Abstract
Dementing disorders are a complex group of neurodegenerative diseases characterised by different, but often overlapping, pathological pathways. Genetics have been largely associated with the development or the risk to develop dementing diseases. Recent advances in molecular technologies permit analyzing of several genes in a small time, but the interpretation analysis is complicated by several factors: the clinical complexity of neurodegenerative disorders, the frequency of co-morbidities, and the high phenotypic heterogeneity of genetic diseases. Genetic counselling supports the diagnostic path, providing an accurate familial and phenotypic characterisation of patients. In this review, we summarise neurodegenerative dementing disorders and their genetic determinants. Genetic variants and associated phenotypes will be divided into high and low impact, in order to reflect the pathologic continuum between multifactorial and mendelian genetic factors. Moreover, we report a molecular characterisation of genes associated with neurodegenerative disorders with cognitive impairment. In particular, the high frequency of rare coding genetic variants in dementing genes strongly supports the role of geneticists in both, clinical phenotype characterisation and interpretation of genotypic data. The smart application of exome analysis to dementia patients, with a pre-analytical selection on familial, clinical, and instrumental features, improves the diagnostic yield of genetic test, reduces time for diagnosis, and allows a rapid and personalised management of disease.
Highlights
Dementia is a disorder that impairs the cognitive function
The application of a multigenic sequencing technology permits the identification of mutations in HTRA1 gene, and in genes involved in disorders to be considered in differential diagnosis of cerebral arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) (CADASIL, CARASAL, COL4A1, and COL4A2-related small vessel disease, Fabry disease, ITM2B-related dementia, RVCLS- retinal vasculopathy, with cerebral leukoencephalopathy and systemic manifestations)
E2 haplotype is associated with hemorrhages, E4 haplotype with β-amyloid accumulation [47,65] Lack of strong confirmation data in genetic susceptibility of Vascular dementia (VaD) seem to support a combined effect of genetic variants and environmental factors
Summary
Dementia is a disorder that impairs the cognitive function. In general, it is a chronic or progressive impairment of cerebral function that determines a complex cognitive decline, frequently associated with mood, and behavioural and personality disorders. The incidence of dementia increases with advanced age, it is not an ineluctable disorder in elderly. The disease affects the elderly (about 5% to 20% of people over 65 years of age), and is a progressive impairment of cognitive function, sometimes with other neurological signs. With the ageing of a population, the dementia incidence will increase every year [2]. The study shows a reduction in dementia incidence of 13% over the years, in Europe and North America. This reduction could be due to the many improvements in early diagnosis and treatment of dementia and prodromic disorders as MCI. It is well known that every human disorder recognises genetic and nongenetic causes. The environment produces epigenetic modifications of the DNA that can modify the functional activity of genes [8,9]
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