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Two pathologically confirmed cases of novel mutations in the MAPT gene causing frontotemporal dementia.

ABSTRACT: MAPT mutations were the first discovered genetic cause of frontotemporal dementia (FTD) in 1998. Since that time, over 60 MAPT mutations have been identified, usually causing behavioral variant FTD and/or parkinsonism clinically. We describe 2 novel MAPT mutations, D252V and G389_I392del, each presenting in a patient with behavioral variant FTD and associated language and cognitive deficits. Neuroimaging revealed asymmetrical left greater than right temporal lobe atrophy in the first case, and bifrontal atrophy in the second case. Disease duration was 8 years and 5 years, respectively. Postmortem examination in both patients revealed a 3-repeat predominant tauopathy, similar in appearance to Pick's disease. These 2 mutations add to the literature on genetic FTD, both presenting with similar clinical and imaging features to previously described cases, and pathologically showing a primary tauopathy similar to a number of other MAPT mutations.

SUBMITTER: Shafei R

PROVIDER: S-EPMC7082764 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Two pathologically confirmed cases of novel mutations in the MAPT gene causing frontotemporal dementia.

Shafei Rachelle R Woollacott Ione O C IOC Mummery Catherine J CJ Bocchetta Martina M Guerreiro Rita R Bras Jose J Warren Jason D JD Lashley Tammaryn T Jaunmuktane Zane Z Rohrer Jonathan D JD

Neurobiology of aging 20191120

MAPT mutations were the first discovered genetic cause of frontotemporal dementia (FTD) in 1998. Since that time, over 60 MAPT mutations have been identified, usually causing behavioral variant FTD and/or parkinsonism clinically. We describe 2 novel MAPT mutations, D252V and G389_I392del, each presenting in a patient with behavioral variant FTD and associated language and cognitive deficits. Neuroimaging revealed asymmetrical left greater than right temporal lobe atrophy in the first case, and b ...[more]

PMID: 31870644

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Project description:IntroductionA third of frontotemporal dementia (FTD) is caused by an autosomal-dominant genetic mutation in one of three genes: microtubule-associated protein tau (MAPT), chromosome 9 open reading frame 72 (C9orf72) and progranulin (GRN). Prior studies of prodromal FTD have identified impaired executive function and social cognition early in the disease but few have studied naming in detail.MethodsWe investigated performance on the Boston Naming Test (BNT) in the GENetic Frontotemporal dementia Initiative cohort of 499 mutation carriers and 248 mutation-negative controls divided across three genetic groups: C9orf72, MAPT and GRN. Mutation carriers were further divided into 3 groups according to their global CDR plus NACC FTLD score: 0 (asymptomatic), 0.5 (prodromal) and 1 + (fully symptomatic). Groups were compared using a bootstrapped linear regression model, adjusting for age, sex, language and education. Finally, we identified neural correlates of anomia within carriers of each genetic group using a voxel-based morphometry analysis.ResultsAll symptomatic groups performed worse on the BNT than controls with the MAPT symptomatic group scoring the worst. Furthermore, MAPT asymptomatic and prodromal groups performed significantly worse than controls. Correlates of anomia in MAPT mutation carriers included bilateral anterior temporal lobe regions and the anterior insula. Similar bilateral anterior temporal lobe involvement was seen in C9orf72 mutation carriers as well as more widespread left frontal atrophy. In GRN mutation carriers, neural correlates were limited to the left hemisphere, and involved frontal, temporal, insula and striatal regions.ConclusionThis study suggests the development of early anomia in MAPT mutation carriers, likely to be associated with impaired semantic knowledge. Clinical trials focused on the prodromal period within individuals with MAPT mutations should use language tasks, such as the BNT for patient stratification and as outcome measures.

Dataset Information

Two pathologically confirmed cases of novel mutations in the MAPT gene causing frontotemporal dementia.

Publications

Two pathologically confirmed cases of novel mutations in the MAPT gene causing frontotemporal dementia.

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