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chapter_6 - Neurodegenerative disorders introduction...

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introduction Neurodegenerative disorders are chronic and progressive conditions, characterized by selective and symmetrical neuronal loss in the motoric, sensory and cognitive systems. The nosological classification of these disorders is based on the pattern of neuronal loss and on the presence of specific neuropathological markers such as: square4 senile plaques and neurofibrillary tangles in Alzheimer disease square4 polyglutamine inclusions and neuron loss in the neostriatum in Huntington disease A Mendelian inheritance pattern can be demonstrated for numerous neurodegenerative disorders. For Huntington disease this even is the case for the large majority of the patients. For other conditions such as Parkinson and Alzheimer disease, amyotrophic lateral sclerosis a Mendelian inheritance pattern is obvious in 1 to 10% of the patients. Numerous disease genes for the neurodegenerative disorders have been identified. This has lead to fundamental insights into the genetic basis of these conditions, including the description of genetic heterogeneity, expression variability, penetrance, … In addition, the identification of the involved genes has lead the way in accurately describing the pathogenesis of these disorders, constructing animal models and in optimizing treatment. Studying these disorders is of major clinical relevance. With the classical clinical tools, the diagnosis of a neurodegenerative disorder can only be made in a stage in which irreparable neuronal damage has occurred. Recent studies have indeed demonstrated that in these conditions neuronal loss initiates many years before the onset of symptoms. Currently, genetic analysis allow to diagnose these conditions (or at least a predisposition to develop these diseases) in a preclinical stage. Early detection is crucial for the initiation of early treatment in order to at least attenuate the disease manifestations. Unfortunately, however, the therapeutic tools for treating these conditions are limited and their clinical efficacy is inadequate. Hopefully, the identification of the metabolic pathways that are deranged in these conditions will help to identify novel targets for therapeutic intervention. The more important neurodegenerative disorders that will be discussed here are Huntington (HD) and Alzheimer disease (AD). Huntington disease (HD): a triplet disorder At least 10 neurodegenerative disorders display a polyglutamine expansion as a pathogenic genetic defect. These diseases have characteristic neuropathological features, suggesting a common pathogenic pathway. The common genetic defect comprises an expansion of trinucleotide repeat (CAG) n , resulting in a polyglutamine tract expansion. The identification of this type of molecular defect lead to the description of a new paradigm in genetics and formed an explanation of the formerly poorly understood phenomenon of anticipation. Of note, the first triplet Neurodegenerative disorders
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disorder identified in humans, the fragile X syndrome, is caused by a (CGG) n
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