We searched Medline (1946 to February, 2013) using the OvidSP platform. A typical search used explode and textword functions. For example, genetics of frontotemporal dementia was searched using the strategy (exp Frontotemporal Dementia/OR frontotemp$.tw) AND (exp genetics/OR [gene OR genes OR genet$].tw). Further studies were identified by searching reference lists of review articles and by searching Web of Science to identify studies that cited seminal papers. Studies were chosen based on
ReviewGenetics of dementia
Introduction
25% of the general population aged 55 years and older have a family history of dementia involving a first-degree relative.1 As a consequence of family medical history awareness campaigns and increased media coverage of the mendelian forms of dementia, a frequently asked question in the clinic is “My mother had dementia, do I have ‘the gene’ and can I test for it?”
Having a family history of dementia does not necessarily mean there is a mendelian form of dementia (or genetic mutation) in the family. In fact, mendelian forms of dementia are rare. For instance, there have been just over 500 families with mendelian forms of Alzheimer's disease reported.2 Thus, most people with a family history of dementia do not need molecular genetic testing and can be reassured.
This Review aims to help clinicians identify the small number of high-risk mendelian families and reassure the low-risk majority. It also aims to help clinicians make informed choices when prioritising genetic testing for the mendelian families.
Section snippets
Mendelian diseases versus complex diseases
Families share environmental and genetic influences, so familial diseases might not always be genetic in origin. The most striking example of an environmental factor causing familial dementia is kuru. Kuru is an infectious prion disease that was found in the 1950s in the Papua New Guinea highlands, where relatives consumed the deceased in funeral rituals. This illness was initially thought to be genetic because of familial segregation3 until experimental work showed that it is a transmissible
A framework for genetic testing in dementia
The first step in considering molecular genetic testing for dementia is to obtain a detailed and accurate family history, to identify families with family histories consistent with mendelian rather than complex inheritance. These are the families who will benefit most from genetic testing. The second step is to obtain an accurate phenotype for the family to inform the choice of genetic test. Genetic testing can then be considered, ideally starting with an affected family member.
Genetic testing for Alzheimer's disease
Clinically, typical Alzheimer's disease is characterised by gradual onset and progressive impairment of episodic memory and at least one other cognitive domain (the 1984 National Institute of Neurological and Communicative Disorders and Stroke–Alzheimer's Disease and Related Disorders Association [NINCDS-ADRDA] criteria).17 These diagnostic criteria have been revised to recognise non-amnestic presentations of Alzheimer's disease (with language, visuospatial, or executive dysfunction) and the
Genetic testing for frontotemporal dementia
Frontotemporal dementia is a heterogeneous group of disorders, characterised by progressive degeneration of the frontal or temporal lobes, or both. Clinically, it is characterised by progressive deterioration in behaviour, speech production, or language, with relative sparing of memory and visuospatial function.52, 53 Frontotemporal dementia is heterogeneous in clinical presentation, imaging features, underlying histopathological subtypes, and genetics among the mendelian families (figure 3).
Genetic testing for familial dementia with additional neurological features
Cognitive impairment is common in neurogenetic disorders, and familial dementia often presents with additional neurological features. Table 3 summarises some of the common neurogenetic disorders with cognitive features, and Rossor and colleagues13 also provide a comprehensive review.
Two disorders deserve a special mention: Huntington's disease and dementia with Lewy bodies. Huntington's disease is one of the most common neurogenetic disorders126 and can present without chorea (table 3). This
Practical aspects of genetic counselling
Genetic testing can be carried out on a symptomatic or on a predictive basis. Symptomatic testing is for people already diagnosed with dementia, whereas predictive testing is for people who are clinically well. Genetic counselling is helpful in both situations, but formal counselling with a geneticist is essential for people undergoing predictive testing. There are several guidelines for genetic testing in Alzheimer's disease and frontotemporal dementia.20, 134
Generally speaking, symptomatic
Conclusions
Dementia is a common disorder, and a family history of dementia is also common. Fortunately, mendelian forms of dementia are rare. Thus, for relatives of most people with dementia, their lifetime risk of dementia is around 20%, compared with about 10% in the general population. However, in the small proportion of families in which there is a strong autosomal dominant family history of early-onset dementia, mutation in one of the dementia-causing genes can often be found. Each offspring of the
Search strategy and selection criteria
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