A novel PSEN2 mutation associated with a peculiar phenotype

Istituto Superiore di Sanità, 00161 Rome, Italy.
Neurology (Impact Factor: 8.29). 05/2008; 70(17):1549-54. DOI: 10.1212/01.wnl.0000310643.53587.87
Source: PubMed


Mutations of presenilin 2 gene are a rare cause of familial Alzheimer disease (AD). We describe an Italian family with hereditary dementia associated with a novel mutation in the presenilin 2 gene.
Clinical investigations of the diseased subjects; interviews with relatives; studies of medical records; pedigree analysis; and neuroradiologic, neuropathologic, and molecular genetic studies were carried out in the pedigree.
Genetic analysis showed a novel PSEN2 A85V mutation present in the proband and in all analyzed affected members, in a subject presenting with an amnesic mild cognitive impairment, and in a young, still asymptomatic subject. The proband showed a clinical phenotype indicative of Lewy body dementia and the neuropathologic examination demonstrated the presence of unusually abundant and widespread cortical Lewy bodies in addition to the hallmark lesions of AD. Other affected members exhibited a clinical phenotype typical of AD.
Our findings add complexity to the spectrum of atypical phenotypes associated with presenilin mutations and should then be taken into account when considering the nosography of neurodegenerative diseases. They also support previous data that specific mutations of genes associated with familial Alzheimer disease may influence the presence and extent of Lewy bodies.

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    • "PSEN1 phenotypes also include extrapyramidal, pyramidal, or cerebellar isolated presentation, rarer in PSEN2 or APP-mutated patients (Table 1). However, prominent parkinsonism associated with dementia and visual hallucinations fulfilling diagnostic criteria for Lewy Body Dementia (LBD) have been only rarely associated with PSEN1 and PSEN2 mutations [40, 58, 59]. "
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    ABSTRACT: The discovery of monogenic forms of Alzheimer's Disease (AD) associated with mutations within PSEN1, PSEN2, and APP genes is giving a big contribution in the understanding of the underpinning mechanisms of this complex disorder. Compared with sporadic form, the phenotype associated with monogenic cases is somewhat broader including behavioural disturbances, epilepsy, myoclonus, and focal presentations. Structural and functional imaging show typical early changes also in presymptomatic monogenic carriers. Amyloid imaging and CSF tau/A β ratio may be useful in the differential diagnosis with other neurodegenerative dementias, especially, in early onset cases. However, to date any specific biomarkers of different monogenic cases have been identified. Thus, in clinical practice, the early identification is often difficult, but the copresence of different elements could help in recognition. This review will focus on the clinical and instrumental markers useful for the very early identification of AD monogenic cases, pivotal in the development, and evaluation of disease-modifying therapy.
    11/2013; 2013(6543):689591. DOI:10.1155/2013/689591
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    • "Additional neurological symptoms and signs appear to occur more commonly in FAD than SAD; myoclonus and seizures have been reported in both APP and PSEN1 families [5] [13] [14] and PSEN1 mutations producing spastic paraparesis [15] and cerebellar ataxia [16] have also been described. Extrapyramidal signs have been reported in both PSEN1 [17] and PSEN2 subjects [18]. Although previous pathological studies have shown some differences between the sporadic and familial forms of the disease (reviewed in [19]), there are few studies directly comparing pathology in the different mutations. "
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    ABSTRACT: Mutations in the presenilin1 (PSEN1) and amyloid beta (A4) precursor protein (APP) genes account for the majority of cases of autosomal dominantly inherited Alzheimer's disease (AD). We wished to assess and compare the patterns of cerebral loss produced by these two groups of mutations. Volumetric magnetic resonance imaging and neuropsychological assessments were performed in individuals with clinical AD carrying mutations in the APP (n = 10) and PSEN1 (n = 18) genes and in healthy controls (n = 18). Voxel-based morphometry (VBM), cortical thickness, and region of interest analyses were performed. Mini-Mental State Examination scores were similar in the two disease groups suggesting similar levels of disease severity. There was evidence that APP subjects have smaller hippocampal volume compared with PSEN1 subjects (p = 0.007), and weak evidence that they have larger whole-brain and grey matter volumes (both p = 0.07). Although there was no evidence of statistically significant differences between APP and PSEN1 in VBM or cortical thickness analyses, effect maps were suggestive of APP subjects having more medial temporal lobe atrophy and conversely PSEN1 subjects showing more neocortical loss. Neuropsychological data were consistent with these regional differences and suggested greater memory deficits in the APP patients and greater impairment in non-memory domains in the PSEN1 group, although these differences were not statistically significant. We conclude that the mechanisms by which APP and PSEN1 mutations cause neuronal loss may differ which furthers our understanding of the neuropathology underlying AD and may inform future therapeutic strategies and trial designs.
    Journal of Alzheimer's disease: JAD 02/2013; 35(1). DOI:10.3233/JAD-121255 · 4.15 Impact Factor
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    ABSTRACT: Les démences représentent un problème de santé public majeur, notamment du fait du vieillissement des populations occidentales. Pourtant, le diagnostic étiologique de certitude d'un syndrome démentiel ne peut être obtenu que par l'analyse neuropathologique et/ou biochimique du tissu cérébral obtenu en post mortem. Les lésions cérébrales aboutissant au déclin cognitif ont des origines diverses (neurodégénératives, vasculaires, métaboliques...) et sont souvent associées. En analysant les données cliniques, neuropathologiques et biochimique issues de la cohorte autopsiques de patients déments suivis au Centre Mémoire de Ressources et de recherche du CHRU de Lille (127 cerveaux prélevés entre 1992 et 2009), nous avons étudié les corrélations entre l'expression clinique du syndrome démentiel et la nature des lésions cérébrales sous jacentes. Nous montrons que les fréquentes associations lésionnelles (lésions de maladie d'Alzheimer, de maladie à corps de Lewy, lésions vasculaires) ont des conséquences sur la pertinence du diagnostic étiologique du syndrome démentiel. Dans le domaine des dégénérescences lobaires frontotemporales (DLFT), nous avons étudié les corrélations clinicopathologiques de 18 patients ayant présenté des troubles inauguraux du langage ou de la parole. Nous avons pu établir des corrélations entre les syndromes cliniques et certaines protéinopathies (tau, TDP-43) associées aux DLFT. L'enquête génétique a permis de mettre en évidence une nouvelle mutation du gène de la progranuline chez un patient. L'analyse pluridisciplinaire des démences permet au clinicien de progresser dans la prédiction des lésions cérébrales du vivant du patient. Cette démarche s'avère indispensable dans l'optique du développement de traitements curatifs des démences neurodégénératives.
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