Neuroscience and Biobehavioral Reviews 42 (2014) 170–179

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Review

Familial Alzheimer’s disease sustained by presenilin 2 mutations: Systematic review of literature and genotype–phenotype correlation Marco Canevelli a,∗ , Paola Piscopo b , Giuseppina Talarico a , Nicola Vanacore c , Alessandro Blasimme d , Alessio Crestini b , Giuseppe Tosto a , Fernanda Troili a , Gian Luigi Lenzi a , Annamaria Confaloni b , Giuseppe Bruno a a

Memory Clinic, Department of Neurology and Psychiatry, University “Sapienza”, Rome, Italy Department of Cell Biology and Neurosciences, National Institute of Health, Rome, Italy c Epidemiology Center, National Institute of Health, Rome, Italy d INSERM UMR 1027, Faculté de Médecine, Université Paul Sabatier – Toulouse III, Toulouse, France b

a r t i c l e

i n f o

Article history: Received 19 September 2013 Received in revised form 19 February 2014 Accepted 21 February 2014 Keywords: Alzheimer’s disease Familial Alzheimer’s disease Presenilin 2 Phenotyping Genotype–phenotype correlation Genetics of dementia

a b s t r a c t Familial Alzheimer’s disease (FAD), despite representing a rare condition, is attracting a growing interest in the scientific community. Improved phenotyping of FAD cases may have a relevant impact both in clinical and research contexts. We performed a systematic review of studies describing the phenotypic features of FAD cases sustained by PSEN2 mutations, the less common cause of monogenic AD. Special attention was given to the clinical manifestations as well as to the main findings coming from the most commonly and widely adopted diagnostic procedures. Basing on the collected data, we also attempted to conduct a genotype–phenotype correlation analysis. Overall, the mutations involving the PSEN2 gene represent an extremely rare cause of FAD, having been reported to date in less than 200 cases. They are mainly associated, despite some peculiar and heterogeneous features, to a typical AD phenotype. Nevertheless, the frequent occurrence of psychotic symptoms may represent a potential distinctive element. The scarcity of available phenotypic descriptions strongly limits the implementation of genotype–phenotype correlations. © 2014 Elsevier Ltd. All rights reserved.

Contents 1. 2.

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4.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Data sources and study selection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Data extraction and critical appraisal of studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3. Genotype–phenotype correlations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4. Statistical analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Study characteristics and data quality . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Mutations, families, and cases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. Clinical phenotype . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4. Neuroimaging, cerebrospinal fluid analysis, and neuropathology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.5. Genotype–phenotype correlations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

∗ Corresponding author at: Memory Clinic, Department of Neurology and Psychiatry, University “Sapienza”, Viale dell’Università 30, 00185 Rome, Italy. Tel.: +39 06 49914604; fax: +39 06 49914604. E-mail address: [email protected] (M. Canevelli). http://dx.doi.org/10.1016/j.neubiorev.2014.02.010 0149-7634/© 2014 Elsevier Ltd. All rights reserved.

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1. Introduction Familial Alzheimer’s disease (FAD) represents a rare autosomal dominantly inherited condition sustained by highly penetrant mutations involving three genes: (a) the amyloid precursor protein (APP) gene on chromosome 21 (Goate et al., 1991); (b) the presenilin 1 (PSEN1) gene on chromosome 14 (Sherrington et al., 1995); and (c) the presenilin 2 (PSEN2) gene on chromosome 1 (Levy-Lahad et al., 1995). To date, over 200 mutations of these genes have been described (Alzheimer Disease & Frontotemporal Dementia Mutation Database, AD&FTDMDB, http://www.molgen.vib-ua.be/ADMutations) (Cruts et al., 2012), although their pathogenic nature remains sometimes unclear. They are believed to cause AD by enhancing the production and/or deposition of amyloid-␤ (A␤) (Selkoe, 1997; Walker et al., 2005). Despite accounting only for the 0.5% of overall AD cases (Campion et al., 1999), FAD has attracted a growing interest in the scientific community. The development of cellular models and transgenic mice harboring APP and presenilins mutations has allowed the detailed exploration of the pathophysiological processes leading to disease, and the investigation of several potential therapeutic agents. In parallel, asymptomatic mutations carriers are being increasingly surveyed and enrolled into longitudinal studies with the aim of elucidating, by adopting recently developed biomarkers, the sequence and magnitude of pathological changes occurring in the preclinical stages of AD (Bateman et al., 2012). In this context, FAD cases may also provide the opportunity of gaining insights about how these pathological events relate to clinical

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manifestations of the disease (Ryan and Rossor, 2010). Similarly, the evaluation of the heterogeneous clinical features associated with FAD mutations may clarify the contribution of several genetic and epigenetic factors in modifying disease phenotype. Nevertheless, to date, available evidences have been mainly focused on the novelty of the mutations and on their potential molecular and functional consequences. Relatively few reports have provided extensive documentation of their clinical characteristics, making difficult operating genotype–phenotype correlations (Larner and Doran, 2006, 2009). PSEN2 mutations represent the less common cause of FAD, accounting for less than 5% of overall cases. PSEN2 gene is positioned on chromosome 1q31–q42; it has 12 exons and is organized into ten translated exons encoding for a 448-amino acid protein. The PSEN2 protein is predicted to consist of nine transmembrane domains and a large loop structure between the sixth and seventh domain and also displays tissue-specific alternative splicing. It is a core component of the gamma secretase complex (Kimberly and Wolfe, 2003). PSEN2 mutations have been reported to increase the ratio of A␤42 to A␤40 fragments in mice and humans, although the mechanism leading to the A␤ generation still remains to be clarified. Since first descriptions (Levy-Lahad et al., 1995; Rogaev et al., 1995), 20 PSEN2 mutations possibly associated with FAD have been reported (Fig. 1; Cruts et al., 2012). Interestingly, they have been frequently related to atypical phenotypes when compared to sporadic late-onset AD cases (Piscopo et al., 2008; Marcon et al., 2009). To date, only one attempt has been made in order to summarize the available evidence concerning the phenotypic characteristics of

Fig. 1. PSEN2 gene showing sites of reported mutations. Probable pathogenic mutations are shown in red. Possible but uncertain mutations are shown in yellow. Not pathogenic mutations are shown in green. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.) Source: Adapted from http://www.molgen.vib-ua.be/ADMutations (Cruts et al., 2012).

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features of humans carrying PSEN2 mutations; (2) describing PSEN2 mutations with possible/proven pathogenicity as defined by the algorithm proposed by Guerreiro et al., (2010) and by the AD&FTDMDB (Cruts et al., 2012); and (3) full-paper. Exclusion criteria were: (1) reporting mutations in animals; and (2) describing not pathogenic PSEN2 mutations. 2.2. Data extraction and critical appraisal of studies

Fig. 2. Flowchart of articles selection.

PSEN2 mutations (Jayadev et al., 2010). Though comprehensive and detailed, this study mainly relied on the description of the authors’ unique collection of FAD cases harboring a specific mutation (i.e. the N141I variant), without systematically providing information about the other variants. Thus, several questions remain unanswered. Which is the clinical phenotype of FAD associated with PSEN2 mutations? Which are the main neuroradiological, biochemical, and neuropathological features exhibited by PSEN2 mutation dementia cases? The aim of the present systematic review is to present and discuss evidence coming from studies describing the phenotypic features of FAD cases caused by PSEN2 mutations. Special attention is given to the clinical manifestations as well as to the main findings coming from the most commonly and widely adopted diagnostic procedures. Basing on the collected data, we also attempt conducting a genotype–phenotype correlation analysis. 2. Methods 2.1. Data sources and study selection The flowchart depicted in Fig. 2 shows the process leading to the selection of the articles of interest for the present review. We performed a literature search using MEDLINE (update to August 2013) and the AD&FTDMDB (http://www.molgen.vibua.be/ADMutations) (Cruts et al., 2012) (update to August 2013). The following search terms were used: “presenilin 2”, “PSEN2”, “PSEN-2” “familial Alzheimer’s disease”, “genetic Alzheimer’s disease”, “autosomal dominant Alzheimer’s disease”. First, only articles in English were retained. Second, on the basis of the title and abstract, another set of papers was excluded because it was clearly out of the specific aims of the present study. After prescreening, the remaining articles were singularly evaluated according to the following inclusion criteria to be considered: (1) reporting clinical and/or instrumental and/or neuropathological

Study selection and appraisal of studies were performed independently by two authors (M.C., and F.T.). Disagreement was resolved by consensus. For each study retained for the present review, authors abstracted clinical data concerning demented subjects with PSEN2 mutations revealed by genotyping or who had at least a child with a PSEN2 mutation. Thus, asymptomatic carriers of PSEN2 mutations were not considered. The following information were extracted: socio-demographic characteristics (origin, age, sex), clinical features (including age at onset, first cognitive disturbances, neuropsychiatric symptoms, atypical manifestations, disease duration, neurological examination, neuropsychological assessment), findings from diagnostic procedures (including morphological and functional neuroimaging, cerebrospinal fluid analysis (CSF)), and neuropathology. Disease duration was calculated only for deceased patients. A set of criteria for data acquisition and reporting in genotype–phenotype correlations has been recently proposed (Grünewald et al., 2013). Accordingly, we evaluated the quality of the retained studies by adopting an ad-hoc score combining both genetic and clinical criteria, as shown in Table 1. Each of the 9 criteria was rated in terms of quality (ranging from 0 to 2) according on whether the considered aspects were adequately conducted/described. The total score was finally obtained by adding the individual scores of all criteria (thus ranging from 0 to 18), with higher scores indicating greater study quality. 2.3. Genotype–phenotype correlations For this purpose, we considered only studies providing phenotypic data about individual PSEN2 mutation dementia cases. Therefore, studies reporting overall features of pedigrees exhibiting the mutation without phenotypically describing each affected family member were not considered for the present analyses. We decided to operate a clinical comparison between subjects harboring the M239V variant and the other PSEN2 mutations. As comparison group we considered patients carrying the N141I variant, whose phenotypic characteristics have been recently extensively reported (Jayadev et al., 2010). The rationale of focusing on the M239V and the N141I variants was both epidemiological and biological. First, they represent the most common PSEN2 mutation variants, accounting for the majority of overall cases. Moreover, they present pathogenic homologue site mutations on the PSEN1 gene (i.e. the M233V and the N135D, respectively) (Houlden et al., 2001; Crook et al., 1997) suggesting that they may significantly alter the protein structure with profound functional consequences. 2.4. Statistical analysis The statistical analyses have been performed using ANOVA test for continuous variables, and chi-square for categorical variables. A correlation analysis between year of publication of PSEN2 mutation and quality score was also performed by means of Pearson correlation index. All data were analyzed with SPSS (version 21.0) and OPENEPI (version 3.1). A p value ≤0.05 was considered as statistically significant.

M. Canevelli et al. / Neuroscience and Biobehavioral Reviews 42 (2014) 170–179 Table 1 Criteria devised to evaluate study quality. Category

Conducting/description of

Mutational analysis

None Sequencing In silico or functional analysis

0 1 2

Demographic data

None AAO AAO, sex, age

0 1 2

Clinical assessment

None Cognitive assessment Cognitive assessment, neurological examination

0 1 2

Cognitive assessment

None Global cognitive measures NP test battery

0 1 2

BPSD

None Any Systematic BPSD evaluation

0 1 2

Neuroimaging

None Structural (e.g. CT, MRI) Structural, functional (e.g. SPECT, PET)

0 1 2

CSF analysis

None Routine CSF analysis AD biomarkers (e.g. A␤1–42 , tau, p-tau)

0 1 2

Diagnosis

None Any dementia Specific dementia referring to criteria

0 1 2

Follow-up

None Disease duration Disease duration, clinical course

0 1 2

Total range

Points

0–18

AAO, age at onset; CSF, cerebrospinal fluid; CT, computed tomography; BPSD, behavioral and psychological symptoms of dementia; MRI, magnetic resonance imaging; NP, neuropsychological; SPECT, single photon emission computed tomography; PET, positron emission tomography.

3. Results 3.1. Study characteristics and data quality We examined a total of 465 articles retrieved from the literature to identify studies of potential interest for the present review (Fig. 2). After excluding papers in a language other than English, abstracts, and articles clearly not pertinent to the aims of our study (n = 414), we further excluded 30 studies, not fulfilling the predefined selection criteria. In particular, most of excluded articles did not describe the phenotypic features of PSEN2 mutations, or reported non pathogenic mutations. Finally, 21 articles were retained for the present evaluation (Levy-Lahad et al., 1995; Rogaev et al., 1995; Piscopo et al., 2008, 2010; Marcon et al., 2004, 2009; Jayadev et al., 2010; Guerreiro et al., 2010; Finckh et al., 2000a, b, 2005; Binetti et al., 2003; Nikisch et al., 2008; Lao et al., 1998; Zekanowski et al., 2003; Giovagnoli et al., 2006; Wallon et al., 2012; Testi et al., 2012; Ezquerra et al., 2003; Lleó et al., 2001, 2002). They comprised 12 family studies/case reports, 6 mutational screenings (all focused on FAD), 2 linkage analyses, and 1 review of literature. Table 2 provides an overview of the included studies with respect to the considered quality criteria. Two studies (Jayadev et al., 2010; Giovagnoli et al., 2006) were not qualitatively rated because providing additional information on already-reported pedigrees. Overall, the quality of the studies was considered acceptable (mean quality score of 10.8 ± 5.0; median 14; interquartile range 6–15; range 2–17). With regard to the specific quality criteria considered, most studies properly described the demographic characteristics of patients, and the clinical diagnosis of dementia

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(referring to standardized diagnostic criteria in most of cases). Conversely, the quality of data concerning behavioral and psychological symptoms of dementia (BPSD), neuroimaging, and CSF analysis was found to be significantly lower. The overall study quality was found to increase over time since 1995 (i.e. first report of a PSEN2 mutation) (r = 0.428; p = 0.067). 3.2. Mutations, families, and cases Thirteen pathogenic PSEN2 mutations have been so far described in literature, as shown in Table 3. Their pathogenicity has been established primarily basing on segregation information and effect on A␤ processing (Cruts et al., 2012; Guerreiro et al., 2010). Most of these mutations were found in single families, excepting for 4 variants (e.g. T122P, N141I, M239V, and M239I) occurring in more than one family. Overall, 31 pedigrees exhibiting a PSEN2 mutation were reported, accounting for a total of 191 affected subjects. The overwhelming majority of these cases was attributable to only two variants, namely the N141I (responsible for 104 cases) and the M239V (responsible for 38 cases) variants. The number of affected people for family ranged from 1 to 26. All the families had a European ancestry. 3.3. Clinical phenotype The clinical features associated to the different PSEN2 mutations are reported in Table 3. Detailed clinical information were available only for 105 cases (55% of total). The overall mean age at onset was 55.3 years, widely ranging from 39 to 83 years. Most of cases (nearly the 65% of total) presented a presenile onset (i.e. 60 years in the 52% of overall cases) (Jayadev et al., 2010). Thus, FAD cases due to PSEN2 mutations may be more easily confused with sporadic AD cases, typically debuting in the seventh to eighth decades of life (60s

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Table 5 Comparison of clinical features by PSEN2 mutation variant. Data are expressed as % or mean ± standard deviation.

AAO (years) AD phenotype (%) Disease duration (years)

N141I (n = 101)

M239V (n = 18)

Other variants (n = 49)

P

53.7 ± 7.8 (n = 85) 100 10.6 ± 4.8 (n = 62)

60.1 ± 10.0 (n = 15) 100 10.3 ± 5.1 (n = 13)

57.6 ± 9.5 (n = 49) 49 9.4 ± 5.5 (n = 49)

0.002 0.001 0.39

AAO, age at onset. Other variants considered: A85V (n = 6), T122P (n = 6), T122R (n = 6), V148I (n = 3), M174 V (n = 1), S175C (n = 6), Q228L (n = 2), Y231C (n = 2), M239I (n = 10), T430M (n = 4), and D439A (n = 3).

and 70s), and then less investigated. Conversely, PSEN1 (Larner and Doran, 2006, 2009) and APP mutations (Ryan and Rossor, 2010) sustain dementia cases with an earlier onset and may consequently be more likely suspected and recognized. Similarly, FAD cases associated with mutations involving these 2 genes, and the PSEN1 gene in particular, are generally characterized by a faster course of the disease and by frequent atypical clinical manifestations (e.g. spastic paraparesis, extrapyramidal and cerebellar signs, prominent language impairment) (Larner and Doran, 2006). These features may render these cases more easily distinguishable. Finally, it has been hypothesized that defects in PSEN2 function may be partially covered by the normal functioning of its close homolog PSEN1, as documented by transgenic mice experiments (Herreman et al., 1999). Moreover, the reduced expression of the PSEN2 protein in the brain (Sherrington et al., 1996) may limit the functional consequences of PSEN2 gene mutations, thus potentially contributing to their low clinical detection. Our results show that PSEN2 mutations give rise mainly to FAD cases with typical phenotype. In fact, they have been found to be mostly characterized by: (1) insidious onset of memory disturbances progressively associated with the involvement of the other cognitive domains; (2) slowly progressive course; (3) frequent occurrence of BPSD during the progression of the dementia syndrome; (4) uncommon atypical features; and (5) “classical” diagnostic findings. Thus, beyond the aggregation in families and the earlier age at onset, they are fairly similar to sporadic AD cases. Nevertheless, a potential distinctive feature may be represented by the higher prevalence of a psychotic phenotype (Canevelli et al., 2013b). Delusions and/or hallucinations were in fact described in the 31% of PSEN2 mutation dementia cases (n = 27 on a total of 86 subjects with available information on BPSD), most of which harboring the N141I variant. This prevalence of psychotic symptoms appear to be higher when compared to cohorts of sporadic AD cases, exhibiting these manifestations in approximately the 7–10% of cases (Canevelli et al., 2013a; Vilalta-Franch et al., 2013). Moreover, it also higher than that observed among overall early-onset AD patients (Van Vliet et al., 2012). Therefore, the early occurrence of delusions and hallucinations may represent an element of clinical suspicion toward FAD due to PSEN2 mutations. Limitations of the available evidence on the topic need to be discussed because potentially affecting the findings of the present review. In our opinion, the major issue characterizing the retained studies (i.e. the available evidence on the topic) is represented by the scarcity of clinical information provided. Most of articles were mostly focused on the biological aspects of the genetic mutations discovered while reporting few data concerning their phenotypic manifestations. Detailed clinical data were available only for just over the half of the identified mutation carriers. A striking minority of subjects underwent the most widely adopted diagnostic procedures (12% of overall cases). Information regarding the response to the common pharmacological treatment implemented were mostly isolated and approximate. Our attempt to perform a genotype–phenotype correlation should be then regarded in this scenario. The results of our analyses show that the specific PSEN2 variants may sustain diverse and distinguishable clinical conditions (i.e. different age at onset and phenotype). However,

the limited availability and reliability of data strongly influence our findings. In particular, the retained studies may have adopted different approaches to report specific clinical information. For example, it was not possible to ascertain whether, in the selected studies, specific manifestations were not reported because really absent from the clinical picture or because there was no information available about their presence. Therefore, we considered each symptom/sign as present/absent only if their presence/absence were clearly stated. However, this decision may have likely affected our results. Moreover, we decided to include in the review also the PSEN2 mutations considered as “possibly pathogenic” (i.e. the lowest grade for pathogenicity according to the algorithm proposed by Guerreiro et al., 2010). This choice was motivated by the aim of providing an exhaustive description of PSEN2 AD cases, thus including most of available evidence. Nevertheless, this may have potentially led to consider in our study also not-causative or neutral variants. An exhaustive description of FAD cases appears of considerable importance for several reasons. Firstly, as stated before, individuals harboring genetic mutations responsible for monogenic AD are triggering increasing scientific interest because allowing the investigation of the physiopathological changes anticipating the onset of overt dementia conditions. In this context, the adequate knowledge of their phenotypic characteristics represents a crucial element enabling to link these pathological changes with the clinical manifestations of the disease. In particular, a special attention is actually addressed to the identification and validation of CSF and neuroimaging biomarkers reflecting in vivo the core features of AD (i.e. amyloid deposition, and neurofibrillary pathology). Nevertheless, these indicators have been very rarely described in the selected studies. Secondly, the accurate description of FAD cases is necessarily the prerequisite for properly performing the procedures of genetic counseling (Canevelli and Blasimme, 2013). In fact, although genetic testing for AD has become more accessible through clinical laboratories and direct-to-consumer testing, we are still unable to properly and exhaustively answer to patients’ questions and worries. The relative paucity of available phenotypic information makes it clearly difficult predicting with good approximation several fundamental aspects such as age at onset, duration of the disease, as well as the main manifestations characterizing its clinical course. Another crucial point in this context is represented by the incomplete penetrance of PSEN2 mutations. In fact, while available evidence has repetitively documented an almost complete penetrance (>95%) (Jayadev et al., 2010), there have been reports of individuals unaffected over the age of 80 (Bird et al., 1996). Consistently with the main aim of our study (i.e. describing the phenotypic characteristics of dementia cases caused by PSEN2 mutations), we did not focus on asymptomatic mutation carriers. Moreover, the clinical data were retrieved from single case reports or case series, thus describing mutation carriers at a punctual point without providing significant longitudinal evaluations. So, it could not be excluded that an asymptomatic mutation carrier may have become demented after the end of the observation period. These two factors have strongly limited our possibility of drawing conclusions concerning the penetrance of PSEN2 mutations.

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Taken together, the incomplete penetrance of some mutations, their variable phenotypic expressivity, and the lack of systematic and accurate phenotyping of FAD cases strongly limit the possibility of implementing genetic counseling procedures. In fact, basing on genetic testing, we cannot actually predict whether one will develop the disease, as well as when or how symptoms will present. This may probably negatively affect the emergence of positive psychological reactions and effective copying skills in subjects resulting as mutation carriers. Despite these considerations, genetic testing still represents the most powerful tool in predicting the development of disease. Thus, it constitutes the core element in approaching FAD cases. In conclusion, our review represents the first attempt to systematically organize the available evidence concerning the phenotypic characteristics of FAD due to PSEN2 mutations. These genetic mutations represent an extremely rare cause of FAD and are responsible for AD cases mostly characterized by typical clinical features and diagnostic findings. Nevertheless, the frequent occurrence of psychotic symptoms may represent a potential distinctive element. Improved phenotyping of monogenic AD cases may have a remarkable impact both in clinical and research contexts. In this regard, we have proposed a set of ad-hoc criteria aiming at enhancing reporting and describing FAD cases. Further studies are needed in order to better clarify the clinical phenotype associated with PSEN2 mutations. Conflict of interest The authors have nothing to disclose as conflicts of interest. References American Psychiatric Association, 2000. Diagnostic and Statistical Manual of Mental Disorders (IV-TR), 4th ed.—text revised. American Psychiatric Association, Washington, DC. Bateman, R.J., Xiong, C., Benzinger, T.L.S., Fagan, A.M., Goate, A., Fox, N.C., Marcus, D.S., Cairns, N.J., Xie, X., Blazey, T.M., Holtzman, D.M., Santacruz, A., Buckles, V., Oliver, A., Moulder, K., Aisen, P.S., Ghetti, B., Klunk, W.E., McDade, E., Martins, R.N., Masters, C.L., Mayeux, R., Ringman, J.M., Rossor, M.N., Schofield, P.R., Sperling, R.A., Salloway, S., Morris, J.C., 2012. Clinical and biomarker changes in dominantly inherited Alzheimer’s disease. N. Engl. J. Med. 367, 795–804. Binetti, G., Signorini, S., Squitti, R., Alberici, A., Benussi, L., Cassetta, E., Frisoni, G.B., Barbiero, L., Feudatari, E., Nicosia, F., Testa, C., Zanetti, O., Gennarelli, M., Perani, D., Anchisi, D., Ghidoni, R., Rossini, P.M., 2003. Atypical dementia associated with a novel presenilin-2 mutation. Ann. Neurol. 54, 832–836. Bird, T.D., Levy-Lahad, E., Poorkaj, P., Sharma, V., Nemens, E., Lahad, A., Lampe, T.H., Schellenberg, G.D., 1996. Wide range in age of onset for chromosome 1—related familial Alzheimer’s disease. Ann. Neurol. 40, 932–936. Campion, D., Dumanchin, C., Hannequin, D., Dubois, B., Belliard, S., Puel, M., ThomasAnterion, C., Michon, A., Martin, C., Charbonnier, F., Raux, G., Camuzat, A., Penet, C., Mesnage, V., Martinez, M., Clerget-Darpoux, F., Brice, A., Frebourg, T., 1999. Early-onset autosomal dominant Alzheimer disease: prevalence, genetic heterogeneity, and mutation spectrum. Am. J. Hum. Genet. 65, 664–670. Canevelli, M., Adali, N., Cantet, C., Andrieu, S., Bruno, G., Cesari, M., Vellas, B., 2013a. Impact of behavioral subsyndromes on cognitive decline in Alzheimer’s disease: data from the ICTUS study. J. Neurol. 260, 1859–1865. Canevelli, M., Adali, N., Voisin, T., Soto, M.E., Bruno, G., Cesari, M., Vellas, B., 2013b. Behavioral and psychological subsyndromes in Alzheimer’s disease using the neuropsychiatric inventory. Int. J. Geriatr. Psychiatry 28, 795–803. Canevelli, M., Blasimme, A., 2013. Next-generation phenotyping and genomic incidental findings: beyond the parkin example. J. Am. Med. Assoc. Neurol. 70, 1589–1590. Crook, R., Ellis, R., Shanks, M., Thal, L.J., Perez-Tur, J., Baker, M., Hutton, M., Haltia, T., Hardy, J., Galasko, D., 1997. Early-onset Alzheimer’s disease with a presenilin-1 mutation at the site corresponding to the Volga German presenilin-2 mutation. Ann. Neurol. 42, 124–128. Cruts, M., Theuns, J., Van Broeckhoven, C., 2012. Locus-specific mutation databases for neurodegenerative brain diseases. Hum. Mutat. 33, 1340–1344. Ezquerra, M., Lleó, A., Castellví, M., Queralt, R., Santacruz, P., Pastor, P., Molinuevo, J.L., Blesa, R., Oliva, R., 2003. A novel mutation in the PSEN2 gene (T430M) associated with variable expression in a family with early-onset Alzheimer disease. Arch. Neurol. 60, 1149–1151. Finckh, U., Alberici, A., Antoniazzi, M., Benussi, L., Fedi, V., Giannini, C., Gal, A., Nitsch, R.M., Binetti, G., 2000a. Variable expression of familial Alzheimer disease associated with presenilin 2 mutation M239I. Neurology 54, 2006–2008.

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Familial Alzheimer's disease sustained by presenilin 2 mutations: systematic review of literature and genotype-phenotype correlation.

Familial Alzheimer's disease (FAD), despite representing a rare condition, is attracting a growing interest in the scientific community. Improved phen...
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