Lewy bodies in the brain of two members of a family with the 717 (Val to Ile) mutation of the amyloid precursor protein gene

doi:10.1016/0304-3940(94)90666-1

Neuroscience Letters

Volume 172, Issues 1–2, 19 May 1994, Pages 77-79

https://doi.org/10.1016/0304-3940(94)90666-1 Get rights and content

Abstract

A second member of the original family with the valine to isoleucine substitution at codon 717 of the amyloid precursor protein died after the clinical diagnosis of Alzheimer's disease had been made in life. Neuropathological examination of the brain revealed not only severe Alzheimer type pathology, with senile plaques and neurofibrillary tangles, but also Lewy bodies both in the cortex and brainstem. Lewy bodies also occurred in our first case, thus showing striking similarities in these two members of the same family. The possibility exists that the occurrence of Lewy bodies may not be coincidental, but could be genetically determined: the same genetic abnormality which determines the deposition of βA4 protein, thus triggering of a chain of events leading to Alzheimer's disease, may result in, or predispose to Lewy body formation.

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Allelic heterogeneity of AD mutations also extends to non-AD proteinopathies. α-Synuclein aggregations in Lewy bodies among families with APP mutations have been reported as early as 1994 (Lantos et al. 1994). Lewy bodies have since been found in ~50% of people carrying APP, PSEN1 and PSEN2 mutations (Cairns et al. 2015; Lippa et al. 1998), a greater proportion of those with sporadic AD (Cairns et al. 2015; Hamilton 2000), as well as in a person with familial amyloidosis due to a gelsolin mutation (Haltia et al. 1991).
Causative genes involved in familial forms of dementias, including Alzheimer's disease (AD), frontotemporal lobar degeneration (FTLD) and dementia with Lewy bodies (DLB), as well as amyotrophic lateral sclerosis and prion diseases where dementia is present as a significant clinical feature, are associated with distinct proteinopathies. This review summarizes the relationship between known genetic determinants of these dementia syndromes and variations in key neuropathological proteins in terms of three types of heterogeneity: (i) Locus Heterogeneity, whereby mutations in different genes cause a similar proteinopathy, as exemplified by mutations in APP, PSEN1 and PSEN2 leading to AD neuropathology; (ii) Allelic Heterogeneity, whereby different mutations in the same gene lead to different proteinopathies or neuropathological severity, as exemplified by different mutations in MAPT and PRNP giving rise to protein species that differ in their biochemistry and affected cell types; and (iii) Phenotypic Heterogeneity, where identical gene mutations lead to different proteinopathies, as exemplified by LRRK2 p.G2019S being associated with variable Lewy body presence and alternative AD neuropathology or FTLD-tau. Of note, the perceived homogeneity in histologic phenotypes may arise from laboratory-specific assessment protocols which can differ in the panel of proteins screened. Finally, the understanding of the complex relationship between genotype and phenotype in dementia families is highly relevant in terms of therapeutic strategies which range from targeting specific genes, to a broader strategy of targeting a downstream, common biochemical problem that leads to the histopathology.
Next-generation sequencing reveals substantial genetic contribution to dementia with Lewy bodies
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We detected two patients with disease-associated mutations in APP. One patient carried the highly penetrant p.V717I mutation, a known cause of familial AD with co-existing Lewy body pathology that has been shown to alter APP protein processing and tau expression (Halliday et al., 1997; Lantos et al., 1994; Muratore et al., 2014). This mutation is located in the transmembrane domain of APP in close proximity to the γ-secretase cleavage site.
Dementia with Lewy bodies (DLB) is the second most common neurodegenerative dementia after Alzheimer's disease. Although an increasing number of genetic factors have been connected to this debilitating condition, the proportion of cases that can be attributed to distinct genetic defects is unknown. To provide a comprehensive analysis of the frequency and spectrum of pathogenic missense mutations and coding risk variants in nine genes previously implicated in DLB, we performed exome sequencing in 111 pathologically confirmed DLB patients. All patients were Caucasian individuals from North America. Allele frequencies of identified missense mutations were compared to 222 control exomes. Remarkably, ~ 25% of cases were found to carry a pathogenic mutation or risk variant in APP, GBA or PSEN1, highlighting that genetic defects play a central role in the pathogenesis of this common neurodegenerative disorder. In total, 13% of our cohort carried a pathogenic mutation in GBA, 10% of cases carried a risk variant or mutation in PSEN1, and 2% were found to carry an APP mutation. The APOE ε4 risk allele was significantly overrepresented in DLB patients (p-value < 0.001). Our results conclusively show that mutations in GBA, PSEN1, and APP are common in DLB and consideration should be given to offer genetic testing to patients diagnosed with Lewy body dementia.
Alzheimer disease: Autosomal dominant forms
2009, Revue Neurologique
Il s’agit d’une mise au point des connaissances concernant les formes autosomiques dominantes de maladie d’Alzheimer (MA). Ces formes sont dues à des mutations de PSEN1 (69 %), de l’APP (13 %), duplication de l’APP (7,5 %), et rarement de PSEN2 (2 %). Le phénotype de ces formes autosomiques dominantes est essentiellement caractérisé par un âge de début précoce, en règle avant 60 ans. La première partie est consacrée à la présentation de phénotypes particuliers qui élargissent le spectre de la MA : hématomes intracérébraux causés par une angiopathie amyloïde sévère, paraplégie spastique, démence à corps de Lewy, et rares ataxies cérébelleuses. La seconde partie est consacrée aux conséquences de ces altérations génétiques sur le métabolisme du peptide Aβ, qui ont fortement contribué à valider l’hypothèse de la cascade amyloïdergique comme primum movens de la MA.
We propose a review devoted to the autosomal dominant forms of Alzheimer disease (AD). These forms are the consequences of either PSEN1 mutations (69%), APP mutations (1%), or APP duplication (7.5%), and exceptionally of PSEN2 mutations (2%). The main characteristic of these AD forms is the early age of onset usually before the age of 60 years. The first part of the review focuses on the identification of unusual clinical and neuropathological phenotypes enlarging the AD spectrum: intracrebral hemorrhages caused by severe amyloid angiopathy, spastic paraparesis, Lewy body dementia and exceptional cerebellar ataxia. The second part concerns the consequences of these mutations on Aβ processing, thus demonstrating the key role of the causal “amyloid cascade”.
The relationship between nosology, etiology and pathogenesis in neurodegenerative diseases
2008, Handbook of Clinical Neurology
Citation Excerpt :
In this regard, it seems that the pathogenesis of sporadic ALS may be more closely related to the non‐tau frontal dementia cases with which it apparently shares pathological features. A surprising observation is that virtually all the Alzheimer subjects with defined APP and presenilin mutations have some Lewy body pathology when evaluated post‐mortem for this (Lantos et al., 1994; Lippa et al., 1998). This observation shows that not only is tau pathology downstream of Aβ in Alzheimer's disease (Hardy et al., 1998), so is α‐synuclein pathology (Hardy, 2003).
The chapter explains that the name of a certain disease often stems from the esteemed clinician who first recognized the problem, suggesting that famous doctors have studied the disorder from which victims suffer for a long time, and so surely there must be hope. From this premise, it follows that Alzheimer's disease, Parkinson's disease, and Huntington's disease are good names. Conversely, names that are technical, cumbersome, or are otherwise not broadly accessible are not good―like frontal temporal dementia (FTD) with Parkinsonism linked to chromosome 17. Sometimes good names that evoke an emotional and memorable response, such as Lou Gehrig's disease, have been proposed to replace cumbersome, frightening names such as amyotrophic lateral sclerosis (ALS) or historically correct names such as Charcot disease. While these names are perhaps more scientific, they are certainly less accessible. Names are thus very important on the clinical side of things. They also dramatically impact the science, which may not be apparent at first blush. The process of naming diseases can obscure the underlying biology and can lead to artificial separations. The chapter discusses the nosology that can hamper research into the fundamental biology of the amyloidopathies, tauopathies, the synucleinopathies and possibly also the FTD/ALS complex of diseases.
A Hundred Years of Alzheimer's Disease Research
2006, Neuron
Citation Excerpt :
The age of onset of cases with APP mutations is typically in the late 40s to mid 50s. Both cases with APP mutations and cases with Down's syndrome can have Lewy bodies as well as tangles (Lantos et al., 1994; Lippa et al., 1999). The majority of families with autosomal dominant Alzheimer's disease did not have APP mutations.
The PARK8 Locus in Autosomal Dominant Parkinsonism: Confirmation of Linkage and Further Delineation of the Disease-Containing Interval
2004, American Journal of Human Genetics
Citation Excerpt :
The findings in the families in our study indicate that a single genetic defect may cause a remarkably wide range of pathology. On the other hand, distinct biologic insults may lead to similar pathology: although LBs are described as the pathological hallmark of PD, they are also found at autopsy in prion disease, type 1 neurodegeneration with brain iron accumulation, Down syndrome, and in some patients with Alzheimer disease who carry an amyloid precursor protein mutation (Lantos et al. 1994; Bugiani et al. 2000; Neumann et al. 2000; Simard and van Reekum 2001). Identification of the gene product of PARK8 will undoubtedly contribute to our understanding the basis of variable clinicopathological findings found in these kindreds.
Recently, a new locus (PARK8) for autosomal dominant parkinsonism has been identified in one large Japanese family. Linkage has been shown to a 16-cM centromeric region of chromosome 12, between markers D12S1631 and D12S339. We tested 21 white families with Parkinson disease and an inheritance pattern compatible with autosomal dominant transmission for linkage in this region. Criteria for inclusion were at least three affected individuals in more than one generation. A total of 29 markers were used to saturate the candidate region. One hundred sixty-seven family members were tested (84 affected and 83 unaffected). Under the assumption of heterogeneity and through use of an affecteds-only model, a maximum multipoint LOD score of 2.01 was achieved in the total sample, with an estimated proportion of families with linkage of 0.32. This LOD score is significant for linkage in a replication study and corresponds to a P value of .0047. Two families (family A [German Canadian] and family D [from western Nebraska]) reached significant linkage on their own, with a combined maximum multipoint LOD score of 3.33, calculated with an affecteds-only model (family A: LOD score 1.67, P=.0028; family D: LOD score 1.67, P=.0028). When a penetrance-dependent model was calculated, the combined multipoint LOD score achieved was 3.92 (family A: LOD score 1.68, P=.0027; family D: LOD score 2.24, P=.0007). On the basis of the multipoint analysis for the combined families A and D, the 1-LOD support interval suggests that the most likely disease location is between a CA repeat polymorphism on genomic clone AC025253 (44.5 Mb) and marker D12S1701 (47.7 Mb). Our data provide evidence that the PARK8 locus is responsible for the disease in a subset of families of white ancestry with autosomal dominant parkinsonism, suggesting that it could be a more common locus.

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Lewy bodies in the brain of two members of a family with the 717 (Val to Ile) mutation of the amyloid precursor protein gene

Abstract

Neurosci. Lett.

Neurobiol. Aging

J. Neurol. Sci.

Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease

Nature (London)