Genetic classification and molecular mechanisms of primary dystonia

BACKGROUND： Primary dystonia is a heterogeneous disease, with a complex genetic basis. In previous studies, primary dystonia was classified according to age of onset, involved regions, and other clinical characteristics. With the development of molecular genetics, new virulence genes and sites have been discovered. Therefore, there is a gradual understanding of the various forms of dystonia, based on new viewpoints. There are 15 subtypes of dystonia, based on the molecular level, i.e., DYT1 to DYT15. OBJECTIVE： To analyze the genetic development of dystonia in detail, and to further investigate molecular mechanisms of dystonia. RETRIEVAL STRATEGY： A computer-based online search was conducted in PubMed for English language publications containing the keywords ＂dystonia and genetic＂ from January 1980 to March 2007. There were 105 articles in total. Inclusion criteria： ① the contents of the articles should closely address genetic classification and molecular mechanisms of primary dystonia; ② the articles published in recent years or in high-impact journals took preference. Exclusion criteria： duplicated articles. LITERATURE EVALUATION： The selected articles were on genetic classification and molecular genetics mechanism of primary dystonia. Of those, 27 were basic or clinical studies. DATA SYNTHESlS： ① Dystonia is a heterogeneous disease, with a complex genetic basis. According to the classification of the Human Genome Organization, there are 15 dystonia subtypes, based on genetics, i.e., DYT1-DYT15, including primary dystonia, dystonia plus syndrome, degeneration plus dystonia, and paroxysmal dyskinesia plus dystonia.② To date, the chromosomes of 13 subtypes have been localized; however, DYT2 and DYT4 remain unclear. Six subtypes have been located within virulence genes. Specifically, torsinA gene expression results in the DYTI genotype; autosomal dominant GTP cyclohydrolase 1 gene expression and recessive tyrosine hydroxylase expression result in the DYT5 genotype, respectively; the epsilon-sarcoglycan gene is involved in DYT11; Na^＋/K^＋-ATP enzyme α 3 chain gene in DYT12; TATA-conjugated protein-associated factor 1 gene in DYT3; and myofibril regulatory factor gene in DYTS. ③ Different types of dystonia exhibit various clinical characteristics and specific clinical manifestations. ④Many elements regarding the molecular mechanism of dystonia have been determined. However, many components remain poorly understood. For example, detailed pathogenesis remains unclear. Various forms of dystonia exhibit similar problems. Moreover, a single form of dystonia may be a result of two or more different chromosomal mutations. In addition, more studies are needed to fully understand chromosome apposition and virulence genes involved in dystonia. CONCLUSION： The discovery of virulence genes and localizations of newly classified forms of dystonia are beneficial to further understanding the molecular mechanisms of dystonia.

Role of DYT1 gene in early-onset primary torsion dystonia

Mutation of the DYT1 gene has been reported to cause early-onset primary torsion dystonia （DYT1） Due to DYT1 gene mutation, defective wild torsinA and the accumulation of mutant torsinA （GAG-deleted DYT1 gene encoded the mutant torsinA, torsinA＆E） play an important role in DYT1 pathogenesis. Intracellular inclusion bodies are formed, and dopamine transport and release are disturbed by interfering functions of endoplasmic reticulum, nuclear membrane, and cytoskeleton of neural cells, resulting in DYT1 onset. Small interfering RNA could serve as a potential therapy for DYT1. However, the exact function of wild torsinA and the pathological effects of torsinAAE require further studies.

Sonographic Alteration of Basal Ganglia in Different Forms of Primary Focal Dystonia： A Cross-sectional Study

Background：Few studies have addressed whether abnormalities in the lenticular nucleus （LN） are characteristic transcranial sonography （TCS） echo features in patients with primary dystonia.This study aimed to explore alterations in the basal ganglia in different forms of primary focal dystonia.Methods：A cross-sectional observational study was performed between December 2013 and December 20 1 4 in 80 patients with different forms of primary focal dystonia and 55 neurologically normal control subjects.TCS was performed in patients and control subjects.Multiple comparisons of multiple rates were used to compare LN hyperechogenicity ratios between control and patient groups.Results：Thirteen individuals were excluded due to poor temporal bone windows,and two subjects were excluded due to disagreement in evaluation by sonologists.Totally,70 patients （cervical dystonia,n =30;blepharospasm,n =30;oromandibular dystonia,n =10） and 50 normal controls were included in the final analysis.LN hyperechogenicity was observed in 51% （36/70） of patients with primary focal dystonia,compared with 12% （6/50） of controls （P 〈 0.001）.Substantia nigra hyperechogenicity did not differ between the two groups.LN hyperechogenicity was observed in 73% （22/30） of patients with cervical dystonia,a greater prevalence than in patients withblepharospasm （33%,10/30,P =0.002） and oromandibular dystonia （40%,4/10,P =0.126）.LN hyperechogenicity was more frequently observed in patients with cervical dystonia compared with controls （73% vs.12%,P 〈 0.001）;however,no significant difference was detected in patients with blepharospasm （33% vs.12%,P =0.021） or oromandibular dystonia （40% vs.12%,P =0.088）.Conclusions：LN hyperechogenicity is more frequently observed in patients with primary focal dystonia than in controls.It does not appear to be a characteristic TCS echo feature in patients with blepharospasm or oromandibular dystonia.