Genetic spectrum and clinical features in a cohort of Chinese patients with isolated dystonia.

Dystonia is a genetically and phenotypically heterogeneous disorder that occurs in isolation (isolated dystonia) or in combination with other movement disorders. To determine the genetic spectrum in isolated dystonia, we enrolled 88 patients with isolated dystonia for whole-exome sequencing (WES). Seventeen mutations, including nine novel ones, were identified in 19 of the 88 patients, providing a 21.59% positive molecular diagnostic rate. Eleven distinct genes were involved, of which TOR1A and THAP1 accounted for 47.37% (9/19) of the positive cases. A novel missense variant, p.S225R in TOR1A, was found in a patient with adolescence-onset generalized dystonia. Cellular experiments revealed that p.S255R results in the abnormal aggregation of Torsin-1A encoding by TOR1A. In addition, we reviewed the clinical and genetic features of the isolated dystonia patients carrying TOR1A, THAP1, ANO3, and GNAL mutations in the Chinese population. Our results expand the genetic spectrum and clinical profiles of patients with isolated dystonia and demonstrate WES as an effective strategy for the molecular diagnosis of isolated dystonia.

Clinical and Molecular Features of POLG-Related Sensory Ataxic Neuropathy with Dysarthria and Ophthalmoparesis.

Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis (SANDO) is a rare mitochondrial disorder associated with mutations in the POLG gene, which encodes the DNA polymerase gamma catalytic subunit. A few POLG-related SANDO cases have been reported, but the genotype-phenotype correlation remains unclear. Here, we report a patient with SANDO carrying two novel missense variants (c.2543G>C, p.G848A and c.452 T>C, p.L151P) in POLG. We also reviewed previously reported cases to systematically evaluate the clinical and genetic features of POLG-related SANDO. A total of 35 distinct variants in the coding region of POLG were identified in 63 patients with SANDO. The most frequent variant was the p.A467T variant, followed by the p.W748S variant. The clinical spectrum of SANDO is heterogeneous. No clear correlation has been observed between the mutation types and clinical phenotypes. Our findings expand the mutational spectrum of POLG and contribute to clinical management and genetic counseling for POLG-related SANDO.

Mutation screening of VPS16 gene in patients with isolated dystonia.

Mutations in VPS16 have been identified to be responsible for generalized dystonia. We screened VPS16 variants in 53 unrelated subjects with isolated dystonia via whole-exome sequencing. A novel pathogenic frameshift mutation p.R643fs* was found in a patient with early-onset multifocal dystonia with prominent oromandibular and bulbar involvement. Our findings expanded the spectrum of VPS16-related dystonia and suggested that mutations in VPS16 should be considered in patients with progressive early-onset dystonia.

The expanding clinical and genetic spectrum of ANO3 dystonia.

INTRODUCTION: Dystonia is a movement disorder with high clinical and genetic heterogeneity. Mutations in Anoctamin-3 (ANO3) gene have been reported to cause dystonia 24 (DYT24). This study aims to clarify the spectrum and frequency of ANO3 rare variants in Chinese populations with primary dystonia and understand the clinical and genetic features of DYT24. METHODS: Sanger sequencing was used to screen all exons and exon-intron boundaries of ANO3 for rare variants in 115 primary dystonia patients. The clinical manifestations of patients with ANO3 variants in our study and previously reported literatures were further characterized. RESULTS: Four distinct variants of ANO3 (c.1127A > G, c.1235 T > A, c.1531-3T > C, c.-11G > T) were identified in six unrelated individuals. Combined with our work and literature review, a total of 35 different rare variants distributed in ANO3 were identified in 62 dystonia patients. The predominant phenotype is cranio-cervical dystonia and more than half of patients develop head/limb tremor. Most of patients presented with isolated dystonia whereas few of them showed combined dystonia. The age of onset ranged from 1 to 69 years and peaked in late adulthood, while for generalized dystonia it peaked in a young age. Half of patients with generalized dystonia experienced deep brain stimulation (DBS). And all of them showed improvement of dystonia by DBS. CONCLUSIONS: This study confirms a relatively high frequency of rare ANO3 variants in Chinese patients with dystonia and indicates that the late adulthood-onset, cranio-cervical dystonia seems to be an important feature of the ANO3 phenotype. Further functional studies are warranted to understand the role of ANO3 in dystonia.

Synkinesis in primary and postparalytic hemifacial spasm: Clinical features and therapeutic outcomes of botulinum toxin A treatment.

Facial synkinesis can be present in both primary and postparalytic hemifacial spasm (HFS). The present retrospective study aimed to summarize the clinical features of synkinesis and explore an appropriate botulinum toxin A (BoNT-A) injection strategy to manage the synkinesis accompanying HFS. Video recordings of 234 patients with primary and postparalytic HFSs were analyzed. Improvements in the severity of spasm and synkinesis owing to BoNT-A treatment were monitored and compared among 36 primary and 12 postparalytic HFS patients with synkinesis and completed follow-up records. BoNT-A was injected into the voluntary facial region (VFR), the synkinetic facial region (SFR), or both VFR and SFR, and the efficacy of these strategies was evaluated and analyzed. Oral-ocular synkinesis in the primary group (32.8%) and ocular-oral synkinesis in the postparalytic group (81.0%) showed the highest incidence. Patients in both the primary and postparalytic groups exhibited a tremendous alleviation of spasm (97.2% vs. 91.7%, P > 0.05) following BoNT-A treatment. In both groups, coinjection and SFR injection were commonly used and effective in treatment of ocular and oral synkinesis, while VFR was frequently used but ineffective for frontal synkinesis. In addition, the improper muscle selection surrounding the mouth corner resulted in pattern change and treatment failure of oral synkinesis. Synkinesis mostly affected the ocular and oral regions. BoNT-A, via treatment of SFR, is effective against synkinesis accompanying HFS.