Dystonia. The term dystonia covers a broad spectrum of movement disorders that are all characterized by sustained muscle contractions that produce repetitive twisting movements and abnormal postures due to concurrent contractions of agonist and antagonist muscles (xx Xxxxxxxx Xxxxxx and Xxxxxxx 2002; Xxxxxxxx 2003; Xxxxxxxx et al. 2006). Dystonia can either be genetically inherited or sporadic. There are currently 17 known genetically inherited dystonic loci that are referred to as DYT1 to DYT17 (Table I-1). Dystonias can be separated into a number of subcategories depending on the phenotype, and each genetically defined dystonia is associated with a well-characterized phenotype. The main subgroups are primary dystonia, dystonia-plus, secondary dystonia, and heredodegenerative. Primary dystonia refers to syndromes in which dystonia is the main phenotypic manifestation. Primary dystonias are unassociated with any prior brain injuries and are generally not responsive to levadopa treatments (xx Xxxxxxxx Xxxxxx and Xxxxxxx 2002; Xxxxx and Xxxxxxx 2002). Primary dystonias often have a genetic basis and can be further subdivided into early onset, which has a median age of onset of 9 years, and late onset, which has a median age of 45 years (xx Xxxxxxxx Xxxxxx and Xxxxxxx 2002; Xxxxx and Xxxxxxx 2002). Early onset primary dystonias tend to be more generalized, starting in a leg or arm and spreading to other limbs and trunk, while late onset primary dystonias tend to remain more focal, especially in the upper part of the body (xx Xxxxxxxx Xxxxxx and Xxxxxxx 2002; Xxxxx and Xxxxxxx 2002). DYT1, 2, 4, 6, 7, 13 and 17 are primary forms of dystonia (Xxxxxx 1985; Xxxxxxx-Xxxxxx et al. 1988; Xxxxxx et al. 1997; Leube et al. 1997; Ozelius et al. 1997; Xxxxxxx et al. 2001; xx Xxxxxxxx Xxxxxx and Xxxxxxx 2002; Xxxxx and Xxxxxxx 2002). Most primary dystonias are autosomal dominant, with the exception of DYT2 and DYT 17 which are both autosomal recessive (xx Xxxxxxxx Xxxxxx and Xxxxxxx 2002; Xxxxx and Xxxxxxx 2002; Chouery et al. 2008). Although the likely genetic loci of DYT6, 7, 13 and 17 have been identified, the only primary dystonia gene that has been identified is the DYT1 gene, which is located on 9q34 and encodes the protein torsinA (Ozelius et al. 1997; xx Xxxxxxxx Xxxxxx and Xxxxxxx 2002; Xxxxx and Xxxxxxx 2002). As of now, the genetic loci for DYT2 and DYT4 are unknown (xx Xxxxxxxx Xxxxxx and Xxxxxxx 2002; Xxxxx and Xxxxxxx 2002). Dystonia-plus dystonia refers to dystonias ...
Dystonia associated mutations cause premature degradation of torsinA protein. SH-SY5Y cells expressing HA-tagged torsinA WT (open square), ΔE (closed circle) or Δ323-8 (closed triangle) were pulse-labeled for 1 hr in [35S]Met/Cys- containing medium and chased with non-radioactive Met/Cys for the indicated time. Time points were taken every 24 hr over 5 days (A) and every 6 hr over the first 24 hr (B). 35S-labeled WT or mutant torsinA proteins were immunoprecipitated from lysates with anti-HA antibodies and detected by SDS-PAGE and autoradiography. The levels of wild-type or mutant torsinA proteins were quantified and plotted relative to the corresponding torsinA levels at 0 h. Data represent mean ± S.E. of the results from at least three independent experiments.
(A) SH-SY5Y cells expressing HA-tagged torsinA WT, ΔE or Δ323-8 were treated with the indicated proteolysis inhibitors or DMSO control. Lysates were analyzed by SDS-PAGE and immunoblotting with anti-HA and anti-actin antibodies.
(B) The relative level of wild-type or mutant torsinA was measured by quantification of the intensity of the wild-type or mutant torsinA band and normalized to the actin level in the corresponding cell lysate. Results are shown as mean ± S.E. from at least three independent experiments. *Significantly different from the corresponding vehicle (DMSO)-treated control cells expressing the same type of torsinA (p < 0.05). #Significantly different from the vehicle-treated, torsinA WT-expressing cells (p < 0.05). . FIGURE II-8. Degradation of torsinA mutants by both the proteasome and lysosome pathways. SH-SY5Y cells expressing HA-tagged torsinA WT (A), ΔE (B), or Δ323-8 (C) were pulse labeled for 1 h with medium containing [35S]Met/Cyc and chased with non-radioactive Met/Cys containing MG132 (closed circle), E64 (closed triangle), or vehicle control (open square) for the indicated time. Lysates were immunoprecipitated with anti-HA antibodies and detected by SDS-PAGE and autoradiography. Proteins levels were quantified using a PhosphorImager and plotted relative to the corresponding torsinA levels at 0 h. Data are shown as mean ± S.E. of the results from at least three independent experiments. The asterisks indicate a statistically significant (p < 0.05) increase in the level of torsinA in MG132-treated cells versus vehicle-treated controls. The plus sign indicates an increase approaching significance (p < 0.065) in the level of torsinA in MG132-treated cells versus vehicle-treated control...
Dystonia. The term dystonia originated in 1911, when Xxxxxxxxx reported on 4 young patients with “dystonia musculorum deformans” (Xxxxxxxxx, 1911). Xxxxxxxxx noted that “muscle tone was hypotonic at one occasion and in tonic muscle spasm at another.” Xxxxxxxxx regarded dystonia as a disorder of muscular origin, though it is now appreciated that central dysfunction causes dystonia. The characterization of dystonia has been updated and refined throughout the last century, culminating in a 2013 consensus definition and classification schema authored by a committee of experts (Xxxxxxxx et al., 2013). The committee defined dystonia as “a movement disorder characterized by sustained or intermittent muscle contractions causing abnormal, often repetitive, movements, postures, or both.” The definition goes on to state that “dystonic movements are typically patterned, twisting, and may be tremulous.” Further, “dystonia is often initiated or worsened by voluntary action and associated with overflow muscle activation.” This definition distinguishes dystonia from other hyperkinetic movement disorders such as chorea and myoclonus. Further, it defines dystonia based on phenomenology, as opposed to specific biological dysfunction, which distinguishes it from inherited and degenerative disorders. Current estimates place the number of patients with dystonia at 3 million worldwide (Cloud and Jinnah, 2010), making dystonia the third most prevalent movement disorder behind essential tremor and PD. The actual number of people with dystonia is likely much higher, however, as proper diagnosis requires access to a highly trained neurologist. Current treatment options for dystonia are either palliative or inadequate. The most common treatment for dystonia is botulinum toxin injection into the affected muscles (Jankovic, 2006), which chemically silences the neuromuscular junction. Oral medications are only effective in some patients and side effects are common. They include anti- muscarinics like trihexyphenidyl (THP) and benztropine, as well as muscle relaxers like benzodiazepines (Xxxxxx et al., 1988). 3,4-L-dihydroxyphenylalanine (L-DOPA), the biochemical precursor to dopamine (DA), and other dopaminergic compounds are effective in a small subset of dystonia patients (Cloud and Jinnah, 2010). Surgical lesion or deep brain stimulation (DBS) of specific basal ganglia or thalamic nuclei are effective in certain patients, but are primarily used as a treatment of last resort (Xxxxxx and Starr, ...
Dystonia. Dystonia is a syndrome of sustained muscle contractions producing writhing movements and abnormal postures. It may be a primary disorder that occurs without other neurological conditions, or it may occur secondary to a central nervous system lesion whose origin may be stroke, trauma, cerebral palsy, or degenerative disease. Dystonia affects approximately 250,000 people in the U.S., making it the third most common movement disorder, following PD and Essential Tremor. Unlike PD, dystonia commonly affects children, with early onset primary dystonia typically presenting in childhood or early adolescence. While the cause of dystonia is not well understood, it is known to be a predominantly hereditary disease and is assumed to originate in motor centers within the basal ganglia. A mutation to a gene, called DYT1, has been linked to a high number of early onset dystonias. Most forms of dystonia respond poorly to currently available systemic medications. Focal dystonias may benefit from botulinum toxin-induced denervation, but this therapy is not applicable to more generalized cases. An index of disease severity has also been established for dystonia and is referred to as the Xxxxx-Xxxx-Xxxxxxx Dystonia Rating Scale or BFMDRS (12). This Index assesses dystonia severity and frequency in nine body regions on a scale of 0-120, where a rating of 0 is again indicative of normal function. The scale is widely used for the evaluation of both adult and pediatric patients, although it has only been specifically validated for adult patients (12,13).
