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Explanation:
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
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 beyond the critical threshold of 36 repeats results in disease, and forms the basis of the polymerase chain reaction based genetic test. Expansion size is inversely related to age at onset, but the range in age at onset for a given repeat size is so large that repeat size is not a useful predictor for individuals. Inheritance is dominant with full penetrance, meaning that almost all mutation carriers will eventually develop the disease, except those with 36–39 repeats where penetrance is reduced. Meiotic instability with a tendency to increasing expansion size, particularly during spermatogenesis, provides the molecular basis for the phenomenon of anticipation. Thus, juvenile onset cases with very large expansions usually have an affected father. A small minority (< 1%) of individuals have expansions in an intermediate range (29–35 repeats), believed to be an asymptomatic but unstable pre-mutation range, which may expand to cause disease in offspring. Dentatorubropallidoluysian atrophy (DRPLA), also caused by a trinucleotide repeat expansion, may be difficult to distinguish clinically from early onset HD, and so is usually tested for with HD.
Predictive genetic testing of asymptomatic at-risk relatives of affected patients is governed by international guidelines (see Hanna and Wood on page ii2). Prenatal testing in known mutation carriers is routinely available, while linkage based exclusion testing is available to those at-risk women who do not wish to know their own gene status. The latter depends on termination of a pregnancy where linkage shows the fetus to have the same 50% genetic risk as the mother. Preimplantation diagnosis based on selection of unaffected IVF embryos is available in some centres.
THE DYSTONIAS
Dystonia is a feature of many hereditary neurodegenerative and metabolic disorders. In most of these disorders, dystonia usually occurs in the setting of a broader clinical phenotype, and careful clinical assessment reveals other features such as cognitive involvement, pyramidal signs, or ocular abnormalities.
Primary dystonias
In this group of disorders, dystonia or dystonic tremor is (with the exception of parkinsonism in dopa responsive dystonia (DRD)) the only clinical manifestation, and imaging and pathology are usually unrevealing. These disorders have a genetic basis, with dominant inheritance in most cases. The most important of these disorders to the neurologist are DYT1 dystonia and DRD.
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