Dystonia最新文献

DYT1 dystonia is an inherited early-onset movement disorder characterized by sustained muscle contractions causing twisting, repetitive movements, and abnormal postures. Most DYT1 patients have a heterozygous trinucleotide GAG deletion mutation (ΔGAG) in DYT1/TOR1A, coding for torsinA. Dyt1 heterozygous ΔGAG knock-in (KI) mice show motor deficits and reduced striatal dopamine receptor 2 (D2R). Striatal cholinergic interneurons (ChIs) are essential in regulating striatal motor circuits. Multiple dystonia rodent models, including KI mice, show altered ChI firing and modulation. However, due to the errors in assigning KI mice, it is essential to replicate these findings in genetically confirmed KI mice. Here, we found irregular and decreased spontaneous firing frequency in the acute brain slices from Dyt1 KI mice. Quinpirole, a D2R agonist, showed less inhibitory effect on the spontaneous ChI firing in Dyt1 KI mice, suggesting decreased D2R function on the striatal ChIs. On the other hand, a muscarinic receptor agonist, muscarine, inhibited the ChI firing in both wild-type (WT) and Dyt1 KI mice. Trihexyphenidyl, a muscarinic acetylcholine receptor M1 antagonist, had no significant effect on the firing. Moreover, the resting membrane property and functions of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, μ-opioid receptors, and large-conductance calcium-activated potassium (BK) channels were unaffected in Dyt1 KI mice. The results suggest that the irregular and low-frequency firing and decreased D2R function are the main alterations of striatal ChIs in Dyt1 KI mice. These results appear consistent with the reduced dopamine release and high striatal acetylcholine tone in the previous reports.

Animal models of DYT-TOR1A dystonia consistently demonstrate abnormalities of striatal cholinergic function, but the molecular pathways underlying this pathophysiology are unclear. To probe these molecular pathways in a genetic model of DYT-TOR1A, we performed laser microdissection in juvenile mice to isolate striatal cholinergic interneurons and non-cholinergic striatal tissue largely comprising spiny projection neurons during maturation. Both cholinergic and GABAergic enriched samples demonstrated a defined set of gene expression changes consistent with a role of torsinA in the secretory pathway. GABAergic enriched striatum samples also showed alteration to genes regulating synaptic transmission and an upregulation of activity dependent immediate early genes. Reconstruction of Golgi-Cox stained striatal spiny projection neurons from adult mice demonstrated significantly increased spiny density, suggesting that torsinA null striatal neurons have increased excitability during striatal maturation and long lasting increases in afferent input. These findings are consistent with a developmental role for torsinA in the secretory pathway and link torsinA loss of function with functional and structural changes of striatal cholinergic and GABAergic neurons. These transcriptomic datasets are freely available as a resource for future studies of torsinA loss of function-mediated striatal dysfunction.

Objective: Blepharospasm is a type of dystonia where the diagnosis is often delayed because its varied clinical manifestations are not well recognized. The purpose of this study was to provide a comprehensive picture of its clinical features including presenting features, motor features, and non-motor features.

Methods: This was a two-part study. The first part involved a systematic literature review that summarized clinical features for 10,324 cases taken from 41 prior reports. The second part involved a summary of clinical features for 884 cases enrolled in a large multicenter cohort collected by the Dystonia Coalition investigators, along with an analysis of the factors that contribute to the spread of dystonia beyond the periocular region.

Results: For cases in the literature and the Dystonia Coalition, blepharospasm emerged in the 50s and was more frequent in women. Many presented with non-specific motor symptoms such as increased blinking (51.9%) or non-motor sensory features such as eye soreness or pain (38.7%), photophobia (35.5%), or dry eyes (10.7%). Non-motor psychiatric features were also common including anxiety disorders (34-40%) and depression (21-24%). Among cases presenting with blepharospasm in the Dystonia Coalition cohort, 61% experienced spread of dystonia to other regions, most commonly the oromandibular region and neck. Features associated with spread included severity of blepharospasm, family history of dystonia, depression, and anxiety.

Conclusions: This study provides a comprehensive summary of motor and non-motor features of blepharospasm, along with novel insights into factors that may be responsible for its poor diagnostic recognition and natural history.

Converging evidence from structural imaging studies in patients, the function of dystonia-causing genes, and the comorbidity of neuronal and behavioral defects all suggest that pediatric-onset dystonia is a neurodevelopmental disorder. However, to fully appreciate the contribution of altered development to dystonia, a mechanistic understanding of how networks become dysfunctional is required for early-onset dystonia. One current hurdle is that many dystonia animal models are ideally suited for studying adult phenotypes, as the neurodevelopmental features can be subtle or are complicated by broad developmental deficits. Furthermore, most assays that are used to measure dystonia are not suited for developing postnatal mice. Here, we characterize the early-onset dystonia in Ptf1a ^Cre ;Vglut2 ^fl/fl mice, which is caused by the absence of neurotransmission from inferior olive neurons onto cerebellar Purkinje cells. We investigate motor control with two paradigms that examine how altered neural function impacts key neurodevelopmental milestones seen in postnatal pups (postnatal day 7-11). We find that Ptf1a ^Cre ;Vglut2 ^fl/fl mice have poor performance on the negative geotaxis assay and the surface righting reflex. Interestingly, we also find that Ptf1a ^Cre ;Vglut2 ^fl/fl mice make fewer ultrasonic calls when socially isolated from their nests. Ultrasonic calls are often impaired in rodent models of autism spectrum disorders, a condition that can be comorbid with dystonia. Together, we show that these assays can serve as useful quantitative tools for investigating how neural dysfunction during development influences neonatal behaviors in a dystonia mouse model. Our data implicate a shared cerebellar circuit mechanism underlying dystonia-related motor signs and social impairments in mice.

Introduction: A common view is that head tremor (HT) in cervical dystonia (CD) decreases when the head assumes an unopposed dystonic posture and increases when the head is held at midline. However, this has not been examined with objective measures in a large, multicenter cohort.

Methods: For 80 participants with CD and HT, we analyzed videos from examination segments in which participants were instructed to 1) let their head drift to its most comfortable position (null point) and then 2) hold their head straight at midline. We used our previously developed Computational Motor Objective Rater (CMOR) to quantify changes in severity, amplitude, and frequency between the two postures.

Results: Although up to 9% of participants had exacerbated HT in midline, across the whole cohort, paired t-tests reveal no significant changes in overall severity (t = -0.23, p = 0.81), amplitude (t = -0.80, p = 0.43), and frequency (t = 1.48, p = 0.14) between the two postures.

Conclusions: When instructed to first let their head drift to its null point and then to hold their head straight at midline, most patient's changes in HT were below the thresholds one would expect from the sensitivity of clinical rating scales. Counter to common clinical impression, CMOR objectively showed that HT does not consistently increase at midline posture in comparison to the null posture.