al 1997) Besides a very recently identified mutation in the

charged multi-vesicular body protein 2B (CHMP2B) at 3p11

(Skibinski et al 2005) all other known FTLD mutations

affect the microtubule-associated protein tau (MAPT

[MIM 157140]) at 17q21 (Hutton et al 1998 Poorkaj

et al 1998 Spillantini et al 1998) To date 38 different

MAPT mutations have been identified in 111 dementia

families worldwide (Rademakers et al 2004 ADampFTD Muta-

tion database httpwwwmolgenuaacbeADMutations) It

was estimated that MAPT mutations explain 5ndash20 of FTLD

in general and 10ndash43 of familial FTLD (Rizzu et al 1999

Poorkaj et al 2001a Rosso et al 2003) Neuropathologically

MAPT mutation carriers are characterized by intraneuronal

andor glial tau-positive inclusions (tauopathy) More recent

genetic and clinicopathological studies however demon-

strated that the majority of FTLD patients could not be

explained by MAPT mutations and lacked tau pathology

(tau-negative FTLD) (Rizzu et al 1999 Mann et al 2000

Morris et al 2001 Poorkaj et al 2001a Rosso et al 2003

Hodges et al 2004 Johnson et al 2005) Surprisingly several

tau-negative FTLD families have been conclusively linked

to a region at 17q21 that contains MAPT (Rademakers

et al 2004) In three conclusively 17q21-linked families

the neuropathological phenotype has been described as

either lsquodementia lacking distinctive histopathologyrsquo (DLDH)

(Lendon et al 1998) or lsquoFTLD with tau-negative and

ubiquitin-positive inclusionsrsquo (FTDU) (Rosso et al 2001

Rademakers et al 2002) In the highly informative Dutch

family 1083 we reduced the candidate region for FTLD at

17q21 to a 48 cM interval encompassing MAPT (Rademakers

et al 2002) Recently we excluded mutations in MAPT by

genomic sequencing of 1385 kb in 17q21-linked tau-negative

FTLD patients from family 1083 and Dutch III (Cruts et al

2005) In addition we and others showed that MAPT is

surrounded by three highly homologous low-copy repeats

(LCRs) in a region of 17 Mb These LCRs induced a genomic

inversion polymorphism explaining the high degree of link-

age disequilibrium in the MAPT genomic region resulting in

two extended haplotypes H1 and H2 (Baker et al 1999 Cruts

et al 2005 Stefansson et al 2005) The presence of multiple

homologous LCRs in the region could be responsible for more

complex genomic rearrangements that underlie 17q21-linked

tau-negative FTLD (Stankiewicz and Lupski 2002) However

so far the molecular defect of tau-negative FTLD remains

unknown (Cruts et al 2005) and an estimation of its

frequency is currently difficult

Here we performed a detailed molecular genetic clinical

and pathological study of 17q21-linked tau-negative FTLD in

Belgium We present convincing evidence that supports a

tau-negative FTLD founder haplotype harbouring a causal

mutation which is responsible for a substantial fraction of

familial FTLD Our data also indicated that this mutation is a

much more important cause of FTLD than MAPT mutations

Materials and methodsPatients families and controlsA total of 98 FTLD patients was derived from a prospective Belgian

study of neurodegenerative and vascular dementia (n = 62)

(Engelborghs et al 2003) and from a collection of demented

patients referred to our Molecular Diagnostic Unit for molecular

genetic testing (n = 36) (Table 1) The local medical ethical com-

mittee approved the prospective Belgian study of neurodegenerative

and vascular dementia and all participating individuals gave written

informed consent Diagnosis of FTLD was reached in consensus by

at least two neurologists using established clinical criteria (Neary

et al 1998) All patients underwent neuroimaging (CT-scan andor

MRI) and neuropsychological testing FTLD patients from the Mole-

cular Diagnostic Unit series were selected on the basis of a clinical

diagnosis of FTLD and medical records provided by the referring

neurologist or gerontologist None of the 98 FTLD patients was

known to be genealogically related A neuropathological diagnosis

was available for seven patients The ascertainment of Belgian con-

trol individuals (n = 181) was described previously (Pals et al 2004)

For molecular genetic studies FTLD index patients or a living

relative was contacted by research nurses under the supervision of

a physician experienced in clinical and molecular genetics of

dementia Detailed information on family history of dementia

was gathered and additional patients and unaffected family members

were asked to participate in genetic studies With written informed

consent blood samples were collected for DNA extraction and the

establishment of lymphoblast cell lines Informed consent was also

requested for autopsy and neuropathological examination The local

medical ethical committee of the University of Antwerp approved

the research protocols for molecular genetic and neuropathological

studies For phase-determined haplotype frequency estimation in

Table 1 General descriptives of Belgian FTLD patients

Male femaleratio

Mean age atonset (range)

Positivefamilyhistory ()a

Prospective dementiastudy (n = 62)

121 651 (40ndash90) 35

Molecular DiagnosticUnit (n = 36)

125 565 (18ndash74) 56

Total FTLD patients(n = 98)

123 614 (18ndash90) 43

aPositive family history was defined as having at least one first

degree relative with dementia

842 Brain (2006) 129 841ndash852 J van der Zee et al

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healthy controls we used 92 DNA samples from 23 healthy tetrads of

Belgian origin each consisting of parents and two children

Mutation analysisMAPT mutation analysis was performed on genomic DNA of the

98 FTLD patients by direct sequencing of exons 1 and 9 to 13 In

addition FTLD patients derived from the Belgian prospective

dementia study and 12 FTLD patients from the Molecular Diagnos-

tic Unit including the index patients of family DR2 (III-6) and DR8

(III-28) were also screened for mutations in the coding exons 3ndash12

of the presenilin-1 gene (PSEN1 [MIM 104311]) and presenilin-2

gene (PSEN2 [MIM 600759]) the amyloid precursor protein gene

(APP [MIM 104760]) coding exons 16 and 17 and coding exon 2 of

the prion protein gene (PRNP [MIM 176640]) More extensive

mutation analysis of MAPT was performed in three individuals of

DR2 (two patients III-8 III-6 one control III-22) and DR8 (two

patients III-28 III-32 one control III-24) and included all MAPT

exons and intron 13 that is retained in human MAPT transcripts

(Poorkaj et al 2001b) Standard 20 ml polymerase chain reaction

(PCR) amplifications on genomic DNA with empirically defined

optimal annealing temperatures were performed and amplification

products were purified Purified products were sequenced in both

directions using the BigDye Terminator Cycle Sequencing kit v31

(Applied Biosystems Foster City CA USA) and analysed on an

ABI3730 automated sequencer (Applied Biosystems Foster City

CA USA)

STR genotyping and MAPT H1ndashH2 haplotypingFor linkage studies 77 DR2 and DR8 family members (Fig 1) were

genotyped using 18 chromosome 17q21 fluorescently labelled STR

markers spanning a 177 cM region between D17S1863 and

D17S1795 Fifteen STR markers were selected from the Marshfield

gender-averaged genetic map and three novel STR markers

Chr17-16 Chr17-19 and Chr17-43 were identified with the Tandem

Repeats Finder program (Benson 1999) (Table 2) Chr17-16

is located in AC00810532 starting at nt 82045 Chr17-19 is

located in AC0916282 at nt 35879 and Chr17-43 is located in

in AC0682348 at nt 138430 For allele sharing analysis in the 98

FTLD patients the relatives of DR2ndashDR8 ancestral haplotype

carriers and the 23 healthy Belgian tetrads 14 of the 18 STR

markers were selected for genotyping Allele frequencies were

calculated in 92 control chromosomes derived from the parents

of the Belgian tetrads Genomic DNA (20 ng) was amplified in

20 ml multiplex PCRs at annealing temperature of 58C by use

of fluorescently labelled primers PCR products were sized on an

ABI 3730 automated sequencer (Applied Biosystems) and genotypes

were assigned using in-house developed genotyping software

For determination of the MAPT extended haplotypes H1 and H2

(Baker et al 1999) the MAPT SNP16 (g8117G gt A numbering

according to GenBank accession number AC0916282) was geno-

typed in the 98 FTLD patients and family members of the FTLD

families DR2 and DR8 (Rademakers et al 2005)

Linkage analysisTwo-point and multi-point log of the odds (LOD) scores were

calculated using MLINK and LINKMAP from the LINKAGE

software package version 52 (Lathrop et al 1985) We assumed

an autosomal dominant inheritance model with reduced age-

dependent penetrance for the trait locus The estimated population

frequency of the disease gene was set at 0001 Nine liability classes

for disease penetrance based on the cumulative risk curve calculated

from the mean onset age for dementia in each family with a max-

imal disease penetrance of 90 when older than 85 years were used

Phenocopy rates were also age-dependent (Ott et al 1995)

Neuropathological and immunohistochemicalanalysisA post-mortem neuropathological study was performed on patient

DR311 The brain was fixed for 3 months in 10 formalin and

classic staining techniques for myelin cytology fibrillary glia neu-

tral fats and lipopigments (periodic acid-Schiff PAS) were

performed on coronal 30 mm hemispheric sections sliced on a

freezing microtome from two frontotemporal lobe regions at the

level of the amygdala and more posterior at the level of the rostral

thalamus Paraffin-embedded blocks were also prepared from the

superior frontal gyrus cingular gyrus superior temporal gyrus hip-

pocampus parahippocampal gyrus occipital gyrus midbrain at the

level of the substantia nigra pons and cerebellum Sections 5 mm

thick were examined by routine histopathological methods and

immunostained with the following antibodies AT8 directed against

hyperphosphorylated protein tau (Innogenetics Zwijnaarde

Belgium) 4G8 against residues 18ndash24 of Ab (Signet Dedham

MA USA) and ubiquitin (Dako Glostrup Denmark) Immunohis-

tochemistries for these antibodies were performed as described

previously (Kumar-Singh et al 2002)

ResultsBelgian FTLD patient seriesMolecular genetic analysis of five dementia genesmdashAPP

PSEN1 PSEN2 MAPT and PRNPmdashin 98 Belgian FTLD

patients (Table 1) showed a mutation in only two patients

One is the familial patient which we reported previously

(Dermaut et al 2004) who carried a PSEN1 Gly183Val

mutation and had pathologically confirmed Pickrsquos disease

In the second patient we identified in this study a novel

MAPT mutation in exon 9 (g110065 G gt A gDNA number-

ing is relative to AC0916282 starting at nt1) predicting an

amino acid substitution at codon 273 (MAPT Gly273Arg)

MAPT Gly273Arg affects the most C-terminal and highly

conserved residue of the first microtubule-binding domain

of tau Age at onset in this patient was 63 years and the disease

started with memory disturbances evolving in FTLD with

parkinsonism The MAPT Gly273Arg mutation was absent

in 181 Belgian control individuals No mutations in APP

PSEN2 or PRNP were observed

In the entire FTLD patient series we obtained autopsy data

for seven patients four patients had a diagnosis of FTDU one

patient had DLDH one had AD and one had Pickrsquos disease

the latter one being the PSEN1 Gly183Val mutation carrier

Belgian FTLD families DR2 and DR8Two FTLD families DR2 and DR8 were ascertained through

two index patients from the Molecular Diagnostic Unit FTLD

series that had no mutation in MAPT and a positive family

history suggestive of autosomal dominant transmission of

Belgian tau-negative FTLD founder effect Brain (2006) 129 841ndash852 843

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dementia For genetic linkage studies we collected blood

samples from 38 and 39 patients and relatives from DR2

and DR8 respectively (Fig 1A and B) Affection status

and onset age were determined using information provided

by family informants and medical records when available

The mean age at onset in family DR2 was 6573 years

(range 58ndash75 years) and 6027 years (range 51ndash68 years) in

family DR8

Fig 1 Pedigrees of Belgian FTLD families DR2 (A) and DR8 (B) Filled symbols represent FTLD patients open symbols representunaffected individuals The number below the individuals denotes age at onset for patients and age at death for obligate carriers Whenavailable affection status and onset age were determined from medical records (III-4 III-6 III-8 and III-10 of family DR2 and III-9 III-18and III-28 of family DR8) for the other patients these were determined using information provided by family informants Anarrowhead indicates the index patient An asterisk () denotes that DNA was available for genotyping

844 Brain (2006) 129 841ndash852 J van der Zee et al

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We selected 18 STR markers covering the minimal FTLD

candidate region at 17q21 (Rademakers et al 2002) to test

linkage in the two multiplex FTLD families DR2 and DR8

For family DR2 two-point LOD scores gt 1 were calculated

for 4 of the 18 STR markers with the highest LOD score of

147 at marker Chr17-43 (recombination fraction u = 0)

(Table 2) For family DR8 nine LOD scores gt 2 were calcu-

lated with one conclusive LOD score of 332 at marker

D17S931 (u = 0) (Table 2) Multi-point linkage analysis raised

the maximum LOD scores to 349 in family DR8 and 179 in

family DR2 in the interval D17S920-D17S931-D17S1795 on

top of D17S931 (u = 0) (data not shown)

In order to confirm linkage to chromosome 17q21 in

families DR2 and DR8 and to delineate a minimal candidate

region on the basis of meiotic recombination events haplo-

types were reconstructed from genotype data of the 18

markers (Fig 2A and B) In family DR8 all patients carried

the complete risk haplotype including individuals (II-1 II-3

II-8 and II-9) who were obligate carriers Both founders (I-1

and I-2) had died before or within the onset age range of

dementia in the family In family DR2 a risk haplotype was

also observed in all patients and obligate recombinants were

identified in two patients defining a candidate region of 177

cM between the centromeric marker D17S1863 (III-4) and

the telomeric marker D17S1795 (III-6) Comparison of the

linked alleles showed that in families DR2 and DR8 identical

risk haplotypes were segregating for all STR markers within

the region flanked by D17S1814 and D17S1795 This finding

implies that families DR2 and DR8 are genetically related and

originate from an unknown common founder Therefore by

combining the segregation data of families DR2 and DR8 we

were able to reduce the minimal candidate region to 804 cM

between D17S1818 and D17S1795 delineated by haplotype

sharing at the centromeric site and a recombinant in family

DR2 (III-4) at the telomeric site As the DR2 and DR8

families are genetically related LOD scores of each family

were summed achieving a maximum LOD score of 528 at

D17S931

Segregation analysis of MAPT SNP16 in families DR2 and

DR8 indicated that the shared disease haplotype contained

the rare extended MAPT H2 haplotype All patients were

heterozygous H1H2 except patient III-32 of family DR8

who was homozygous H2H2

DR2ndashDR8 haplotype sharing analysis in theBelgian FTLD patient seriesGenotyping of 14 STR markers spanning the 8 cM DR2ndashDR8

disease locus in 98 Belgian FTLD patients revealed that the

DR2ndashDR8 linked alleles and MAPT H2 haplotype were

shared by five additional familial FTLD patients (DR251

DR261 DR271 DR281 and DR311 Table 3) Additional

blood samples were collected in these FTLD families DR25

(n = 6) DR26 (n = 2) DR27 (n = 8) DR28 (n = 4) and DR31

(n = 3) Segregation analysis in relatives of the five index

patients confirmed that the shared alleles constituted a

single haplotype which co-segregated with the disease

(Fig 3) The DR2ndashDR8 haplotype was absent in 92 control

chromosomes

Clinical features associated withthe DR2ndashDR8 haplotypeWhen considering all patients with the DR2ndashDR8 haplotype

we calculated a mean onset age of 6325 years (n = 28 range

51ndash75 years) and a mean disease duration 605 years (n = 20

range 1ndash20 years) More detailed clinical characteristics of 11

DR2ndashDR8 haplotype carriers are compared in Table 4 In 9

out of 11 FTLD patients language impairments ranging from

progressive non-fluent aphasia (PNFA) (n =4) to reduced

spontaneous speech (n = 3) word-finding problems (n = 1)

or post-stroke aphasia (n = 1) were present at presentation

In addition and consistent with prominent phatic symptoms

neuroimaging revealed lateralization of the brain atrophy

andor hypoperfusion to the left side in the majority

(7 out of 11) of the patients (Table 4 Fig 4) In the one

patient with progressive behavioural and personality changes

but without speech impairment (DR271) the structural and

functional defect was more pronounced at the right side

Neuropathology of DR2ndashDR8 haplotypecarrier DR311On macroscopic examination the brain of the index patient

of family DR31 (DR311) demonstrated severe frontotem-

Table 2 Two-point LOD scores at 17q21 in BelgianFTLD families DR2 and DR8

Marker Physicaldistance (Mb)

Geneticdistance (cM)

LOD scoreat u = 0

DR2 DR8

D17S1863 0 0 147 002D17S1818 847 97 02 226D17S1814 942 107 081 000D17S800 1036 113 017 279D17S1787 1103 113 078 04D17S1793 1166 124 006 067D17S902 1305 134 142 237D17S951 1323 129 03 279D17S1861 1421 129 101 247D17S934 1446 129 071 288Chr17-16 1473 ndash 012 181D17S810 1489 129 038 059Chr17-19 1541 ndash 058 095D17S920 1622 134 07 041D17S931 164 161 145 332Chr17-43 1673 ndash 147 176D17S1785 1743 161 047 26D17S1795 1933 177 106 272

Maximal two-point LOD scores are indicated in bold For all STRmarkers observed alleles were assigned equal allele frequenciesPhysical distances of the STR markers were deduced from theUCSC Human Genome Browser Genetic positions of theSTR markers were obtained from the Marshfieldgender-averaged map

Belgian tau-negative FTLD founder effect Brain (2006) 129 841ndash852 845

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poral atrophy mainly affecting the frontal gyri Coronal fro-

zen sections of the frontal regions confirmed a clear neuronal

loss severe demyelination of the white matter fibrillary glio-

sis microspongiosis and an enormous dilatation of the fron-

tal horn of the lateral ventricle In addition PAS staining

revealed numerous lipofuscin granules in neurons astrocytes

and pericapillary pericytes as well as numerous subpial and

perivascular corpora amylacea Sections stained with cresyl

violet showed severe neuronal loss astrocytic gliosis and

microspongiosis No ballooned or chromatolytic neurons

were observed In general the lesions were most outspoken

in the prefrontal regions and much less prominent in tem-

poral regions Immunohistochemistry was performed on

paraffin sections from select regions superior frontal gyrus

cingular gyrus superior temporal gyrus hippocampus para-

hippocampal gyrus occipital gyrus cerebellum substantia

nigra and pons With exception of the right hippocampus

where a few AT8-positive neurofibrillary tangles were

observed all other brain regions were AT8-negative Staining

with 4G8 revealed rare perivascular Ab deposits in the

entorhinal zone of the hippocampus but was completely

negative in all other regions With an antibody directed

against ubiquitin rare intraneuronal cytoplasmic structures

were observed in the superior frontal gyrus superior tem-

poral gyrus and hippocampus These perinuclear inclusions

had a pleiomorphic appearance ranging from thin filamen-

tous threads to more tortuous and granular structures

(Fig 5A and B) No Lewy bodies were observed Very rare

ubiquitin-positive intranuclear inclusions were observed

exclusively in sections from the superior frontal gyrus

(Fig 5A) These intranuclear ubiquitin-positive structures

were morphologically identical to the lsquocat eyersquo-like inclusions

described previously in inherited tau-negative FTLD brains

(Rosso et al 2001 Rademakers et al 2002) The neuro-

pathological diagnosis was consistent with FTDU

DiscussionIn this study we examined the frequency of tau-negative

FTLD linked to 17q21 in a series of 98 well-characterized

Belgian FTLD patients The male female ratio and onset

A

Fig 2 Pedigrees of Belgian FTLD families DR2 (A) and DR8 (B) showing chromosome 17q21 haplotypes of selected family membersbased on 18 informative STR markers allele lengths are indicated in base pairs The disease haplotype is boxed in black Inferred haplotypesare shown between parentheses For deceased patients genotype data of at-risk offspring was used to deduce their haplotypesFor confidentiality reasons haplotypes are shown only for patients and obligate carriers the number of at-risk individuals includedin the genotyping is indicated within diamonds In family DR8 the risk haplotype was arbitrarily set for I-1 An arrowheadindicates the index patient

846 Brain (2006) 129 841ndash852 J van der Zee et al

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B

Fig 2 Continued

Table 3 Allele sharing analysis of STR markers and MAPT haplotypes spanning the 8 cM DR2ndashDR8 ancestral haplotype

Marker Linkedallele (bp)in DR2ndashDR8a

Frequencyof linkedalleles ()b

Patient of Belgian FTLD families

DR2 III-6 DR8 III-32 DR251 DR261 DR271 DR281 DR311

D17S1814 465 19 465-463 465-451 465-451 465-457 465-463 465-451 465-451D17S800 367 10 367-361 367-361 367-361 367-361 367-365 367-359 367-361D17S1787 181 35 181-179 181-179 181-177 181-179 181-177 181-181 181-177D17S1793 392 81 392-392 392-388 392-394 392-392 392-392 392-396 392-392D17S951 143 23 143-135 143-137 143-135 143-135 143-143 143-137 143-133D17S1861 278 6 278-264 278-280 278-262 278-268 278-276 278-274 278-274D17S934 359 27 359-363 359-359 359-363 359-357 359-371 359-361 359-359Chr17-16 401 22 401-397 401-397 401-397 401-397 401-403 401-397 401-401D17S810 186 30 186-182 186-186 186-182 186-182 186-180 186-180 186-180MAPT haplotypec H2 33 H2-H1 H2-H2 H2-H1 H2-H1 H2-H1 H2-H1 H2-H1D17S920 326 64 326-330 326-326 326-326 326-332 326-330 326-332 326-330D17S931 277 9 277-267 277-265 277-267 277-267 277-267 277-267 277-275Chr17-43 233 47 233-233 233-241 233-233 233-237 233-221 233-235 233-233

aLinked alleles are in bold bAllele frequencies were calculated in 92 control chromosomes cMAPT haplotypes were determined by genotypingthe MAPT htSNP16 according to Rademakers et al 2005

Belgian tau-negative FTLD founder effect Brain (2006) 129 841ndash852 847

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Fig 3 Pedigrees of Belgian FTLD families DR25 DR26 DR27 DR28 and DR31 showing chromosome 17q21 haplotypes ofselected relatives based on 14 STR markers allele lengths are indicated in base pairs The index patients (indicated with an arrowhead)were selected on the basis of allele sharing with the DR2ndashDR8 ancestral haplotype The disease haplotype is boxed in black TheDR2ndashDR8 ancestral haplotype is highlighted in bold Inferred haplotypes are shown between parentheses For confidentiality reasonshaplotypes are shown only for patients and obligate carriers the number of at-risk individuals included in the genotyping isindicated within diamonds

848 Brain (2006) 129 841ndash852 J van der Zee et al

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Table

4C

linic

alfindin

gsin

the

FTD

LD

R2ndashD

R8

hap

loty

pe

carr

iers

Indiv

idual

Gen

der

Onse

tag

e(y

ears

)A

geat

dea

th(dagger

)or

curr

ent

age

()

(yea

rs)

Dis

ease

dura

tion

(yea

rs)

Pre

senting

sym

pto

ms

Pre

senting

dia

gnosi

sD

iagn

osi

sat

follo

w-u

pSt

ruct

ura

lneu

roim

agin

g(C

TM

RI)

Funct

ional

neu

roim

agin

g(P

ET

SPEC

T)

DR

2III-

8M

66

71

(dagger)

5Im

pai

red

mem

ory

and

conce

ntr

atio

nFT

DFT

DG

lobal

mai

nly

subco

rtic

alat

rophy

(CT

)N

A

DR

2III-

10

M69

71

()

gt2

Apat

hy

reduce

dsp

onta

neo

us

spee

ch

agra

mm

atis

mve

rbal

per

seve

rations

dys

arth

ria

FTD

NA

Glo

bal

moder

ate

cort

ical

and

subco

rtic

alat

rophy

(MR

I)

Rel

ativ

efr

onta

lan

dfr

onto

par

ieta

lH

Ple

ftgt

righ

tR

elat

ive

HP

of

the

left

thal

amus

Dia

stas

isof

fronta

lco

rtic

alac

tivi

ty(S

PEC

T)

DR

2III-

6F

63

71

()

gt8

Non-fl

uen

tap

has

ia

per

sonal

ity

chan

ges

(mai

nly

apat

hy)

PN

FAFT

DG

lobal

cort

ical

and

subco

rtic

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(MR

I)

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(SPEC

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8III-

28

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gt6

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n)

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-findin

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8III-

18

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(dagger)

4Im

pai

red

mem

ory

re

duce

dsp

onta

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us

spee

ch

echola

liaap

athy

FTD

FTD

Glo

bal

cort

ical

and

subco

rtic

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rophy

(CT

)Se

vere

rela

tive

bifr

onta

lH

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leftgt

righ

t(S

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311

M66

70

(dagger)

4N

on-fl

uen

tap

has

iaPN

FAFT

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lobal

cort

ical

and

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or

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rtic

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of

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261

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68

(dagger)

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gres

sive

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of

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rtic

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sition

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cere

bel

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(PET

)D

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Non-fl

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has

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AR

elat

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FTLD

subdia

gnose

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rogr

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venon-fl

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tap

has

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NFA

)an

dfr

onto

tem

pora

ldem

entia

(FT

D)w

ere

mad

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cord

ing

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tablis

hed

criter

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eary

etal

1998)

Neu

ropsy

cholo

gica

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ingl

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nem

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on

com

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mogr

aphy

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)w

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the

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FTLD

(Pic

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1997)

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agin

g

Belgian tau-negative FTLD founder effect Brain (2006) 129 841ndash852 849

by guest on June 1 2013httpbrainoxfordjournalsorg

Dow

nloaded from

ages in the present Belgian FTLD patient sample are in line

with previously reported FTLD series (Johnson et al 2005)

Also the percentage of familial FTLD (43) was very similar

to that reported in a nationwide study on the prevalence of

FTLD conducted in The Netherlands (Rosso et al 2003) and

other studies (Poorkaj et al 2001a) Although the number of

autopsies is small (n = 7) to draw conclusions on the pre-

valence of the different pathological subtypes tau-negative

FTLD (FTDU and DLDH) was clearly much more prevalent

(5 out of 7 71) than tau-positive FTLD (1 out of 7 29) in

line with previous reports (Mann et al 2000 Morris et al

2001 Rosso et al 2003 Hodges et al 2004 Johnson et al

2005) Surprisingly however the MAPT mutation frequency

(1) was low compared with other studies (5ndash20) (Rizzu

et al 1999 Poorkaj et al 2001a) and suggested that

(an)other genetic defect(s) different from classical MAPT

mutations explain(s) the majority of familial FTLD in Bel-

gium

From two patients of our Belgian FTLD population we

collected two multiplex families DR2 and DR8 Both families

were linked to the same 17q21 haplotype indicating that they

are part of a single extended pedigree giving a summed LOD

score of 528 at D17S931 The DR2ndashDR8 candidate region of

8 cM encompassed the minimal 48 cM candidate region we

previously identified in the Dutch 17q21-linked FTDU family

1083 (Rademakers et al 2002) Comparing haplotype data of

the Belgian FTDU families DR2ndashDR8 with that obtained in

Dutch family 1083 (Rademakers et al 2002) did not identify

significant allele sharing pointing to allelic heterogeneity at

this locus Also in the Belgian FTDU families the linked

haplotype comprised the extended MAPT haplotype H2

whereas other FTDU families linked to 17q21 segregated

the extended MAPT haplotype H1 as part of their disease

haplotype (1083 Dutch III) The latter observation argues

against a causal role of the H1ndashH2 inversion polymorphism

in 17q21-linked tau-negative FTLD However since in all

these families MAPT is comprised within the disease haplo-

type we cannot exclude that MAPT does play a role in the

disease mechanism of tau-negative FTLD although different

from that in tauopathies with aggregated tau and MAPT

mutations

Interestingly we identified the DR2ndashDR8 haplotype in

another five patients with positive family history in the

same FTLD series Together with the two index patients

from families DR2 and DR8 the DR2ndashDR8 haplotype there-

fore explained 7 (7 out of 98) of FTLD in the overall series

and 17 (7 out of 42) of familial FTLD All DR2ndashDR8 hap-

lotype carriers were living throughout the region of the neigh-

bouring provinces of Antwerp and Flemish Brabant in the

Dutch-speaking region of Belgium Flanders The sharing of a

common haplotype and the close geographical proximity of

the seven families are indicative of a common ancestor Most

probably our data underestimated the actual frequency of

the underlying genetic defect since in our FTLD series we

observed several patients who shared alleles in smaller seg-

ments of the DR2ndashDR8 ancestral haplotype Information of

Fig 4 Brain perfusion single photon emission computed tomo-graphy (SPECT) of FTLD patient DR311 four years after onset ofthe disease showing relative bilateral frontal and temporalhypoperfusion with left more pronounced than right

A

B

Fig 5 Ubiquitin immunohistochemistry of superior frontal gyrusof FTLD patient DR311 (A) The arrowhead points towards anubiquitin-positive cat eye-shaped intranuclear inclusion Thearrows show ubiquitin-positive structures in neuronal perikarya(B) The arrow shows a filamentous tortuous ubiquitin-positivestructure in the perikaryon of a neuron the nucleus beingindicated by the letter N (Scale bar = 5 mm)

850 Brain (2006) 129 841ndash852 J van der Zee et al

by guest on June 1 2013httpbrainoxfordjournalsorg

Dow

nloaded from

these partial haplotypes would be most helpful in reducing the

candidate region to a more amenable size for gene cloning

However several of the partial haplotypes were also present

in control individuals and thus potentially unrelated to dis-

ease We are currently collecting additional family members

of each potential partial sharer for haplotype segregation

studies to allow identification of true sharers

Clinically DR2ndashDR8 haplotype carriers presented with

FTLD at a mean onset age of 6325 years and had disease

duration of 605 years These clinical features are similar to

what is reported for the other conclusive 17q21-linked tau-

negative families 1083 HDDD2 and Dutch III (Rademakers

et al 2002) Interestingly the DR2ndashDR8 haplotype carriers

often presented with language impairments which correlated

with predominant structural andor functional brain defects

at the left side Disproportionate dysphasia was also reported

in family HDDD2 (Lendon et al 1998) but not in the Dutch

families 1083 (Rademakers et al 2002) and Dutch III (Rosso

et al 2001) These results suggest that the presence of phatic

impairments might define an allelic subtype of 17q21-linked

tau-negative FTLD

We have not yet obtained brain pathology in the conclu-

sively linked pedigree DR8 (LOD score gt 3) only in one of

the ancestral haplotype carriers (DR311) In this patient the

ubiquitin positive cat eye-shaped intranuclear inclusions were

rare but morphologically identical to those described pre-

viously in other tau-negative 17q21-linked FTLD families

1083 and Dutch III (Rosso et al 2001 Rademakers et al

2002) In contrast in the HDDD2 family DLDH was the

pathological diagnosis (Lendon et al 1998 Zhukareva

et al 2001) Given the rarity of such inclusions presented

here we speculate that FTDU and DLDH belong to a spec-

trum of pathological manifestations that can be caused by the

same or a similar genetic defect at 17q21 We do however

realize that extrapolating the FTDU pathology data to the

17q21-linked families might seem premature However the

sharing data we observed is highly significant since the ances-

tral haplotype was absent from 92 control chromosomes

supporting our interpretation that the sharing between the

seven families is unlikely coincidental and that they are part of

the same founder pedigree Further we have already obtained

informed consent for brain autopsy of several patients in the

seven founder families in case of death which will allow

future detailed studies of brain pathology and FTDU speci-

fically Also availability of frozen brain material would allow

studies of MAPT mRNA and protein stability Previous such

studies in the Dutch III FTDU family showed normal MAPT

mRNA and isoform distributions (Rosso et al 2001) This is

in contrast with the report of loss of all tau protein isoforms

in family HDDD2 but normal tau mRNA (Zhukareva et al

2001)

In conclusion we identified a highly penetrant MAPT con-

taining ancestral haplotype in a population of 98 genealogi-

cally unrelated Belgian FTLD patients explaining a substantial

portion of familial FTLD (17) The haplotype carriers were

characterized by frequent language impairments the neuro-

pathological presence of tau-negative ubiquitin-positive

neuronal inclusions and absence of MAPT mutations In

contrast in the same patient series we have identified only

one MAPT mutation carrier among the familial FTLD

patients (2) indicating that 17q21-linked tau-negative

FTLD is much more frequent among Belgian FTLD patients

Our findings strongly suggest that the ancestral DR2ndashDR8

haplotype harbours a frequent causal mutation for 17q21-

linked tau-negative FTLD

Electronic database informationAccession numbers and URLs for data presented in this arti-

cle are as follows

Online Mendelian Inheritance in Man (OMIM) http

wwwncbinlmnihgovOmim

ADampFTD Mutation Database httpwwwmolgenuaac

beFTDMutations

Marshfield Center for Medical Genetics httpresearch

marshfieldclinicorggenetics

VIB8 Genetic Service Facility httpwww

vibgeneticservicefacilitybe

UCSC Genome Bioinformatics httpgenomeucscedu

GenBank httpwwwncbinlmnihgovGenbank [for

microsatellite markers Chr17-16 (accession number

AC00810532) Chr17-19 (accession number AC0916282)

Chr17-43 (accession number AC0682348) and for MAPT

(accession number AC0916282)]

AcknowledgementsThe authors are grateful to the family members for their kind

cooperation in this study and to the personnel of the VIB8

Genetic Service Facility (httpwwwvibgeneticservicefacility

be) for the genetic analyses The research described in this

paper was supported by the Special Research Fund of the

University of Antwerp the Fund for Scientific Research Flan-

ders (FWO-F) the Interuniversity Attraction Poles program

P519 of the Belgian Science Policy Office the International

Alzheimer Research Foundation Belgium the EU contract

LSHM-CT-2003-503330 (APOPIS) and the Alzheimerrsquos

Association USA SE RR and MC are postdoctoral fel-

lows and IG and VB are PhD fellows of the FWO-F RV is

a clinical investigator of the FWO-F Funding to pay the Open

Access publication charges for this article was provided by

The Special Research Fund of the University of Antwerp

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Association of an extended haplotype in the tau gene with progressive

supranuclear palsy Hum Mol Genet 1999 8 711ndash15

Benson G Tandem repeats finder a program to analyze DNA sequences

Nucleic Acids Res 1999 27 573ndash80

Brown J Ashworth A Gydesen S Sorensen A Rossor M Hardy J et al

Familial non-specific dementia maps to chromosome 3 Hum Mol

Genet 1995 4 1625ndash8

Belgian tau-negative FTLD founder effect Brain (2006) 129 841ndash852 851

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Dow

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Chow TW Miller BL Hayashi VN Geschwind DH Inheritance of

frontotemporal dementia Arch Neurol 1999 56 817ndash22

Cruts M Rademakers R Gijselinck I van der Zee J Dermaut B De Pooter T

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dementia uncovers a highly homologous family of low copy repeats in

the tau region Hum Mol Genet 2005 14 1753ndash62

Dermaut B Kumar-Singh S Engelborghs S Theuns J Rademakers R Sacrens J

et al A novel presenilin 1 mutation associated with Pickrsquos disease but not

beta-amyloid plaques Ann Neurol 2004 55 617ndash26

Engelborghs S Dermaut B Goeman J Saerens J Marien P Pickut BA et al

Prospective Belgian study of neurodegenerative and vascular dementia

APOE genotype effects J Neurol Neurosurg Psychiatry 2003 74 1148ndash51

Foster NL Wilhelmsen K Sima AA Jones MZ DrsquoAmato CJ Gilman S

Frontotemporal dementia and parkinsonism linked to chromosome 17

a consensus conference Conference Participants Ann Neurol 1997 41

706ndash15

Harvey RJ Skelton-Robinson M Rossor MN The prevalence and causes of

dementia in people under the age of 65 years J Neurol Neurosurg

Psychiatry 2003 74 1206ndash9

Hodges JR Davies RR Xuereb JH Casey B Broe M Bak TH et al

Clinicopathological correlates in frontotemporal dementia Ann Neurol

2004 56 399ndash406

Hosler BA Siddique T Sapp PC Sailor W Huang MC Hossain A et al

Linkage of familial amyotrophic lateral sclerosis with frontotemporal

dementia to chromosome 9q21-q22 JAMA 2000 284 1664ndash69

Hutton M Lendon CL Rizzu P Baker M Froelich S Houlden H et al

Association of missense and 50-splice-site mutations in tau with the

inherited dementia FTDP-17 Nature 1998 393 702ndash5

Johnson JK Diehl J Mendez MF Neuhaus J Shapira JS Forman M et al

Frontotemporal lobar degeneration demographic characteristics of 353

patients Arch Neurol 2005 62 925ndash30

Kumar-Singh S Cras P Wang R Kros JM van Swieten J Lubke U et al

Dense-core senile plaques in the Flemish variant of Alzheimerrsquos disease are

vasocentric Am J Pathol 2002 161 507ndash20

Lathrop GM Lalouel JM Julier C Ott J Multilocus linkage analysis in

humans detection of linkage and estimation of recombination Am J

Hum Genet 1985 37 482ndash98

Lendon CL Lynch T Norton J Mckeel DW Busfield F Craddock N et al

Hereditary dysphasic disinhibition dementiamdasha frontotemporal dementia

linked to 17q21-22 Neurology 1998 50 1546ndash55

Mann DM McDonagh AM Snowden J Neary D Pickering-Brown SM

Molecular classification of the dementias Lancet 2000 355 626

Morris HR Khan MN Janssen JC Brown JM Perez-Tur J Baker M et al The

genetic and pathological classification of familial frontotemporal dementia

Arch Neurol 2001 58 1813ndash6

Neary D Snowden JS Gustafson L Passant U Stuss D Black S et al

Frontotemporal lobar degeneration a consensus on clinical diagnostic

criteria Neurology 1998 51 1546ndash54

Ott A Breteler MM Van Harskamp F Claus JJ van der Cammen TJ

Grobbee DE et al Prevalence of Alzheimerrsquos disease and vascular

dementia association with education The Rotterdam study BMJ 1995

310 970ndash3

Pals P Lincoln S Manning J Heckman M Skipper L Hulihan M et al

Alpha-synuclein promoter confers susceptibility to Parkinsonrsquos disease

Ann Neurol 2004 56 591ndash5

Pickut BA Saerens J Marien P Borggreve F Goeman J Vandevivere J

et al Discriminative use of SPECT in frontal lobe-type dementia

versus (senile) dementia of the Alzheimerrsquos type J Nucl Med 1997 38

929ndash34

Poorkaj P Bird TD Wijsman E Nemens E Garruto RM Anderson L et al

Tau is a candidate gene for chromosome 17 frontotemporal dementia Ann

Neurol 1998 43 815ndash25

Poorkaj P Grossman M Steinbart E Payami H Sadovnick A Nochlin D et al

Frequency of tau gene mutations in familial and sporadic cases of

non-Alzheimer dementia Arch Neurol 2001a 58 383ndash7

Poorkaj P Kas A DrsquoSouza I Zhou Y Pham Q Stone M et al A genomic

sequence analysis of the mouse and human microtubule-associated protein

tau Mamm Genome 2001b 12 700ndash12

Rademakers R Cruts M Dermaut B Sleegers K Rosso SM Van den

Broeck M et al Tau negative frontal lobe dementia at 17q21 significant

finemapping of the candidate region to a 48 cM interval Mol Psychiatry

2002 7 1064ndash74

Rademakers R Cruts M van Broeckhoven C The role of tau (MAPT) in

frontotemporal dementia and related tauopathies Human Mutat 2004 24

277ndash95

Rademakers R Melquist S Cruts M Theuns J Del-Favero J Poorkaj P et al

High-density SNP haplotyping suggests altered regulation of tau gene

expression in progressive supranuclear palsy Hum Mol Genet 2005 14

3281ndash92

Ratnavalli E Brayne C Dawson K Hodges JR The prevalence of

frontotemporal dementia Neurology 2002 58 1615ndash21

Rizzu P van Swieten JC Joosse M Hasegawa M Stevens M Tibben A et al

High prevalence of mutations in the microtubule-associated protein tau in

a population study of frontotemporal dementia in the Netherlands Am J

Hum Genet 1999 64 414ndash21

Rosso SM Kaat LD Baks T Joosse M de Koning I Pijnenburg Y et al

Frontotemporal dementia in The Netherlands patient characteristics and

prevalence estimates from a population-based study Brain 2003 126

2016ndash22

Rosso SM Kamphorst W de Graaf B Willemsen R Ravid R Niermeijer MF

et al Familial frontotemporal dementia with ubiquitin-positive inclusions

is linked to chromosome 17q2l-22 Brain 2001 124 1948ndash57

Skibinski G Parkinson NJ Brown JM Chakrabarti L Lloyd SL Hummerich H

et al Mutations in the endosomal ESCRTIII-complex subunit CHMP2B in

frontotemporal dementia Nat Genet 2005 37 806ndash8

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 USA 1998 95 7737ndash41

Stankiewicz P Lupski JR Molecular-evolutionary mechanisms for genomic

disorders Curr Opin Genet Dev 2002 12 312ndash9

Stefansson H Helgason A Thorleifsson G Steinthorsdottir V Masson G

Barnard J et al A common inversion under selection in Europeans Nat

Genet 2005 37 129ndash37

Stevens M van Duijn CM Kamphorst W de Knijff P Heutink P

van Gool WA et al Familial aggregation in frontotemporal dementia

Neurology 1998 50 1541ndash5

Zhukareva V Vogelsberg-Ragaglia V Van Deerlin VMD Bruce J

Shuck T Grossman M et al Loss of brain tau defines novel sporadic

and familial tauopathies with frontotemporal dementia Ann Neurol

2001 49 165ndash75

852 Brain (2006) 129 841ndash852 J van der Zee et al

by guest on June 1 2013httpbrainoxfordjournalsorg

Dow

nloaded from