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Genetic disorders of the central nervous system have a propensity to cause movement disorders or ataxia, as a part of the phenotype, or sometimes as the main phenotypic manifestation. The Online Mendelian Inheritance in Man (OMIM) database lists over 500 entries for disorders of which ataxia or a movement disorder form part. Neurologists should be alert to the possibility that patients with complex disorders involving involuntary movements or unsteadiness may have a genetic disorder.
Only those gene loci with relevance to the practising neurologist will be discussed; a more complete listing of other loci, many of which apply only to individual kindreds, is available in referenced review articles.
Huntington’s disease (HD) is the prototypic neurogenetic disorder, one of the first to be mapped (1983) and subsequently cloned (1993), and the model on which presymptomatic genetic testing is based.
The clinical triad of movement disorder, psychiatric features, and eventual dementia will be well known to neurologists. Chorea is the first manifestation in about two thirds of patients, initially a mild fidgetiness apparent only to the careful observer, which gradually progresses and may be the only clinical manifestation of HD for several years. Severe chorea may respond well to neuroleptics such as sulpiride. Personality change and eye movement disorders including slow saccades, and head thrusting or blinking to generate saccadic eye movements, are also common early features. A wide range of movement disorders including parkinsonism, loss of postural stability, and dystonia eventually supervene, leading to increasingly functional impairment. Progressive weight loss, often resulting in cachexia, is common. Presentation is usually in the forth or fifth decades, but may be at almost any age. The juvenile onset form of HD may present with parkinsonism, the so-called Westphal variant, while late onset forms may cause chorea alone.
Expansion of a polyglutamine (CAG) trinucleotide repeat …