NEUROGENETIC DISEASES - MOLECULAR DIAGNOSIS AND THERAPEUTIC APPROACHES

A neurogenetic disorder is defined as a clinical disease caused by a d efect in one or more genes which affect the differentiation and functi on of the neuroectoderm and its derivatives. Genetic findings in vario us neurogenetic disorders are discussed. Huntington disease, spinobulb ar muscular atrophy, and the autosomal dominant cerebellar ataxias are examples of autosomal dominant disorders caused by the expansion of t rinucleotides (CAG) within disease genes. The CAG expansions appear to result in a gain of gene function. Prenatal, presymptomatic, and diff erential diagnostic tests are based on the detection of the repeat exp ansions. Point mutations within disease genes result in many additiona l neurogenetic disorders. An autosomal dominant form of amyotrophic la teral sclerosis and various types of cranio-synostotic syndromes are d escribed. The mutations in the disease genes also appear to result in a gain of gene function. Molecular diagnosis in these disorders is bas ed on the direct examination of the mutated gene by methods such as si ngle-strand conformation polymorphism analysis, denaturing gradient ge l electrophoresis, and direct DNA sequencing. In many neurogenetic dis orders the disease gene has not yet been identified. Here molecular di agnosis relies on indirect approaches based on methods such as the ana lysis of linkage and of allelic association. Hereditary forms of dysto nia are presented as examples. Common sporadic neurological disorders such as Alzheimer and Parkinson diseases frequently have multifactoria l 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 th erapeutic 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 mus t be overcome before gene therapy becomes feasible in most monogenic n eurological diseases.