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 neuro-metabolic 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.

Motor phenotypes and molecular networks associated with germline deficiency of Ciz1

“…Moreover, estrogen and other sex hormones are known to exert important effects on cell-cycle checkpoints and other cell cycle proteins (Heckler and Riggins, 2015). In the context of dystonia, it should be noted that most patients with isolated dystonia are females with age of onset in the perimenopausal period (LeDoux, 2012a; LeDoux, 2012b). Comparably, the incidence of breast cancer rises in the postmenopausal period (Jatoi et al, 2008).…”

“…Genetic factors play an important role in the development of isolated dystonia, a common movement disorder characterized by involuntary and sustained muscle contractions causing twisting and repetitive movements (Albanese et al, 2013, LeDoux, 2012b; LeDoux, 2012a). To date, >20 monogenic inherited dystonias and dystonia-related disorders (DYT1-25) have been reported in Online Mendelian Inheritance in Man (OMIM) (Xiao et al, 2014).…”

“…To date, >20 monogenic inherited dystonias and dystonia-related disorders (DYT1-25) have been reported in Online Mendelian Inheritance in Man (OMIM) (Xiao et al, 2014). Moreover, dystonia can also be a presenting or prominent clinical manifestation of numerous hereditary neurological diseases (LeDoux, 2012b). In 2012, a missense variant (c.790A > G, p.S264G) in Cip1-interacting zinc finger protein 1 ( CIZ1 ) was identified in a large multiplex pedigree with adult-onset isolated cervical dystonia (Xiao et al, 2012).…”

Diagnosis and Treatment of Dystonia

“…Some dystonias have no apparent pathology in the nervous system, while others are associated with defects that can be detected by neuroimaging or post-mortem histopathological studies. At the molecular level, multiple genes have been discovered for rare subtypes of dystonia, 8,9 and they are involved in diverse biochemical processes. 9–11 At the anatomical level, several brain regions have been implicated, leading to the concept that dystonia does not arise from dysfunction of a single brain region, but rather from dysfunction of a motor network.…”

Blepharospasm in a multiplex African-American pedigree

“…The distribution of the BSP phenotype in our pedigree is most consistent with autosomal dominant inheritance as has been the case for most isolated dystonia genes ( TOR1A , THAP1 , GNAL , and CIZ1 ) [18]. Although in silico tools such as CADD provide useful information on the deleteriousness of missense variants, they do not reliably predict pathogenicity.…”