Genetics of movement disorders

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By Amitabh Gupta MD PhD

The field of movement disorders has undergone unprecedented growth over the past 2 decades in the discovery of numerous genetic loci that result in clinical disease. Although identification of appropriate alleles is relatively new, the genetic basis for movement disorders had been recognized by George Huntington and Kinnier Wilson, among others, in their seminal papers on the diseases that bare their names. Huntington pointed to the stigma and concern about genetic diseases as follows:

The hereditary chorea, as I shall call it, is confined to certain and fortunately a few families, and has been transmitted to them, an heirloom from generations away back in the dim past. It is spoken by those in whose beings the seeds of the disease are known to exist, with a kind of horror, and not at all alluded to except through dire necessity, when it is mentioned as ‘that disorder’ (Huntington 1872).

Although physicians had recognized genetic influence of movement disorders for more than a century, it was not until 1977 when spinocerebellar atrophy (SCA1) became the first neurologic disorder linked to a specific chromosome (HLA region of chromosome 6) (Jackson et al 1977). Later, Huntington disease was the first neurologic disorder mapped using polymorphic DNA markers (Gusella et al 1983). The advent of chromosome analysis led to a shift from the standard classification system based on phenomenology to one that is based on inheritance patterns, eg, autosomal dominant ataxias (Harding 1982). More recently, discovery of causative genes and the proteins that their mutations abnormally produce has added to a better understanding of disease processes, and the classification of genetic diseases has shifted from patterns of inheritance to classifying diseases according to specific mutated genes and proteins (eg, tauopathies, synucleinopathies, triplet repeat expansion disorders, among others). The primary aim of this clinical summary is to provide an overview of the genetic movement disorders. It is important to note that this a rapidly expanding field, and entire books devoted to this topic (Pulst 2003) are rapidly becoming outdated, particularly with research progress being made through increasingly sophisticated genetic tools.