A novel presenilin 2 mutation (V393M) in early‐onset dementia with profound language impairment

Lindquist, Suzanne G.; Hasholt, Lis; Bahl, Justyna M.C.; Heegaard, Nhh; Andersen, Birgit; Nørremølle, Anne; Stokholm, Jette; Schwartz, Marianne; Batbayli, Mustafa; Laursen, Henning; Pardossi‐Piquard, Raphaëlle; Chen, F.; George-Hyslop, Peter St; Waldemar, Gunhild; Nielsen, Jørgen E.

doi:10.1111/j.1468-1331.2008.02256.x

Cited by 20 publications

(14 citation statements)

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“…In general, these focal variants have been reported less, in ADAD 14,15 . Importantly, in SAD these variants appear to occur more frequently at younger ages of onset.…”

Section: Discussionmentioning

confidence: 90%

Neurological manifestations of autosomal dominant familial Alzheimer’s disease: a comparison of the published literature with the Dominantly Inherited Alzheimer Network observational study (DIAN-OBS)

Tang

Ryman

McDade

et al. 2016

The Lancet Neurology

100

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Background To evaluate the prevalence rates of non-amnestic neurological symptoms of autosomal dominant Alzheimer’s disease (ADAD) in the DIAN Observational Study (DIAN–OBS) and the published literature. Analyses were conducted to clarify the prevalence of neurological manifestations of ADAD mutation carriers as a group. Methods Using the DIAN-OBS study database and 189 peer-reviewed publications on ADAD families, we extracted individual-level data on age of symptom onset, disease course from onset to death, and the presence of fourteen neurological findings that have been reported in association with ADAD and included symptomatic subjects only. The primary outcomes were the rates of various neurological symptoms and the contribution of age and specific mutations on the prevalence of the neurological symptoms. Analyses were done using descriptive statistics, comparisons of means and frequencies and multivariable linear regression. Findings Our meta-analysis dataset includes 1228 affected individuals, with detailed clinical descriptions of 753. The DIAN–OBS dataset included 107 individuals with detailed clinical data. The most prevalent non-amnestic cognitive manifestations in DIAN were those typical of mild-moderate Alzheimer’s disease, including visual agnosia (95% CI 45·7%–64·6%), aphasia (43·8%–62·7%), and behavioral changes (51·5%–70·0%). The prevalence of non-amnestic cognitive manifestations from the published literature were (95% CI 3·9%–7·2%) for visual agnosia, (20%–26%) for aphasia, and (28·4%–35·1%) for behavioral changes. Prevalence of non-cognitive neurological manifestations in DIAN was low, including myoclonus and spasticity (3·8%–15·0%), seizures (0·5%–9·1%) and moderate for parkinsonism (5·3%–17·1%). Whereas, in the published literature the prevalence was (95% CI 16·6%–22·2% and 12·5%–17·6%) for myoclonus and spasticity, (10·1%–15·0%) for parkinsonism, and (17·4%–23·2%) for seizures. Age of onset appears to influence the prevalence of several non-cognitive manifestations in both groups, stroke being more prevalent at older ages of onset with motor symptoms being more prevalent at younger age of onset and at an older age of onset. Further, symptoms were overall more common in later clinical stages of disease. Interpretation Comparing the prevalence of non-amnestic and non-cognitive clinical features in DIAN with the published literature indicates that previous reports of non-cognitive features are likely overestimated whereas DIAN identifies higher non-amnestic cognitive symptoms in addition to memory impairment. The non-cognitive clinical manifestations of AD appear to be in a minor fraction of mild-moderate ADAD and is likely influenced by disease severity, environmental and genetic factors in addition to genetic status. The results of this work clarify the clinical presentations of ADAD including the effects of age and disease stage. Attention to these neurologic symptoms and screening for ADAD mutations are warranted if present. Future work is needed to determine the factors which caus...

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“…In general, these focal variants have been reported less, in ADAD 14,15 . Importantly, in SAD these variants appear to occur more frequently at younger ages of onset.…”

Section: Discussionmentioning

confidence: 90%

Neurological manifestations of autosomal dominant familial Alzheimer’s disease: a comparison of the published literature with the Dominantly Inherited Alzheimer Network observational study (DIAN-OBS)

Tang

Ryman

McDade

et al. 2016

The Lancet Neurology

100

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“…One of the first mutations to be identified was a point mutation located within the second transmembrane domain that resulted in the substitution of an isoleucine for an asparagine at residues 141 (N141l) 118. Most recently, a V393M mutation located within the seventh transmembrane domain has been described126 (Figure 4). A comprehensive list of PSEN2 mutations is available through the NCBI database (http://www.molgen.ua.ac.be/ADmutations).…”

Section: Genetics Of Admentioning

confidence: 99%

Review Article: Genetics of Alzheimer Disease

Bekris

Bird

et al. 2010

J Geriatr Psychiatry Neurol

807

543

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Alzheimer disease (AD) is the most common causes of neurodegenerative disorder in the elderly individuals. Clinically, patients initially present with short-term memory loss, subsequently followed by executive dysfunction, confusion, agitation, and behavioral disturbances. Three causative genes have been associated with autosomal dominant familial AD (APP, PSEN1, and PSEN2) and 1 genetic risk factor (APOEε4 allele). Identification of these genes has led to a number of animal models that have been useful to study the pathogenesis underlying AD. In this article, we provide an overview of the clinical and genetic features of AD.

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“…In vitro expression of PS2 V393M cDNA did not result in a detectable increase in the secreted A β 42/40 peptide ratio. However, patients heterozygous for this missense mutation are characterized by profound language impairment [133]. …”

Section: Presenilinmentioning

confidence: 99%

Early Onset Alzheimer’s Disease and Oxidative Stress

Meraz-Ríos

Franco-Bocanegra

Toral-Ríos

et al. 2014

Oxidative Medicine and Cellular Longevity

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Alzheimer's disease (AD) is the most common cause of dementia in elderly adults. It is estimated that 10% of the world's population aged more than 60–65 years could currently be affected by AD, and that in the next 20 years, there could be more than 30 million people affected by this pathology. One of the great challenges in this regard is that AD is not just a scientific problem; it is associated with major psychosocial and ethical dilemmas and has a negative impact on national economies. The neurodegenerative process that occurs in AD involves a specific nervous cell dysfunction, which leads to neuronal death. Mutations in APP, PS1, and PS2 genes are causes for early onset AD. Several animal models have demonstrated that alterations in these proteins are able to induce oxidative damage, which in turn favors the development of AD. This paper provides a review of many, although not all, of the mutations present in patients with familial Alzheimer's disease and the association between some of these mutations with both oxidative damage and the development of the pathology.

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A novel presenilin 2 mutation (V393M) in early‐onset dementia with profound language impairment

Abstract: The possible pathogenic nature of the mutation is not clarified. We discuss the limitations of functional PSEN2 studies and the challenges associated with genetic counselling of family members at risk.

Cited by 20 publications

References 10 publications

Neurological manifestations of autosomal dominant familial Alzheimer’s disease: a comparison of the published literature with the Dominantly Inherited Alzheimer Network observational study (DIAN-OBS)

Neurological manifestations of autosomal dominant familial Alzheimer’s disease: a comparison of the published literature with the Dominantly Inherited Alzheimer Network observational study (DIAN-OBS)

Review Article: Genetics of Alzheimer Disease

Early Onset Alzheimer’s Disease and Oxidative Stress

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