A presenilin 1 R278I mutation presenting with language impairment

Dementia Research Centre, Department of Neurodegenerative Disease, Institute of Neurology, London, UK.
Neurology (Impact Factor: 8.29). 12/2004; 63(9):1702-4. DOI: 10.1212/01.WNL.0000143060.98164.1A
Source: PubMed


Presenilin (PSEN)1 mutations are responsible for many cases of autosomal dominant Alzheimer disease (AD), although the clinical spectrum has not been fully defined. The authors describe two members of a kindred with a novel PSEN1 mutation (R278I) presenting with language impairment and relative preservation of memory. Screening for PSEN1 mutations may be appropriate in cases of familial dementia even where the clinical phenotype is not typical of AD.

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    • "Several PS1 mutations have been reported to present language impairment including G209V, H163Y and R278I, these were detected in one patient that underwent initial clinical diagnosis of progressive nonfluent aphasia (Godbolt et al., 2004). Language deficits have been described in association with many other mutations later in the disease. "
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    ABSTRACT: Alzheimer's disease (AD) is a progressive brain disorder that causes gradual and irreversible loss of higher brain functions and is the most common cause of dementia in the elderly,, as assessed by autopsy and clinical series. Furthermore, it has an annual incidence of approximately 3% in the 65-74 age group. This incidence rate doubles with every increment of 5 years above the age of 65. In Morocco, AD affects almost 30,000 individuals and this number will possibly increase to 75,000 by 2020 (projections of the World Health Organization (WHO)). Genetically, Alzheimer disease is caused by a mutation in one of at least 3 genes: presenilin 1 (PS1), presenilin 2 (PS2) and amyloid precursor protein(APP). Most cases are late onset and apparently sporadic, most likely as a result of a combination of environmental and non-dominant genetic factors. In Morocco, the genes predisposing individuals to Alzheimer's disease (AD) and predicting disease incidence remain elusive. The purpose of the present study was to evaluate the genetic contribution of mutations in the PS1 and PS2 genes to familial early-onset AD cases and sporadic late-onset AD cases. Seventeen sporadic late-onset AD cases and eight familial early-onset AD cases were seen at the memory clinic of the University of Casablanca Neurology Department. These patients underwent standard somatic neurological examination, cognitive function assessment, brain imaging and laboratory tests. Direct sequencing of each exon in PS1 and PS2 genes was performed on genomic DNA of AD patients. Further, we identified 1 novel frameshift mutation in the PS1 gene and 2 novel frameshift mutations in the PS2 gene. Our mutational analysis reports a correlation between clinical symptoms and genetic factors in our cases of Early Onset Alzheimer's Disease (EOAD). These putative mutations cosegregate with affected family members suggesting a direct mutagenic effect.
    Full-text · Article · Apr 2014 · Neuroscience
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    • "It is therefore highly unlikely that another disease process accounted for the atypical clinical phenotype in this case [18] [19]. While language deficits, in particular anomia, are common in familial AD, these tend to manifest later in the illness with only one previous case due to a different mutation (PSEN1 R278I) reported as presenting with nv-PPA [20] [21]. Second, this case highlights the heterogeneity of the P264L mutation. "
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    ABSTRACT: Primary progressive aphasia (PPA) represents a diverse group of language-led dementias most often due to frontotemporal lobar degeneration. We report clinical, neuropsychological, and neuroimaging data in the case of a 47-year-old woman presenting with non-fluent PPA due to a genetically confirmed pathogenic Presenilin 1 P264L mutation. This case highlights an unusual clinical presentation of familial Alzheimer's disease and a novel presentation of the P264L mutation. The case adds to accumulating evidence that particular mutations can promote specific brain network degeneration, with wider implications for understanding the sporadic forms of Alzheimer's disease and PPA.
    Full-text · Article · Apr 2013 · Journal of Alzheimer's disease: JAD
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    • "Although a complete discussion of genotype-phenotype correlations in familial AD is beyond the scope of this review, mutations in PSEN1 and amyloid precursor protein (APP) can both produce non-amnestic, atypical EOAD [48,49]. For example, PSEN1 can result in non-fluent aphasia [50] in addition to more typical amnestic AD, while APP can be associated with severe cerebral amyloid angiopathy presenting with hemorrhage and seizures along with memory decline [51]. The same mutation may even result in different syndromes. "
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    ABSTRACT: With increasing knowledge of clinical in vivo biomarkers and the pathological intricacies of Alzheimer's disease (AD), nosology is evolving. Harmonized consensus criteria that emphasize prototypic illness continue to develop to achieve diagnostic clarity for treatment decisions and clinical trials. However, it is clear that AD is clinically heterogeneous in presentation and progression, demonstrating variable topographic distributions of atrophy and hypometabolism/hypoperfusion. AD furthermore often keeps company with other conditions that may further nuance clinical expression, such as synucleinopathy exacerbating executive and visuospatial dysfunction and vascular pathologies (particularly small vessel disease that is increasingly ubiquitous with human aging) accentuating frontal-dysexecutive symptomatology. That some of these atypical clinical patterns recur may imply the existence of distinct AD variants. For example, focal temporal lobe dysfunction is associated with a pure amnestic syndrome, very slow decline, with atrophy and neurofibrillary tangles limited largely to the medial temporal region including the entorhinal cortex. Left parietal atrophy and/or hypometabolism/hypoperfusion are associated with language symptoms, younger age of onset, and faster rate of decline - a potential 'language variant' of AD. Conversely, the same pattern but predominantly affecting the right parietal lobe is associated with a similar syndrome but with visuospatial symptoms replacing impaired language function. Finally, the extremely rare frontal variant is associated with executive dysfunction out of keeping with degree of memory decline and may have prominent behavioural symptoms. Genotypic differences may underlie some of these subtypes; for example, absence of apolipoprotein E e4 is often associated with atypicality in younger onset AD. Understanding the mechanisms behind this variability merits further investigation, informed by recent advances in imaging techniques, biomarker assays, and quantitative pathological methods, in conjunction with standardized clinical, functional, neuropsychological and neurobehavioral evaluations. Such an understanding is needed to facilitate 'personalized AD medicine', and eventually allow for clinical trials targeting specific AD subtypes. Although the focus legitimately remains on prototypic illness, continuing efforts to develop disease-modifying therapies should not exclude the rarer AD subtypes and common comorbid presentations, as is currently often the case. Only by treating them as well can we address the full burden of this devastating dementia syndrome.
    Preview · Article · Jan 2013 · Alzheimer's Research and Therapy
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