Frontotemporal dementia: genetics and genetic counseling dilemmas.

Memory and Aging Center, University of California, San Francisco, Department of Neurology, San Francisco, California 94143-1207, USA.
The Neurologist (Impact Factor: 1.08). 10/2004; 10(5):227-34.
Source: PubMed

ABSTRACT Frontotemporal dementia (FTD) is a neurodegenerative disease with early symptoms of personality change and/or language disorder. Approximately 40% of individuals with FTD have a family history of dementia; however, in our experience, less than 10% have clear autosomal dominant inheritance. Mutations in the microtubule-associated protein tau (MAPT) gene have been reported in up to 50% of hereditary cases, but are unusual except in families with more than 3 individuals with FTD. The genetics of FTD is complicated by clinical heterogeneity, variable expression, phenocopies, misdiagnoses, and lost family histories. The objective of this paper is to enable physicians to recognize hereditary patterns and genetic concerns of FTD families and to understand genetic counseling strategies.
The complexity of FTD genetics and genetic counseling are illustrated using 4 case histories. Case 1 demonstrates the difficulty obtaining a reliable FTD family history. Case 2 illustrates how psychiatric phenocopies can make family linkage studies difficult. The lack of genotype and phenotype correlation and issues of predictive genetic testing within FTD families are the subject of case 3, and case 4 shows how normal aging language difficulties and cognitive changes can be misinterpreted when a family history of dementia is present.
Physicians seeing patients with possible FTD should be aware of the risk of a genetic etiology. A 3-generation family history should be obtained with attention to neurologic, psychiatric, and behavioral symptoms. Variable expression and phenocopies are confounding factors when assessing a possible genetic etiology. Referral of the patient and family for genetic counseling is recommended.

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    ABSTRACT: Background: Frontotemporal dementia (FTD) is defined as primary neurodegeneration of the anterior temporal and/or frontal lobes resulting in a group of associated conditions marked by changes in cognition, language, personality, and social functioning. FTD was previously thought to be a rare disease. However, researchers report that FTD is the third most common form of dementia. Because adults with FTD have deficits in language, cognition, and behaviour, familiarity with FTD subtypes, associated deficits, and currently available management strategies is warranted.Aims: The aims of this tutorial are (a) to define frontotemporal dementia including behavioural and language characteristics of the three clinically distinct FTD subtypes (frontotemporal variant, nonfluent progressive aphasia, semantic dementia); (b) to identify similarities and differences between FTD and Alzheimer's dementia; and (c) to discuss management strategies for patients with FTD.Main Contribution: Different subtypes and presentations of FTD as well as the neurological, behavioural, and language symptoms that have been consistently identified are reviewed. Behavioural and language symptoms of the two FTD subtypes with primary language disturbances (nonfluent progressive aphasia and semantic dementia) are also reviewed. Patients with FTD are frequently misdiagnosed as presenting with Alzheimer's dementia due to limitations in the literature describing the differing profiles of the two populations. When considering neurological changes, behavioural changes, language and communication behaviours, and disease progression, these patient populations are distinct and easily differentiated. Finally, management strategies are discussed. Although there is no cure for FTD, medical intervention can address some of the associated symptoms, and behavioural techniques may manage the client's environment and prolong communication abilities.Conclusions: General discussion seeks to differentially diagnose FTD dementia from Alzheimer's dementia as well as to clarify the language and communication symptoms of FTD subtypes. Future research directions are suggested for developing evidence‐based direct and indirect management strategies.
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    ABSTRACT: IMPORTANCE A significant portion of frontotemporal lobar degeneration (FTLD) is due to inherited gene mutations, and we are unaware of a large sequential series that includes a recently discovered inherited cause of FTLD. There is also great need to develop clinical tools and approaches that will assist clinicians in the identification and counseling of patients with FTLD and their families regarding the likelihood of an identifiable genetic cause. OBJECTIVES To ascertain the frequency of inherited FTLD and develop validated pedigree classification criteria for FTLD that provide a standardized means to evaluate pedigree information and insight into the likelihood of mutation-positive genetic test results for C9orf72, MAPT, and GRN. DESIGN Information about pedigrees and DNA was collected from 306 serially assessed patients with a clinical diagnosis of FTLD. This information included gene test results for C9orf72, MAPT, and GRN. Pedigree classification criteria were developed based on a literature review of FTLD genetics and pedigree tools and then refined by reviewing mutation-positive and -negative pedigrees to determine differentiating characteristics. SETTING Academic medical center. PARTICIPANTS Patients with FTLD. MAIN OUTCOMES AND MEASURES Familial risk. RESULTS The rate of C9orf72, MAPT, or GRN mutation-positive FTLD in this series was 15.4%. Categories designating the risk level for hereditary cause were termed high, medium, low, apparent sporadic, and unknown significance. Thirty-nine pedigrees (12.7%) met criteria for high, 31 (10.1%) for medium, 46 (15.0%) for low, 91 (29.7%) for apparent sporadic, and 99 (32.4%) for unknown significance. The mutation-detection rates were as follows: high, 64.1%; medium, 29%; low, 10.9%; apparent sporadic, 1.1%; and unknown significance, 7.1%. Mutation-detection rates differed significantly between the high and other categories. CONCLUSIONS AND RELEVANCE Mutation rates are high in FTLD spectrum disorders, and the proposed criteria provide a validated standard for the classification of FTLD pedigrees. The combination of pedigree criteria and mutation-detection rates has important implications for genetic counseling and testing in clinical settings.
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