The genetics of dystonias

Abstract

Dystonia has been defined as a syndrome of involuntary, sustained muscle contractions affecting one or more sites of the body, frequently causing twisting and repetitive movements or abnormal postures. Dystonia is also a clinical sign that can be the presenting or prominent manifestation of many neurodegenerative and neurometabolic disorders. Etiological categories include primary dystonia, secondary dystonia, heredodegenerative diseases with dystonia, and dystonia plus. Primary dystonia includes syndromes in which dystonia is the sole phenotypic manifestation with the exception that tremor can be present as well. Most primary dystonia begins in adults, and approximately 10% of probands report one or more affected family members. Many cases of childhood- and adolescent-onset dystonia are due to mutations in TOR1A and THAP1. Mutations in THAP1 and CIZ1 have been associated with sporadic and familial adult-onset dystonia. Although significant recent progress had been made in defining the genetic basis for most of the dystonia-plus and heredodegenerative diseases with dystonia, a major gap remains in understanding the genetic etiologies for most cases of adult-onset primary dystonia. Common themes in the cellular biology of dystonia include G1/S cell cycle control, monoaminergic neurotransmission, mitochondrial dysfunction, and the neuronal stress response.

Figure 2.1

TorsinA, THAP1, and CIZ1. (A) Functional domains of torsinA and the location of coding variants that have been associated with dystonia. Walker A and B motifs are involved in ATP binding and hydrolysis. SS, signal sequence; H, hydrophobic domain; SI, sensor 1; and S2, sensor 2. (B) Functional domains of THAP1 and the location of coding variants that have been associated with dystonia. THAP, thanatos-associated protein domain; Pro, low-complexity proline-rich region; and NLS, nuclear localization signal. M1?, c.2delT or c.1A>G. (C) Functional domains of CIZ1 and the location of variants that have been associated with cervical dystonia. QD1, glutamine-rich domain 1; NLS, putative nuclear localization sequence; QD2, glutamine-rich domain 2; ZF, zinc finger domains; AD, acidic domain; and MH3, matrin (MATR3)-homologous domain 3. For color version of this figure, the reader is referred to the online version of this book.