Genetics of movement disorders

The contribution of genes to etiology is variable for different movement disorders. Some diseases are by definition genetic, such as Huntington’s disease (HD) - in all cases caused by expanded repeats in the Huntingtin (HTT) gene. Other disorders such as Parkinson’s disease may have monogenic causes but are largely the result of nongenetic factors. Dystonia and the atypical parkinsonisms have high genetic burdens in their etiologies, with reduced penetrance being a common feature. Essential tremor (ET) and restless legs syndrome (RLS) may be familial, although no monogenic causes have been elucidated; rather, risk-conferring alleles contribute to etiology. In this chapter, we review the genetic causes of these movement disorders. We focus on the monogenic causes of autosomal dominant (SNCA, LRRK2, VPS35) and recessive (PARKIN, PINK1, DJ-1) Parkinson’s disease, of isolated (TOR1A, THAP1, GNAL) and combined (GCH1, TH, ATP1A3, PRKRA, TAF1, SGCE) dystonia, and of the paroxysmal movement disorders (PRRT2, MR1, SLC2A1). We also briefly cover Huntingtin and the genes that have been linked to atypical parkinsonism, essential tremor, and restless legs syndrome. Importantly, we include new reports of genes that have been identified via next-generation sequencing, with the caveat that a number still require independent validation in more genetic and functional studies. Because the genetics of movement disorders are complex, genetic testing results determining the clinical diagnosis can only be recommended for genes that are unequivocally disease causing. However, gene panel testing is slowly transitioning into clinical utility, heralding the transition of movement disorder genetics from bench to bedside.