Dataset Information

Phenotypic characteristics of Alzheimer patients carrying an ABCA7 mutation.

ABSTRACT:

Objective

To generate a clinical and pathologic phenotype of patients carrying rare loss-of-function mutations in ABCA7, identified in a Belgian Alzheimer patient cohort and in an autosomal dominant family.

Methods

We performed a retrospective review of available data records, medical records, results of CSF analyses and neuroimaging studies, and neuropathology data.

Results

The mean onset age of the mutation carriers (n = 22) was 73.4 ± 8.4 years with a wide age range of 36 (54-90) years, which was independent of APOE genotype and cerebrovascular disease. The mean disease duration was 5.7 ± 3.0 years (range 2-12 years). A positive family history was recorded for 10 carriers (45.5%). All patient carriers except one presented with memory complaints. The 4 autopsied brains showed typical immunohistochemical changes of late-onset Alzheimer disease.

Conclusions

All patients carrying a loss-of-function mutation in ABCA7 exhibited a classical Alzheimer disease phenotype, though with a striking wide onset age range, suggesting the influence of unknown modifying factors.

SUBMITTER: Van den Bossche T

PROVIDER: S-EPMC4917260 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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Publications

Phenotypic characteristics of Alzheimer patients carrying an ABCA7 mutation.

Van den Bossche Tobi T Sleegers Kristel K Cuyvers Elise E Engelborghs Sebastiaan S Sieben Anne A De Roeck Arne A Van Cauwenberghe Caroline C Vermeulen Steven S Van den Broeck Marleen M Laureys Annelies A Peeters Karin K Mattheijssens Maria M Vandenbulcke Mathieu M Vandenberghe Rik R Martin Jean-Jacques JJ De Deyn Peter P PP Cras Patrick P Van Broeckhoven Christine C

Neurology 20160401 23

<h4>Objective</h4>To generate a clinical and pathologic phenotype of patients carrying rare loss-of-function mutations in ABCA7, identified in a Belgian Alzheimer patient cohort and in an autosomal dominant family.<h4>Methods</h4>We performed a retrospective review of available data records, medical records, results of CSF analyses and neuroimaging studies, and neuropathology data.<h4>Results</h4>The mean onset age of the mutation carriers (n = 22) was 73.4 ± 8.4 years with a wide age range of 3 ...[more]

PMID: 27037232

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Project description:The missense mutation p.R406W in microtubule-associated protein tau leads to frontotemporal lobar degeneration with an amnestic, Alzheimer's disease-like phenotype with an autosomal dominant pattern of inheritance. In 2003, we described the pedigree of a Belgian family, labelled ADG, with 28 p.R406W patients. Over 18 years follow-up, we extended the family with 10 p.R406W carriers and provided an in-depth clinical description of the patients. Additionally, genetic screening was used to identify p.R406W carriers in Belgian cohorts of frontotemporal dementia and Alzheimer's disease patients and to calculate p.R406W frequency. In the frontotemporal dementia cohort, we found four p.R406W carriers (n = 647, 0.62%) and three in the Alzheimer's disease cohort (n = 1134, 0.26%). Haplotype sharing analysis showed evidence of a shared haplotype suggesting that they are descendants of a common ancestor. Of the p.R406W patients, we describe characteristics of neuropsychological, imaging and fluid biomarkers as well as neuropathologic examination. Intriguingly, the phenotypic spectrum among the p.R406W patients ranged from typical behavioural variant frontotemporal dementia to clinical Alzheimer's disease, based on CSF biomarker analysis and amyloid PET scan. Heterogeneous overlap syndromes existed in between, with highly common neuropsychiatric symptoms like disinhibition and aggressiveness, which occurred in 100% of frontotemporal dementia and 58% of clinical Alzheimer's disease patients. This was also the case for memory problems, 89% in frontotemporal dementia and 100% in clinical Alzheimer's disease patients. Median age at death was significantly lower in patients with frontotemporal dementia (68 years) compared to clinical Alzheimer's disease patients (79 years), although the sizes of the sub-cohorts are limited and do not allow prognostic predictions. Post-mortem brain analysis of one p.R406W patient with behavioural variant frontotemporal dementia revealed frontotemporal lobar degeneration with tau pathology. Notably, neuropathological investigation showed only 3R tau isoforms in the absence of 4R tau reactivity, an unusual finding in microtubule-associated protein tau-related frontotemporal lobar degeneration. No traces of amyloid pathology were present. Prevalence of the p.R406W mutation was relatively high in both frontotemporal dementia and Alzheimer's disease Belgian patient cohorts. These findings grant new insights into genotype-phenotype correlations of p.R406W carriers. They may help in further unravelling of the pathophysiology of this tauopathy and in facilitating the identification of patients with p.R406W-related frontotemporal lobar degeneration, both in clinical diagnostic and research settings.

Project description:Background and objectivesPutative loss-of-function (pLOF) ABCA7 variants that increase Alzheimer disease (AD) risk were identified; however, deep phenotypic characterization of these variants in mutation carriers is limited. We aimed to obtain deep clinical phenotypes of ABCA7 pLOF mutation carriers from a large retrospectively reviewed series.MethodsGenotypes were determined for 5,353 individuals evaluated at Mayo Clinic for 6 reported ABCA7 pLOF variants (p.E709fs, p.Trp1214X, p.L1403fs, c.4416+2T>G, p.E1679X, and c.5570+5G>C). Medical records of 100 mutation carriers were reviewed for demographics, clinical phenotypes, and diagnoses. Eleven mutation carriers had autopsy-based neuropathologic diagnoses.ResultsWe confirmed that ABCA7 pLOF mutations confer AD risk in our series of 2,495 participants with AD and 2,858 cognitively unaffected participants. Clinical review of 100 mutation carriers demonstrated phenotypic variability of clinical presentations with both memory and nonmemory cognitive impairment and a subset presenting with motor symptoms. There was a wide range of age at onset of cognitive symptoms (ages 56-92 years, mean = 75.6). Ten of the 11 autopsied mutation carriers had AD neuropathology. ABCA7 pLOF mutation carriers had higher rates of depression (41.6%) and first-degree relatives with cognitive impairment (38.1%) compared with the general population.DiscussionOur study provides a deep clinical review of phenotypic characteristics of mutation carriers for 6 ABCA7 pLOF mutations. Although memory impairment was the most common initial symptom, nonmemory cognitive and/or motor symptoms were present in a substantial number of mutation carriers, highlighting the heterogeneity of clinical features associated with these mutations. Likewise, although AD neuropathology is the most common, it is not the only autopsy-based diagnosis. Presence of earlier ages at onset, higher rates of depression, and first-degree relatives with cognitive impairment among mutation carriers suggest that these genetic variants may have more aggressive clinical features than AD in the general population. This deep phenotyping study of ABCA7 pLOF mutation carriers provides essential genotype-phenotype correlations for future precision medicine approaches in the clinical setting.

Dataset Information

Phenotypic characteristics of Alzheimer patients carrying an ABCA7 mutation.

Objective

Methods

Results

Conclusions

Publications

Phenotypic characteristics of Alzheimer patients carrying an ABCA7 mutation.

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