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Cambridge University Press
Online publication date:
May 2012
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Book description

Progress in genetic knowledge is profoundly affecting medical practice, and no clinical specialty has more diseases associated with genetic mutations than neurology. As a more complete picture of the genes which give rise to neurological disease is obtained, trainee and practising neurologists need a guide to basic principles and the more important clinical entities with a genetic component. It is against this background that Neurogenetics: A Guide for Clinicians has been written. The book opens with coverage of genetic testing and counselling. Subsequent chapters discuss genetic factors for all the major neurological diseases, including epilepsy, Alzheimer's disease, Parkinsonism and muscular dystrophies. No book in this field can hope to be fully up to date with the latest research; rather this work provides a framework on which to add new genetic discoveries. Neurogenetics: A Guide for Clinicians provides a synoptic overview for neurologists, medical geneticists and scientists working in the field.


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  • Chapter 6 - Huntington's disease
    pp 64-82
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    The future for genetic medicine is bright. Soon we will know much more about human genetic variation, genomic control, and even how we got to the top of the evolutionary tree. The 3.08 billion base pairs (bp) of Homo sapiens DNA have now been sequenced and this ranks with the highest achievements of humans to date. The assignment of a mutation in a gene causing a human disease is the first step in genetic variation. One human disease area for which there is rising hope of early success is the field of pharmacogenetics. The ENCODE project is endeavoring to identify the functional elements in the genome. Advanced draft or complete sequences are now available for five mammals: human, mouse, rat, chimpanzee and dog. Neurogenetics is still in its infancy but it is now part of the core curriculum of most residency training schemes.
  • Chapter 7 - Parkinsonism
    pp 83-102
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    Advances in genetics have probably had more practical applications in the field of the inherited neurological disorders than in any other area of medicine. A remarkably high number of serious neurological disorders follow single-gene Mendelian inheritance, in both childhood and adult life. Genetic testing now forms an important and integral part of both neurological and clinical genetics practice and has greatly enhanced both diagnostic precision and the options associated with genetic counseling. This chapter focuses on the use and implications of testing, especially in relation to genetic counseling. Risk estimations in relation to carrier testing for both autosomal and X-linked recessive disorders may, in fact, be quite complex and may need the overall family structure to be considered. The chapter also presents some of the numerous issues that need to be considered in relation to presymptomatic testing.
  • Chapter 8 - Prion diseases
    pp 103-120
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    Alzheimer's disease is the major cause of dementia in the elderly and afflicts about four million Americans. This chapter focuses on AD and discusses other dementias to the extent to which they contribute to our understanding of AD. While AD is easily the most prevalent dementing disease, other rarer dementias offer useful comparators. These include dementia with Lewy bodies (DLB), prion disease, Worster drought syndrome (British dementia), and frontal temporal dementia (FTD) with tangles (FTDP-17T). The genetic findings have enabled the creation of transgenic mice that model parts of the disease process. While Alzheimer patients are undoubtedly better treated than they were 15 years ago, the only direct benefit to patients from this gene-based approach to research, to date, has been the availability of genetic testing in the kindreds with amyloid beta precursor protein gene (APP) and presenilin mutations.
  • Chapter 9 - Channelopathies
    pp 121-135
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    The current classification of epileptic seizures, epilepsies, and epilepsy syndromes is considered first. The presence of progressive neurological signs is a cause for concern and suggests a degenerative disorder. Investigations may include biochemical investigation, EEG, video telemetry, cranial imaging, and DNA diagnostics. Affected males with fragile-X have an increased frequency of epilepsy. Estimates of its prevalence vary from 28% to 45%. Seizures may be generalized tonic-clonic, partial with or without secondary generalization, or of multiple types. Advances in human molecular genetic techniques have allowed positional cloning strategies to be applied to identification of the defective genes and their protein products. A number of studies have been performed on the incidence of epilepsy in the offspring of epileptic parents, and provide an empiric risk of 1. 7%-7. 3%, with a median of 4. 2% for all types of seizures, including febrile convulsions and single seizures.
  • Chapter 10 - Amyotrophic lateral sclerosis and other disorders of the lower motor neuron
    pp 136-147
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    This chapter reviews the major advances in autosomal recessive and autosomal dominant ataxias, discusses the use of genetic tests in these disorders, and summarizes some current ideas regarding pathogenesis. It also presents a list of the autosomal recessive ataxias that have been genotypically characterized to date. Mutations in ataxia with isolated vitamin E deficiency (AVED) are scattered throughout the gene and some of them may be associated with a mild phenotype, late onset, retinitis pigmentosa, and retained reflexes. A syndrome of ataxia associated with optic atrophy, visual loss, and cochlear degeneration has been mapped to chromosome. The spinocerebellar ataxia (SCAs) exhibits many phenotypic similarities so that it is almost impossible to diagnose the genotype from the phenotype alone. Many persons from families with ataxia will request predictive testing and occasionally prenatal testing. Disease-modifying therapies are under investigation and include antioxidants and drugs that may modify excitotoxicity or apoptosis.
  • Chapter 11 - The muscular dystrophies
    pp 148-165
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    The Huntington's disease (HD) locus was one of the first disease associated loci to be mapped using restriction fragment length polymorphisms. The prevalence of HD in populations of Western European descent is usually given as approximately 4-10 per 100,000. HD onset has been described as between the ages of 2 and 87 years. HD can produce a wide range of phenotypic presentations and, as the disease progresses, the signs and symptoms often change. The most well recognized neuropathological classification is the Vonsattel grade. The HD predictive testing guidelines recommend that individuals at risk are seen for two to four counseling sessions spread over a three-month period, before disclosure of the test results. Diagnostic testing for HD usually is undertaken by neurologists when patients present with the neurological signs and symptoms of the disease. Currently, there are several large clinical trials ongoing, including high-dose creatine, coenzyme Q10, and memantine.
  • Chapter 12 - Charcot–Marie–Tooth diseases
    pp 166-187
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    Parkinson's disease (PD) appears as a sporadic disorder in most patients. This chapter discusses the genetics of the Mendelian forms of PD identified to date, focusing on five genes: a-synuclein, parkin, DJ-1, PINK1, and LRRK2 that have been associated conclusively with this disease. Other chromosomal loci including PARK3, PARK10, and PARK11 have been identified by genome-wide approaches, and these regions might harbor further genes for PD. For a few other genes including UCH-L1, NR4A2, SNCAIP, HtrA2/Omi, and GBA there is weaker evidence of association with PD. These loci and genes are also briefly discussed. Emerging data delineate mutations in the LRRK2 gene as the cause of up to 10% of the familial late onset autosomal dominant PD forms, and also of a few sporadic cases. The importance of genetic testing for PD patients is expected to increase in the near future, also raising important ethical issues.
  • Chapter 13 - Mitochondrial disorders
    pp 188-211
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    The human prion diseases have traditionally been classified into Creutzfeldt-Jakob disease (CJD), Gerstmann-Sträussler syndrome (GSS) and kuru. The clinically defined categories: CJD, GSS, and kuru may be divided further into three etiological categories: sporadic, acquired, and inherited. The coding sequences of mammalian prion protein genes are highly conserved in a similar way to other structural proteins, presumably by deleterious selection of coding mutations. Symptomatic treatment of various neurological and psychiatric features can be provided and a range of supportive services are likely to be required in the later stages of the disease. A number of approaches to rational therapeutics are being studied in experimental models. Anti-PrP antibodies have been shown to block progression of peripheral prion propagation in mouse models, and humanized versions of these antibodies could, in principle, be developed and used for both post-exposure prophylaxis and during established clinical disease.
  • Chapter 14 - The neurofibromatoses and related disorders
    pp 212-228
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    This chapter provides a clinicians' guide to the key clinical, genetic, and treatment aspects of the main single-gene neurological channelopathies. It considers the major skeletal muscle channelopathies followed by the main CNS channelopathies. The periodic paralyses (PP) are disorders in which patients experience focal or generalized episodes of muscle weakness of variable duration. Hypokalemic periodic paralysis can also be caused by missense mutations in the voltage sensor of domain 2 of SCN4A. Expression studies indicate that the SCN4A mutations associated with hypo-PP cause loss of function of the channel. Many studies indicate a strong genetic contribution to the risk of developing idiopathic generalized epilepsy, as well as febrile seizures. Inherited variability in the coding sequence of the GABRD gene, encoding the subunit of GABAA receptors, has also been suggested to act as a susceptibility factor for generalized epilepsy.
  • Chapter 15 - The future of neurogenetics
    pp 229-233
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    This chapter reviews the epidemiology, clinical phenotype, and genetic basis of the heritable forms of amyotrophic lateral sclerosis (ALS) and other disorders of the lower motor neuron (LMN) including Kennedy's disease, the spinal muscular atrophies (SMA), and hereditary motor neuropathies (HMN). The first successful genome-wide linkage study on FALS described linkage to chromosome 21q21. Mutations were subsequently identified in the gene encoding Cu/Zn superoxide dismutase (SOD1). Many people with sporadic ALS seek genetic counseling once they become aware that ALS can be genetic and are better informed about gene testing. The implications of gene screening should always be discussed in detail with the family prior to testing. Consent and DNA from an affected individual should be obtained before predictive testing in at-risk individuals is considered. The penetrance of different SOD1 mutations in particular varies greatly and must be taken into consideration when ascribing risk to a particular gene carrier.


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