Myoclonus-dystonia (DYT11, DYT-SGCE) — a channelopathy?

Introduction. Kaczyńska et al. reported a family with myoclonus-dystonia (M-D) caused by a truncating SGCE mutation, in which two members had epilepsy. Further, patients had mild psychiatric and developmental deficits.Clinical reflections. Characteristic motor features of M-D include myoclonus, dystonia and tremor. A wide range of additional disease manifestations are known. A few patients with M-D have seizures.Clinical implications. Altered neuronal excitability has been found in the pathogenesis of M-D. This may explain the partial effectiveness of antiepileptics and a lower seizure threshold, and could encourage trials of other membrane stabilisers. Careful clinical observations of seemingly well-known diseases remain important

Development and testing of a self administered version of the Freezing of Gait Questionnaire

Background: The Freezing of Gait Questionnaire (FOGQ) was developed in response to the difficulties of observing and quantifying freezing of gait (FOG) clinically as well as in laboratory settings. However, as the FOGQ is a clinician-administered patient-reported rating scale it cannot be used in postal surveys. Here we report the development and measurement properties of a self-administered version of the FOGQ (FOGQsa). Methods: A clinical sample and a postal survey sample of non-demented people with Parkinson's disease (PD; total n = 225) completed the FOGQsa and questionnaires concerning physical functioning (PF) and fall-related self efficacy (FES). Additional questions (No/Yes) regarded previous falls and whether they were afraid of falling. The clinical sample was also assessed with the Unified PD Rating Scale (UPDRS). Thirty-five participants completed FOGQsa and were also assessed with the original version (FOGQ) in a clinical interview. Results: There were no differences (P = 0.12) between FOGQ (median, 10; q1-q3, 2-14) and FOGQsa (median, 8; 214) scores. The Spearman (r(s)) and intra-class correlations between the two were 0.92 and 0.91 (95% CI, 0.82-0.95), respectively. For FOGQsa, corrected item-total correlations ranged between 0.68-0.89. Reliability was 0.93 (95% CI, 0.91-0.94). FOGQsa scores correlated strongest with UPDRS Item 14 (Freezing; r(s), 0.76) and with FES (r(s), -0.74). The weakest correlation was found with age (r(s), 0.14). Fallers scored significantly (p < 0.001) higher on FOGQsa compared to non-fallers, median scores 8 (q1-q3, 4-14) versus 2 (0-7). Those expressing a fear of falling scored higher (p < 0.001) than those who did not, median scores 2 (0-7) versus 6 (2-14). Conclusions: The present findings indicate that the FOGQsa is as reliable and valid as the original interview administered FOGQ version. This has important clinical implications when investigating FOG in large scale studies

Eltoprazine counteracts l-DOPA-induced dyskinesias in Parkinson's disease:A dose-finding study

In advanced stages of Parkinson's disease, serotonergic terminals take up l-DOPA and convert it to dopamine. Abnormally released dopamine may participate in the development of l-DOPA-induced dyskinesias. Simultaneous activation of 5-HT1A and 5-HT1B receptors effectively blocks l-DOPA-induced dyskinesias in animal models of dopamine depletion, justifying a clinical study with eltoprazine, a 5-HT1A/B receptor agonist, against l-DOPA-induced dyskinesias in patients with Parkinson's disease. A double-blind, randomized, placebo-controlled and dose-finding phase I/IIa study was conducted. Single oral treatment with placebo or eltoprazine, at 2.5, 5 and 7.5 mg, was tested in combination with a suprathreshold dose of l-DOPA (Sinemet®) in 22 patients with Parkinson's disease (16 male/six female; 66.6 ± 8.8 years old) with l-DOPA-induced dyskinesias. A Wilcoxon Signed Ranked Test was used to compare each eltoprazine dose level to paired randomized placebo on the prespecified primary efficacy variables; area under the curve scores on Clinical Dyskinesia Rating Scale for 3 h post-dose and maximum change of Unified Parkinson's Disease Rating Scale part III for 3 h post-dose. Secondary objectives included effects on maximum Clinical Dyskinesia Rating Scale score, area under the curve of Rush Dyskinesia Rating Scale score for 3 h post-dose, mood parameters measured by Hospital Anxiety Depression Scale and Montgomery Asberg Depression Rating Scale along with the pharmacokinetics, safety and tolerability profile of eltoprazine. A mixed model repeated measures was used for post hoc analyses of the area under the curve and peak Clinical Dyskinesia Rating Scale scores. It was found that serum concentrations of eltoprazine increased in a dose-proportional manner. Following levodopa challenge, 5 mg eltoprazine caused a significant reduction of l-DOPA-induced dyskinesias on area under the curves of Clinical Dyskinesia Rating Scale [-1.02(1.49); P = 0.004] and Rush Dyskinesia Rating Scale [-0.15(0.23); P = 0.003]; and maximum Clinical Dyskinesia Rating Scale score [-1.14(1.59); P = 0.005]. The post hoc analysis confirmed these results and also showed an antidyskinetic effect of 7.5 mg eltoprazine. Unified Parkinson's Disease Rating Scale part III scores did not differ between the placebo and eltoprazine treatments. The most frequent adverse effects after eltoprazine were nausea and dizziness. It can be concluded that a single dose, oral treatment with eltoprazine has beneficial antidyskinetic effects without altering normal motor responses to l-DOPA. All doses of eltoprazine were well tolerated, with no major adverse effects. Eltoprazine has a favourable risk-benefit and pharmacokinetic profile in patients with Parkinson's disease. The data support further clinical studies with chronic oral eltoprazine to treat l-DOPA-induced-dyskinesias

Memantine and reduced time with dyskinesia in Parkinson's Disease.

The partial glutamate antagonist amantadine is currently used in clinical practice, to reduce dyskinesia developing as a side-effect of levodopa treatment in patients suffering from Parkinson's disease (PD). This study was aimed at evaluating the antidyskinetic effect of another glutamate antagonist, memantine

Myoclonus-dystonia (DYT11, DYT-SGCE) - a channelopathy?

INTRODUCTION: Kaczyńska et al. reported a family with myoclonus-dystonia (M-D) caused by a truncating SGCE mutation, in which two members had epilepsy. Further, patients had mild psychiatric and developmental deficits. CLINICAL REFLECTIONS: Characteristic motor features of M-D include myoclonus, dystonia and tremor. A wide range of additional disease manifestations are known. A few patients with M-D have seizures. CLINICAL IMPLICATIONS: Altered neuronal excitability has been found in the pathogenesis of M-D. This may explain the partial effectiveness of antiepileptics and a lower seizure threshold, and could encourage trials of other membrane stabilisers. Careful clinical observations of seemingly well-known diseases remain important

Neuronal and glial differentiation within expanded glial cultures derived from the lateral and medial ganglionic eminences.

Attached glial-like cell cultures were established from the lateral and medial ganglionic eminences (LGE and MGE) and from the neocortex (Cx) of E13.5 mouse embryos, and expanded over four to five passages under epidermal growth factor (EGF) stimulation. Following removal of EGF and serum, we analysed the generation of neurons and glial cells within the cultures. Significant numbers of βIII-tubulin-positive neurons were generated in both the LGE (about 7% of total cell numbers) and the MGE (around 2%). However, only few βIII-tubulin-positive cells with neuronal morphologies were detected in the differentiated Cx cultures. The newly formed neurons were to a large extent GABAergic, and many of the MGE-derived, but not the LGE-derived, cells expressed the MGE-marker NKX2.1. Most cells in all cultures still appeared astroglial-like, expressing glial fibrillary acidic protein (GFAP), but in addition, CNPase-positive cells with oligodendroglial morphologies were present in the MGE (0.68%), and, to a lesser extent (0.2%), in the LGE cultures. The present results demonstrate that cells of expanded glial cultures from both the LGE and MGE can give rise to significant and, to a certain extent, region-specific neuronal and glial cell types under differentiating conditions

Ex vivo and in vitro studies of transgene expression in rat astrocytes transduced with lentiviral vectors.

Implantation of cells genetically modified to express therapeutic genes into the brain has been proposed as a potential treatment for neurodegenerative diseases. In the current study embryonic rat-derived astrocytes were cultured and transduced with a lentiviral vector expressing the reporter gene green fluorescent protein (GFP) and subsequently grafted into the adult rat brain. The proportion of GFP expressing cells was stable, albeit small (1%), at all survival times, up to 6 weeks, the longest time point studied. In parallel in vitro studies, the astrocytes were lentivirally transduced to express either one of the two isoforms of glutamate decarboxylase (GAD(65) or GAD(67)) or glial cell line-derived neurotrophic factor (GDNF). When transducing 293T cells with the two GAD vectors, released GABA could be measured using high-performance liquid chromatography. Further studies of rat astrocytes transduced with the same vectors resulted in a level of GAD activity about 10 times higher than the activity of an intact rat striatum. One hundred thousand astrocytes transduced with LV-GDNF released approximately 27 ng of GDNF per hour. Thus, taken together, our observations provide support for the use of rat astrocytes in ex vivo gene transfer of these proteins in animal models of CNS disorders, e.g., Parkinson's disease or epilepsy

Neuronal differentiation following transplantation of expanded mouse neurosphere cultures derived from different embryonic forebrain regions.

In vitro, expanded neurospheres exhibit multipotent properties and can differentiate into neurons, astrocytes and oligodendrocytes. In vivo, cells from neurospheres derived from mouse fetal forebrain have previously been reported to predominantly differentiate into glial cells, and not into neurons. Here we isolated stem/progenitor cells from E13.5 lateral ganglionic eminence (LGE), medial ganglionic eminence (MGE) and cortical primordium, of a green fluorescent protein (GFP)-actin transgenic mouse. Free-floating neurospheres were expanded in the presence of epidermal growth factor (EGF) and basic fibroblast growth factor (bFGF) and implanted after five to six passages into the striatum, hippocampus and cortex of neonatal rats. Cell suspensions of primary LGE tissue were prepared and grafted in parallel. Grafted cells derived from the primary tissue displayed widespread incorporation into all regions, as visualized with the mouse-specific antibody M2, or mouse satellite DNA in situ hybridization, and differentiated into both neurons, astrocytes and oligodendrocytes. Grafts of neurosphere cells derived from the LGE, MGE and cortical primordium differentiated primarily into astrocytes, but contained low but significant numbers of GFP-immunoreactive neurons. Neurons derived from LGE neurospheres were of three types: cells with the morphology of medium-sized densely spiny projection neurons in the striatum; cells with interneuron-like morphologies in striatum, cortex and hippocampus; and cells integrating into SVZ and migrating along the RMS to the olfactory bulb. MGE- or cortical primordium-derived neurospheres differentiated into interneuron-like cells in both striatum and hippocampus. The results demonstrate the ability of in vitro expanded neural stem/progenitor cells to generate both neurons and glia after transplantation into neonatal recipients, and differentiate in a region-specific manner into mature neurons with morphological features characteristic for each target site