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Journal of Alzheimer’s Disease 29 (2012) 1–10 DOI 10.3233/JAD-2012-120172 IOS Press
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The French Series of Autosomal Dominant Early Onset Alzheimer’s Disease Cases: Mutation Spectrum and Cerebrospinal Fluid Biomarkers
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a Inserm
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b CNR-MAJ,
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U1079, CHU et Facult´e de M´edecine-Pharmacie, Rouen, France Rouen University Hospital, Lille University Hospital and Paris Salpˆetri`ere University Hospital, Paris, France c Biochemistry Laboratory, Rouen University Hospital, Rouen, France d Department of Neurology, CMRR and INSERM U825, Purpan University Hospital, Toulouse, France e EA1046, Deparment of Neurology, Lille Nord University Hospital, Lille Nord, France f CRCICM, IM2A, UMR-S975 AP-HP, University Hospital Piti´ e-Salpˆetri`ere, Paris, France g Department of Neuropsychology, CMRR, University Hospital, Groupe Hospitalier Est, Bron, France h Department of Neurology, CMRR, Nantes University Hospital, France i Department of Neurology, CMRR, University Hospital Nord, Saint Etienne, France j CMRR Nord, INSERM U 839, Lariboisi` ere University Hospital, Paris, France k CMRR, Grenoble University Hospital, Grenoble, France l CMRR, Gui de Chauliac Hospital, Montpellier University Hospital, Montpellier, France m Department of Neurology, CMRR Hˆ opitaux Civils de Colmar, France n Department of Neurology, CMRR, Nancy University Hospital, France o Neuropathology Laboratory, Rouen University Hospital, Rouen, France p Escourolle Neuropathology Laboratory, CRCICM AP-HP, University Hospital Piti´ e-Salpˆetri`ere, Paris, France q Neuropathology Laboratory, Rangueil University Hospital, Toulouse, France r Neuropathology Laboratory and INSERM U1028, CNRS UMR 5292, University Lyon, Lyon, France s Departement of Pathology, Hautpierre Hospital, Strasbourg, France
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David Wallona,b , St´ephane Rousseaua,b , Anne Rovelet-Lecruxa,b , Muriel Quillard-Murainec , Lucie Guyant-Mar´echalb , Olivier Martinaudb , J´er´emie Pariented , Mich`ele Pueld , Adeline Rollin-Sillaireb,e , Florence Pasquierb,e , Isabelle Le Berb,f , Marie Sarazinb,f , Bernard Croisileg , Claire Boutoleau-Bretonni`ereh , Catherine Thomas-Ant´erioni , Claire Paquetj , Olivier Moreaudk , Audrey Gabellel , Franc¸ois Sellalm , Mathilde Sauv´een , Annie Laquerri`ereo , Charles Duyckaertsp , Marie-Bernadette Delisleq , Nathalie Streichenbergerr , B´eatrice Lanness , Didier Hannequina,b,1 , Dominique Campiona,b,1,∗ and the collaborators of the GMAJ project2
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Handling Associate Editor: Sylvain Lehmann Accepted 9 March 2012
1 These
authors contributed equally to this work. to: Dr. Dominique Campion, Inserm U1079, Facult´e de M´edecine, 22 boulevard Gambetta, 76183 Rouen, France. Tel.: +33 235148280; Fax: +33 235148237; E-mail:
[email protected]. ∗ Correspondence
ISSN 1387-2877/12/$27.50 © 2012 – IOS Press and the authors. All rights reserved
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D. Wallon et al. / The French Series of Autosomal Dominant Early
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Keywords: Alzheimer’s disease, APP, CSF biomarkers, early-onset, genetics, PSEN1, PSEN2
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Abstract. We describe 56 novel autosomal dominant early-onset Alzheimer families (ADEOAD) with PSEN1, PSEN2, and AβPP mutations or duplications, raising the total of families with mutations on known genes to 111 (74 PSEN1, 8 PSEN2, 16 AβPP, and 13 AβPP duplications) in the French series. In 33 additional families (23% of the series), the genetic determinism remained uncharacterized after this screening. Cerebrospinal fluid (CSF) biomarker levels were obtained for patients of 58 families (42 with known mutations and 16 without genetic characterization). CSF biomarkers profile was consistent with an AD diagnosis in 90% of families carrying mutations on known genes. In families without genetic cause identified, CSF biomarkers were consistent with AD diagnosis in 14/16 cases. Overall, these results support further genetic heterogeneity in the determinism of ADEOAD and suggest that other major genes remain to be characterized.
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Supplementary data available online: http://www.j-alz.com/issues/30/vol30-4.html#supplementarydata04 42
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MATERIALS AND METHODS
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Subjects
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A minority of Alzheimer disease (AD) patients present symptoms beginning before the age of 65. Within this group of early-onset AD, a familial aggregation is often found and, in a subset of families, the pattern of inheritance is consistent with autosomal dominant inheritance [1]. So far, autosomal dominant early-onset Alzheimer disease (ADEOAD) cases are linked either to point mutations or indels within 3 genes (Amyloid-β Protein Precursor (AβPP)) [2], presenilin 1 (PSEN1), and presenilin 2 (PSEN2)) [3, 4] or to duplications of the AβPP gene [5]. Mutations in PSEN1 are the most frequent with 185 different mutations recorded to date. Thirty-two mutations (including duplications) are known in AβPP and 13 in PSEN2 (data from AD-FTD Database: http://www.molgen.ua.ac.be/ADMutations). On clinical grounds, while most of these changes cause a typical AD phenotype, several of them are associated with atypical presentations such as spastic paraparesis [6–10], frontal variants [11–16], severe cerebral amyloid angiopathy [17–19], or cerebellar ataxia [20–22]. Besides establishing the full mutation spectrum for these genes and the genotype/phenotype correlations, an important question is to assess the proportion of ADEOAD families not explained by alterations on known genes. In the past 15 years, all patients from French families consistent with ADEOAD were referred to our center for genetic testing on a nationwide basis. We have previously reported the mutation spectrum for part of this series [1, 5, 8, 23]. The aim of the present study is to report additional data collected during the last 5 years on novel families, in order to further analyze the respective involvement of each gene and to update our estimate of the proportion of unexplained families. In addition, CSF biomarkers are now available for a large subsample of these new cases,
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allowing us to determine the sensitivity of biomarkers for diagnosing AD due to known mutations.
INTRODUCTION
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Clinical diagnosis of AD was performed according to the National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer’s Disease and Related Disorder Association for probable AD [24]. Diagnosis of ADEOAD was made if at least 2 first-degree relatives suffered from AD in at least two generations with an age of onset before 65 years for both. All patients gave written consent to participate in the study. The local ethical committee approved the study. Before diagnosis, patients underwent a comprehensive clinical examination including personal medical and family history, neurological examination, neuropsychological assessment, APOE genotyping and, for some, lumbar puncture with CSF biomarker analysis. Neuropathological examination, using standard procedures [25–27], was performed when possible. CSF analysis CSF biomarkers analysis was carried out in 6 different laboratories using a standardized procedure. CSF samples were obtained using a Sprotte needle in polypropylene collection tubes and aliquoted after centrifugation into polypropylene Eppendorf tubes, then frozen at −80◦ C within 1 h. A42 , Tau (total-tau protein), and P-Tau (phospho-tau protein) measurements were performed using an enzyme-linked immunosorbent assay (ELISA) (Innogenetics Ghent, Belgium) according to the manufacturer’s instructions. The analysis of all biomarkers was performed in 2 runs and averaged for statistical analyses. For each biomarker,
74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91
92 93 94 95 96 97 98 99 100 101 102 103
D. Wallon et al. / The French Series of Autosomal Dominant Early
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Table 1 French ADEOAD families previously unreported with PSEN1 mutations
4 5 5 5 5 5 5 6 6 6 6 6 7 7 7 7 7 7 7 8 8 8 8 8 8 8 8
3-3 2-3 3-3 3-3 3-3 3-3 3-3 3-4 3-3 3-4 3-4 3-3 3-3 3-3 3-4 2-3 3-3 3-4 3-3 3-3 3-3 3-3 3-3 3-3 3-3 3-3 3-3
EXT 262 EXT 238 ANG 008 ALZ 139 ALZ 248 ALZ 104 ALZ 279 EXT 358 ALZ 430 EXT 226 ALZ 428 ALZ 064 ALZ 013 EXT 134 ALZ 243 ALZ 250 EXT 141 EXT 359 SAL 613 ALZ 512 EXT 140 EXT 142 EXT 143 EXT 369 SAL 294 EXT 048 DF 149
c.1129A>T c.1171G>T c.1171G>T c.1229G>A c.1254G>T
10 11 11 11 12
3-3 3-3 3-3 3-3 3-3
EXT 138 ALZ 116 EXT 035 EXT 074 BRE 014 32
♦ nucleotide
1 1 1 1 1 1 2 1 3 1 1 2 2 2 1 1 1 1 2 1 3 3 1 1 1 1 1
1 3 1 1 1 45
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c.236C>T c.344A>G c.347C>T c.416T>A c.416T>C c.416T>C c.436A>C c.449T>C c.488A>G c.488A>G c.488A>G c.495G>C c.551A>G c.551A>G c.617G>C c.666G>C c.668A>G c.689G>T c.699G>A c.779C>T c.784T>G c.791C>T c.791C>T c.791C>T c.818A>G c.856C>G c.869 955del
PS (n) AS (n) Coseg Pathogenicity AOO range (years) DD (years) nature 7 2 5 2 4 2 6 6 6 4 7 4 8 3 3 4 2 2 2 6 8 3 5 8 4 3 4
n/a n/a n/a n/a n/a n/a Yes n/a Yes n/a n/a Yes Yes n/a n/a n/a n/a n/a Yes n/a Yes Yes n/a n/a n/a n/a n/a
Definite Definite Definite Definite Definite Definite Definite Probable Definite Definite Definite Definite Definite Definite Definite Definite Definite Possible Definite Definite Definite Definite Definite Definite Probable Definite Definite
[60–62] [39-40] [38–44] [37–50] [55–63] [42–55] [39–41] [54–65] [42–45] [36–44] [31–40] [37–47] [43–52] [51-52] [58–60] [44–47] [31–34] [50–58] [24–30] [34–38] [54–63] [47–55] [48–57] [47–58] [50–63] [41–45] [42–47]
[4–10] 3 [3–5] 10 [8–11] [9–15] [9–12] [5–10] [6–10] [8–12] [6–9] [2–11] [5–14] [7-8] [7] [5–10] 5 20 11 [8] [8] [6–19] [4–8] [6–11] [9] [7–10] [11–15]
2 7 2 4 2 137
n/a Yes n/a n/a n/a 8
Probable Definite Definite Definite Definite
[50] [54-55] [45–50] [40–60] [31–35] [24–63]
[8-9] [5–10] 3 [6–10] [5-6] [2–19]
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ID fam
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APOE (index case)
dA
Exon
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p.Ala79Val p.Tyr115Cys p.Thr116Ile p.Met139Lys p.Met139Thr p.Met139Thr p.Met146Leu p.Leu150Pro p.His163Arg p.His163Arg p.His163Arg p.Trp165Cys p.Glu184Gly p.Glu184Gly p.Gly206Ala p.Gln222His p.Gln223Arg p.Ser230Ile p.Met233Ile p.Ala260Val p.Leu262Val p.Pro264Leu p.Pro264Leu p.Pro264Leu p.Glu273Gly p.Leu286Val p.[S290C;T291 S319del] p.Arg377Trp p.Val391Phe p.Val391Phe p.Cys410Tyr p.Leu418Phe Total & [range]
Nucleotide change♦
rre
Protein change
change: according to RefSeq. NM 000021.3. ID Fam: family code; PS: patients sampled; coseg: cosegregation with the disease; AOO: Age of onset; AS: affected subjects in the same family; DD: disease duration; (bold): mutation previously unreported; n/a: not applicable.
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Genetic analysis
106 107 108 109 110 111 112 113 114 115
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we verified that the mean value did not significantly differ between each laboratory (data not shown). The following cut-offs were used to define a biochemical AD signature: A42 (350 pg/mL), and P-Tau (>60 pg/mL). We also calculated the Innogenetics Amyloid-Tau Index (IATI) using the formula [A42 ]/(240 + 1.18[Tau]) (value 0.211 was considered abnormal) [29, 30]. Two criteria differing by stringency were used to classify CSF samples as supporting an AD diagnosis: either (i) all three biomarkers were abnormal or (ii) IATI and [PTau]/[A42 ] ratios were both abnormal.
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Genomic DNA was isolated using Flexigen DNA kit (Qiagen) according to standard procedures. The entire coding regions of PSEN1 and PSEN2 and exons
16 and 17 of the AβPP gene were PCR amplified using specific primers (supplementary Table 1; available online: http://www.j-alz.com/issues/30/vol304.html#supplementarydata04). Each PCR product was then sequenced using an ABI3100 (Applied Biosystem) genetic analyzer. For each subject, APOE genotype was determined by gene amplification and cleavage with Hha1 [31]. AβPP duplications were determined using quantitative multiplex PCR of short fluorescent fragments (QMPSF) as previously described [5]. We used the Guerreiro’s algorithm [32] and the AD-FTD Database [33] to classify mutation pathogenicity. Statistical analysis CSF biomarkers were compared between 3 groups of patients, depending on their genetic status:
121 122 123 124 125 126 127 128 129 130 131 132 133
134
135 136
144 145
146
147 148 149 150 151 152 153 154 155
RESULTS Since 2005, 56 novel families were identified: 32 families with PSEN1 mutations (including 7 previously unreported mutations) (Table 1), 8 with PSEN2 mutations (1 previously unreported) (Table 2), 9 with AβPP mutations (all previously known) (Table 3), and 7 with AβPP duplication (Table 4). Combining these 56 novel families with previously reported pedigrees [1, 23], a total of 111 families with presenilins and AβPP alterations were characterized
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(supplementary Tables 2–5 for the whole series). In addition, 33 families remained negative for these genetic defects (supplementary Table 6). Overall, the mutation screening was positive in 111/144 families (77%). Mean age of onset for patients with PSEN1 mutations was 43.6 years [24–63] and 50% of them began the disease before 40 years old. Mean age of onset was 55.9 years [53–69] for patients with PSEN2 mutation, 50.8 years [35–61] for AβPP mutations, and 51.3 years [41–65] for AβPP duplication. In the 33 families without alteration on known genes, mean age of onset was 58.4 years [44–74]. Classical AD phenotype associating memory loss, apraxia, and impairment of spatial skills was the most frequent but several atypical signs were also present (Table 5). Indeed, patients from 8 different families with PSEN1 mutations (p.Leu113Pro; p.Met139Val; p.Met139Thr; p.Trp165Cys; p.Glu184Gly; p.Glu280Gly; p.[S290C;T291 S391del]) were initially affected by behavioral modifications compatible with a frontal
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Table 2 French ADEOAD families previously unreported with PSEN2 mutation Protein change
Nucleotide change♦
Exon
APOE (index case)
p.Arg71Trp p.Arg71Trp p.Lys161Arg p.Met239Val p.Met239Val p.Met239Val p.Met239Val p.Met239Val Total & [range]
c.211C>T c.211C>T c.482A>G c.715A>G c.715A>G c.715A>G c.715A>G c.715A>G
4 4 5 7 7 7 7 7
3-4 3-4 3-4 3-4 3-4 3-4 3-4 3-4
ID fam
PS (n)
AS (n)
Coseg
Pathogenicity nature
AOO range (years)
DD (years)
EXT 075 EXT 179 EXT 114 ALZ 400 TOU 035 ALZ 434 ROU 360 EXT 062 8
2 1 1 1 1 1 1 1 9
2 3 3 2 5 5 6 2 28
Yes n/a n/a n/a n/a n/a n/a n/a 1
Definite Definite Possible Definite Definite Definite Definite Definite
[63-64] [55-56] [61–69] [47–55] [53–62] [48–67] [49–57] [47–60] [47–69]
[6–9] [7–16] [7–16] [7–13] [15] [4–11] [10–19] [5–7] [4–19]
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i) patients with PSEN1 and PSEN2 mutations, ii) patients with AβPP mutations, and iii) patients with AβPP duplications. We compared A42 , Tau, and PTau concentrations, IATI and [A42 ]/[P-Tau] ratios in each group using a Mann-Withney U Test. We also analyzed the correlations between biomarker concentrations or ratios and age or disease duration with the Spearman correlation coefficient. The significance was set at p < 0.05.
♦ nucleotide change: according to RefSeq. NM 000447.2. ID Fam: family code; PS: patients sampled; coseg: cosegregation with the disease; AOO: Age of onset; AS: affected subjects in the same family; DD: disease duration; (bold): mutation previously unreported; n/a: not applicable.
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Table 3 French ADEOAD families previously unreported with AβPP mutation
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Protein change
Nucleotide change♦
Exon
APOE (index case)
ID fam
PS (n)
AS (n)
Coseg
Pathogenicity nature
AOO range (years)
DD (years)
p.Val715Ala p.Val717Ile p.Val717Ile p.Val717Ile p.Val717Ile p.Val717Ile p.Val717Ile p.Val717Ile p.Leu723Pro Total & [range]
c.2144T>C c.2149G>A c.2149G>A c.2149G>A c.2149G>A c.2149G>A c.2149G>A c.2149G>A c.2168T>C
17 17 17 17 17 17 17 17 17
3-3 3-3 3-3 3-3 3-3 3-3 3-3 3-4 3-4
EXT 147 PRO 003 ALZ 221 ALZ 066 EXT 076 EXT 148 ALZ 431 EXT 286 ALZ 523 9
1 1 1 2 1 1 2 1 1 11
10 4 3 4 5 3 3 2 7 41
n/a n/a n/a Yes n/a n/a Yes n/a n/a 2
Definite Definite Definite Definite Definite Definite Definite Definite Definite
[40–44] [51–55] [40–54] [53–61] [45–48] [47–55] [49–52] [53–60] [54–57] [40–61]
[6–13] [10] [8–10] [8] [8–11] [5–10] [5–7] 5 [3-4] [5–11]
♦ nucleotide
change: according to RefSeq. NM 000484.3. ID Fam: family code; PS: patients sampled; coseg: cosegregation with the disease; AOO: Age of onset; AS: affected subject in the same family; DD: disease duration; n/a: not applicable.
156 157 158 159 160 161 162 163 164 165 166 167 168 169 170 171 172 173 174 175 176
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Table 4 French ADEOAD families previously unreported with AβPP duplications APOE (index case)
ID fam
PS (n)
AS (n)
Coseg
AOO range (years)
DD (years)
3-4 3-3 3-3 3-3 2-3 3-3 3-3
EXT 298 EXT 279 EXT 054 EXT 145 EXT 144 EXT 187 ALZ 254 7
1 1 1 1 2 1 1 8
3 2 3 2 4 3 2 19
n/a n/a n/a n/a Yes n/a n/a 1
[ 50–53 ] [50] [41–55] [48–52] [42–64] [45–60] [52–55] [41–65]
[6–10] 4 [10–13] [0–6] n/a [5–10] [6–10] [0–15]
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0.83 1.18 1.6 6 9.7 14.2 14.7 Total & [range]
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Duplication size (Mb)
ID Fam: family code; PS: patients sampled; coseg: cosegregation with the disease; AOO: Age of onset; AS: affected subjects in the same family; DD: disease duration; n/a: not applicable.
183 184 185 186 187 188 189 190 191 192 193 194 195 196 197 198 199 200 201 202 203 204 205 206 207 208 209 210 211 212 213 214 215
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duplications. No correlation was found between biomarker levels and age or disease duration (data not shown). In the 33 families without alteration on known genes, CSF biomarkers were obtained for 16 patients and 14 values were consistent with an AD diagnosis (supplementary Table 7). Twenty-five neuropathological examinations were obtained in 18 patients with PSEN1 mutations and 7 with AβPP duplications. In all cases, the diagnosis was consistent with moderate to severe AD [25, 26, 34]. Cotton wool plaques were found in 9 patients with PSEN1 mutations (p.Pro117Ala, p.Glu120Asp, p.Leu173Trp, p.Pro264Leu, p.[S290C;T291 S319del], p.Phe386Ser, p.Leu418Phe). Among them, 5 suffered from spastic paraplegia. In two patients with p.Leu113Pro PSEN1 mutation that harbored clinical symptoms and imaging reminiscent of fronto-temporal dementia [11], the neuropathological examination showed a large number of neuritic plaques predominantly in the frontal cortex. TDP-43 and ubiquitin immunostaining was negative and western blot analysis showed a classical four bands of phosphorylated tau. These results allowed for the definite classification of the disease associated with this mutation as a frontal AD variant. A pathology in a patient with ataxic clinical phenotype, harboring the p.Pro117Ala PSEN1 mutation, was severe in the cortex with cotton wool plaques, and moderate in the cerebellum and brainstem nuclei. The pattern of amyloid deposits in cerebellum consisted in diffuse deposits in the molecular layer and focal deposits including cored plaques in the Purkinje layer and sometimes in the granular layer. For 13 PSEN1 patients (81.6%) and all AβPP duplications, the cerebral amyloid angiopathy (CAA) affecting white matter, cortical or meningeal vessel, was rated as moderate to severe with massive A40 deposits in vessels walls. The brain of three PSEN1 patients (p.Leu113Pro; p.Leu173Trp; p.[S290C;T291 S319del]) and one patient with AβPP
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variant of AD. Spastic paraparesis, occurring 2 years before (n = 2) or up to 5 years after the onset of cognitive decline (n = 9), was described in 11 families harboring 7 PSEN1 mutations (p.Leu173Trp; p.Gln223Arg; p.Pro264Leu; p.Glu280Gly; p.[S290C; T291 S319del]; p.Thr291Pro; p.Phe386Ser). Patients from 6 families with PSEN1 mutation (p.Tyr115His; p.Pro117Ala; p.Met139Thr; p.Glu184Gly; p.Met233Thr; p.Leu235Pro) suffered from early myoclonic epilepsy. Cerebellar ataxia was present in 4 families harboring the following PSEN1 mutations: p.Tyr115His; p.Pro117Ala; p.Leu173Trp; p.Leu235Pro. Three patients harboring 2 different PSEN1 mutations (p.Cys410Tyr; p.Met233Ile) presented early extrapyramidal signs (beginning up to 5 years after the onset of the disease). Concerning AβPP duplications, intracerebral hemorrhages were found in 7 families, and early seizures were observed in 16 cases from 6 families and revealed the disease in 2 cases. Finally, one case with AβPP duplication met the clinical criteria for Lewy body dementia. Overall, the proportion of atypical forms reached 18% of families with identified mutations. CSF was obtained for 42 patients carrying mutations (supplementary Table 6). The three biomarkers were each abnormal in 69% of CSF samples. When using the less stringent IATI and [P-Tau]/[A42 ] ratio, 90% of the samples were consistent with an AD diagnosis. The results were atypical for five patients, exhibiting only two out of three abnormal biomarker levels and a normal [P-Tau]/[A42 ] ratio. In 3 cases, the level of A42 was normal. In another case Tau was normal and in the last case the P-Tau level was normal. We did not, however, encounter a single, totally normal sample (i.e., normal A42 , Tau, and P-Tau values) in our series of ADEOAD cases. For each biomarker, the mean value did not differ between patients bearing PSEN1/PSEN2 mutations, AβPP mutations, or AβPP
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216 217 218 219 220 221 222 223 224 225 226 227 228 229 230 231 232 233 234 235 236 237 238 239 240 241 242 243 244 245 246 247 248 249 250 251 252 253 254
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D. Wallon et al. / The French Series of Autosomal Dominant Early Table 5 Atypical phenotypes in patients carrying mutations Gene
Mutation or duplication size
Neuropathological findings
References with similar phenotype
Frontal variant of AD
PSEN1
p.Leu113Pro
Frontal cortex predominant neuritic plaques localization, severe CAA, LBP
[11]
p.Leu173Trp p.Gln223Arg p.Pro264Leu p.Glu280Gly p.[S290C;T291 S319del] p.Thr291Pro p.Phe386Ser p.Tyr115His
PSEN1
p.Pro117Ala p.Met139Thr p.Glu184Gly p.Met233Thr p.Leu235Pro 0,55 Mb 0,58 Mb 0,78 Mb 1,6 Mb 1,8 Mb 4 Mb 6,4 Mb 14,7 Mb 0,55 Mb
rre
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AβPP duplication
AβPP duplication
Early extrapyramidal syndrome
PSEN1
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Cerebellar ataxia
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Intracerebral hemorrhages
AβPP duplication PSEN1
0,58 Mb 0,78 Mb 1,18 Mb 6 Mb 6,4 Mb 9,7 Mb p.Cys410Tyr p.Met233Ile p.Met233Ile 0,55 Mb p.Tyr115His p.Pro117Ala
p.Leu173Trp p.Leu235Pro
CWP, moderate CAA, LBP CWP, LBP CWP
uth
Early myoclonic epilepsy
PSEN1
dA
Spastic paraparesis
[44]
or P
p.Met139Val p.Met139Thr p.Trp165Cys p.Glu184Gly p.Glu280Gly p.[S290C;T291 S391del])
roo f
Atypical phenotype
CWP
[43]-ERROR
[10, 45] [8, 46] [8, 47, 48] [6, 49] [8]
CWP, severe CAA CWP
[6] CAA
[50]
CAA CAA
[17] [17] [17] [17] [17]
CAA
[50]
CAA CAA
[17] [17]
CAA
[17]
CAA, LBP
[50]
CWP, moderate amyloid pathology in cerebellum CWP
[22]
CAA: Cerebral Amyloid Angiopathy; LBP: Lewy Bodies Pathology; CWP: Cotton Wool Plaques.
D. Wallon et al. / The French Series of Autosomal Dominant Early
262 263 264 265 266 267 268 269 270 271 272 273 274 275 276 277 278 279 280 281 282 283 284 285 286 287 288 289 290 291 292 293 294 295 296 297 298 299 300 301 302 303
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260
dA
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This series of 253 cases from 144 families established since 1993 is arguably one of the most important reported so far. Cases were referred by 23 expert centers in France according to our guidelines (at least 2 first-degree AD relatives in at least two generations with age of onset under 65 years). Based on the estimated prevalence of ADEOAD [23], we consider that roughly 1/3 of all ADEOAD cases living in France have been ascertained. The proportion of families carrying a PSEN1 mutation (51%) is more important than PSEN2 or AβPP (6% and 11%, respectively). The proportion of PSEN2 mutations is low but since these mutations are known to be associated with later onset [35], the true involvement of this gene in mendelian forms of AD could have been underestimated. The proportion of AβPP duplications reaches 9%, nearly equivalent to that of AβPP point mutations, although no particular emphasis was put on identifying cases with CAA. On clinical grounds, the proportion of families affected by spastic paraplegia reaches 15% of families carrying PSEN1 mutations. So far, spastic paraplegia has been reported to be associated with over 20 PSEN1 mutations [9]. Five of these mutations were retrieved in our families (p.Gln223Arg; p.Pro264Leu; p.Glu280Gly; p.[S290C;T291 S319del]; p.Thr291Pro), as well as two others (p.Leu173Trp; p.Phe386Ser) that have not yet been described. Several PSEN1 mutations have been reported as associated with a frontal variant of AD [36]. In our series, 11% of PSEN1 patients suffered from initial behavioral modifications demonstrating that a frontal variant of AD is a fairly common clinical phenotype. This series also illustrates the variety of neuropathological lesions associated with ADEOAD. First, cotton wool plaques were found in almost 47% of neuropathologically examined patients harboring a PSEN1 mutation, and only half of them presented a spastic paraparesis phenotype. Second, we reported one ataxic patient harboring the p.Pro117Ala PSEN1 mutation, which showed paradoxically moderate amyloid deposits in the cerebellum. AD lesions in cerebellum are well documented in sporadic and familial AD. Indeed, A deposits in molecular and granular layer have been described in 89% of cases from a large autopsy series [21] but none showed cerebellar signs. Conversely, neuropathological description of ataxic
cases are scarce [37]. Third, we reported 4 cases with Lewy body pathology in cortical structures. Lewy bodies are very common in the amygdala of PSEN1 and PSEN2 mutation, respectively 96% [38] and 75% [35]. However, the cortical distribution seems to be, as in our series, more mutation-dependent. In families with mutations on known genes, the proportion of cases with AD signature reached 90% when both IATI and [P-Tau]/[A42 ] ratios were used [30]. The normal level of A42 in 3 atypical samples could be explained by an increased amyloid production. The [A42 ]/[A40 ] ratio (not available in the present study) might help to improve the biomarker interpretation in such cases [39]. In families without identified causal mutation, the proportion of cases with positive biomarkers was quite similar, thus supporting the accuracy of our diagnoses. No gene-specific profile was detected for biomarkers. In particular, patients with APP duplications, who exhibit a 1.5 fold increase in APP expression [40], do not differ from other AD patients regarding A level in CSF. Together, these results reinforce the importance of CSF biomarkers as new diagnostic tools in AD [41, 42]. Twenty-three percent of the families were negative for the three examined genes, a proportion quite similar to our previous estimate on a smaller sample, although in the present study the inclusion criteria (age of onset before age 65 rather than age 60) have been slightly relaxed. These families are primary candidates for genetic investigations using next generation sequencing technologies. Very recently, rare CNVs exclusive to these extreme forms of AD have been identified in several of these patients [43].
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ACKNOWLEDGMENTS This work was supported by a grant from the Clinical Research Hospital Program from the French Ministry of Health (GMAJ, PHRC 2008/067) to DH and DC and sponsored by the University Hospital of Rouen. We thank Tracey Avequin for her help in editing the manuscript. We are indebted to the banque d’ADN et de cellules, Piti´e Salpˆetri`ere. Authors’ disclosures available online (http://www.jalz.com/disclosures/view.php?id=1217). PHRC GMAJ COLLABORATORS 2 The
collaborators of the French GMAJ project include Didier Hannequin, Dominique Campion, David Wallon, Olivier Martinaud, Lucie Guyant-
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