Neurogenetic diseases: molecular diagnosis and therapeutic approaches |
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Authors: | U Müller M B Graeber |
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Institution: | (1) Institut für Humangenetik, Justus-Liebig-Universität, Schlangenzahl 14, D-35392 Giessen, Germany;(2) Labor für Molekulare Neuropathologie, Institut für Neuropathologie, Ludwig-Maximilians Universität, Thalkirchner Strasse 36, D-80337 München, Germany |
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Abstract: | A neurogenetic disorder is defined as a clinical disease caused by a defect in one or more genes which affect the differentiation and function of the neuroectoderm and its derivatives. Genetic findings in various neurogenetic disorders are discussed. Huntington disease, spinobulbar muscular atrophy, and the autosomal dominant cerebellar ataxias are examples of autosomal dominant disorders caused by the expansion of trinucleotides (CAG) within disease genes. The CAG expansions appear to result in a gain of gene function. Prenatal, presymptomatic, and differential diagnostic tests are based on the detection of the repeat expansions. Point mutations within disease genes result in many additional neurogenetic disorders. An autosomal dominant form of amyotrophic lateral sclerosis and various types of craniosynostotic syndromes are described. The mutations in the disease genes also appear to result in a gain of gene function. Molecular diagnosis in these disorders is based on the direct examination of the mutated gene by methods such as single-strand conformation polymorphism analysis, denaturing gradient gel electrophoresis, and direct DNA sequencing. In many neurogenetic disorders the disease gene has not yet been identified. Here molecular diagnosis relies on indirect approaches based on methods such as the analysis of linkage and of allelic association. Hereditary forms of dystonia are presented as examples. Common sporadic neurological disorders such as Alzheimer and Parkinson diseases frequently have multifactorial causes. Investigations into the molecular basis and the development of diagnostic tests in these two important diseases are discussed. At present no curative therapies exist in neurogenetic disorders. Gene therapeutic approaches, however, provide promise for a cure in at least some of these diseases. Basic principles of gene therapy are explained and attempts at gene therapy in Alzheimer and Parkinson diseases are described. Finally, some of the many obstacles are summarized that must be overcome before gene therapy becomes feasible in most monogenic neurological diseases.Abbreviations
AD
Alzheimer disease
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ALS
Amyotrophic lateral sclerosis
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apoE
Apolipoprotein E
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APP
Amyloid precursor protein
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AR
Androgen receptor
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DGGE
Denaturing gradient gel electrophoresis
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DRPLA
Dentatorubral pallidoluysian atrophy
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HD
Huntington disease
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MJD
Machado-Joseph diseas
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NGF
Nerve growth factor
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PCR
Polymerase chain reaction
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PD
Parkinson disease
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SBMA
Spinobulbar muscular atrophy
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SCA
Spinocerebellar ataxias
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SSCP
Single-strand conformation polymorphism |
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Keywords: | Expanding trinucleotide repeat Gene therapy Linkage mapping Mutation analysis Risk calculation |
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