Chapter 366

The human nervous system is the organ of consciousness, cognition, ethics, and behavior; as such, it is the most intricate structure known to exist. More than one-third of the 23,000 genes encoded in the human genome are expressed in the nervous system. Each mature brain is composed of 100 billion neurons, several million miles of axons and dendrites, and >1015 synapses. Neurons exist within a dense parenchyma of multifunctional glial cells that synthesize myelin, preserve homeostasis, and regulate immune responses. Measured against this background of complexity, the achievements of molecular neuroscience have been extraordinary. This chapter reviews selected themes in neuroscience that provide a context for understanding fundamental mechanisms that underlie neurologic disorders.

The landscape of neurology has been transformed by modern molecular genetics. More than 350 different disease-causing genes have been identified, and >1000 neurologic disorders have been genetically mapped to various chromosomal locations. Several hundred neurologic and psychiatric disorders now can be diagnosed through genetic testing (http://www.ncbi.nlm.nih.gov/sites/GeneTests/?db=GeneTests). The vast majority of these disorders represent highly penetrant mutations that cause rare neurologic disorders; alternatively, they represent rare monogenic causes of common phenotypes. Examples of the latter include mutations of the amyloid precursor protein in familial Alzheimer's disease, the microtubule-associated protein tau (MAPT) in frontotemporal dementia, and α-synuclein in Parkinson's disease. These discoveries have been profoundly important because the mutated gene in a familial disorder often encodes a protein that is also pathogenetically involved (although not mutated) in the typical, sporadic form. The common mechanism involves disordered processing and, ultimately, aggregation of the protein, leading to cell death (see “Protein Aggregation and Neurodegeneration,” below).

There is great optimism that complex genetic disorders that are caused by combinations of genetic and environmental factors have become tractable problems. Genome-wide association studies (GWAS) have been carried out in many complex neurologic disorders, with many hundreds of variants identified, nearly all of which confer only a small increment in disease risk (1.15–1.5 fold). GWAS are rooted in the “common disease, common variant” hypothesis, as they examine potential risk alleles that are relatively common (e.g. >5%) in the general population. More than 1000 GWAS have been carried out to date, with notable successes such as the identification of >50 risk alleles for multiple sclerosis. Furthermore, when bioinformatics tools are used, risk variants can be aligned in functional biologic pathways to identify novel pathogenic mechanisms as well as to reveal heterogeneity (e.g., different pathways in different individuals). Despite these successes, many experienced geneticists question the value of common disease-associated variants, particularly whether they are actually causative or merely mark the approximate locations of more important—truly causative—rare mutations.

This debate has set the stage for the next revolution in human genetics, made possible by the development of increasingly efficient and cost-effective high-throughput sequencing methodologies. It is currently possible to sequence an entire human genome in approximately an hour, at a cost of only $4000 for the entire coding sequence (“whole-exome”) ... ### MyAccess Sign In Username Password Want access to your institution's subscription? Sign in to your MyAccess Account while you are actively authenticated on this website via your institution (you will be able to tell by looking in the top right corner of any page – if you see your institution’s name, you are authenticated). You will then be able to access your institute’s content/subscription for 90 days from any location, after which you must repeat this process for continued access. Ok ### About MyAccess If your institution subscribes to this resource, and you don't have a MyAccess account, please contact your library's reference desk for information on how to gain access to this resource from off-campus. ## Subscription Options ### AccessMedicine Full Site: One-Year Subscription Connect to the full suite of AccessMedicine content and resources including more than 250 examination and procedural videos, patient safety modules, an extensive drug database, Q&A, Case Files, and more.$995 USD

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