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Opn7b is a non-visual G protein-coupled receptor expressed in zebrafish. Here we find that Opn7b expressed in HEK cells constitutively activates the G i/o pathway and illumination with blue/green light inactivates G protein-coupled inwardly rectifying potassium channels. This suggests that light acts as an inverse agonist for Opn7b and can be used as an optogenetic tool to inhibit neuronal networks in the dark and interrupt constitutive inhibition in the light. Consistent with this prediction, illumination of recombinant expressed Opn7b in cortical pyramidal cells results in increased neuronal activity. In awake mice, light stimulation of Opn7b expressed in pyramidal cells of somatosensory cortex reliably induces generalized epileptiform activity within a short (<10 s) delay after onset of stimulation. Our study demonstrates a reversed mechanism for G protein-coupled receptor control and Opn7b as a tool for controlling neural circuit properties. Microbial rhodopsins can be used to control action potentials, while animal opsins can be used to control intracellular signaling pathways. The authors identify Opn7b as constitutively active G i/o coupled receptor that can be deactivated by light and used to modulate neuronal activity.

IntroductionMoyamoya angiopathy (MMA) is a rare vasopathy, especially among European Caucasians. Data about demographics, clinical presentation, comorbid conditions, radiological findings as well as laboratory and cerebral spinal fluid (CSF) data are sparse.MethodsPatients with MMA treated in the Alfried Krupp Hospital, Essen, Germany, between 2010 and 2017 with focus on demographic, clinical, radiological and laboratory as well as CSF data were evaluated retrospectively. Patients with non-Caucasian family background were excluded from this study.ResultsAltogether 200 European Caucasian patients with MMA were identified. There was a female predominance of 3.2:1. The mean age at first presentation was 32.9 years and the mean age of diagnosis was 36.0 years. Eleven of 194 index patients (5.7%) showed a familial presentation. In 11.6% posterior cerebral artery was additionally involved, in 4% additionally cerebral aneurysm and in 2.5% dysgenesis of corpus callosum was found. Most patients suffered from transient ischemic attacks (71.5%) and stroke (82%). Cerebral hemorrhage was found in 9.5%. Livedo racemosa was an associated symptom in 12.8% of patients and thyroid diseases were found in 23.8%.ConclusionsCompared with Asian data, cerebral hemorrhages are infrequent and female predominance is accentuated among European Caucasians. Some former unknown rare features like associated livedo racemosa, dysgenesis of corpus callosum and associated syncope have been discovered systematically for the first time in this huge European Caucasian cohort.

BackgroundThe lacking awareness of healthcare providers bears the risk of delayed or false diagnoses in rare diseases. No systematic data about misdiagnoses of Moyamoya angiopathy (MMA) are available.ObjectiveTo evaluate the rate and pattern of missed diagnoses in MMA.MethodsRetrospective analysis of a consecutive case series from a single German referral center. Rates of missed or delayed diagnoses in Caucasian MMA patients were calculated based on discharge letters from other hospitals and systematic chart review.ResultsOut of 192 Caucasian patients eventually diagnosed with MMA at our center, an initial misdiagnosis was identified in 119 patients (62%). The time between onset and diagnosis was 1 year in 24 patients, 2 years in 23 patients, 3 years in 10 patients, and > 3 years in 49 patients (mean 5.28, median 3, standard deviation 5.11, and range 4–26 years). The most common misdiagnoses were cerebral vasculitis (31%), etiologically ill-defined stroke diagnoses (30.2%), and MS (3.6%).ConclusionsThis is the first systematic report which shows that patients with MMA are at high risk to be falsely diagnosed and treated. Depiction of typical vascular abnormalities in angiopathy is essential. Normal CSF cell counts, negative oligoclonal bands, and lack of infratentorial lesions as well as gadolinium-positive T1 lesions on MRI may be red flags differentiating this vasculopathy from vasculitis and MS.

•High incidence of movement disorder symptoms in MMA.•Direct bypass surgery can be used effectively to treat involuntary movements.•MMA should be considered in the differential diagnosis of movement symptoms. Movement disorders are a rare manifestation of Moyamoya angiopathy (MMA). Data on prevalence and clinical presentation are warranted. Possible involuntary movements include focal motor seizures, tremor, limb-shaking transient ischemic attacks, choreiform and spastic or dystonic movement disorders. We developed a questionnaire to systematically assess movement disorders in MMA. Patients’ history of involuntary movements and their clinical presentation were assessed systematically by interview. Additionally, demographic data were assessed as well as localization of movements, possible trigger factors and the presence of other symptoms. The questionnaire was administered to 63 European patients with MMA. The response rate was high with 93.6% participating patients. Twenty-eight patients (47.4%) reported involuntary movement disorders including periodic tremor, irregular jerks, involuntary movements with loopy or pranced character, stiffness and muscle cramps. From those patients, 16 (57.1%) individuals had the symptoms prior to the diagnosis of MMA. The most common involuntary movements were irregular jerks witnessed by 17 (60.7%) patients, followed by stiffness and muscle cramps in 10 (35.7%). Eight (28.6%) Patients suffered from unintended loopy and pranced character, while 4 individuals (14.3%) remembered periodic tremor. Of the 28 patients who witnessed movement disorders, 23 had undergone revascularization surgery (82.1%). From the latter subgroup, movement disorders were reversed in 7 out of 12 patients (58.3%) with irregular jerks and 4 out of 7 patients (57.1%) with unintended loopy and pranced character. Our study elucidates the high incidence of movement disorders in an unselected consecutively recruited cohort of European MMA patients.

BackgroundDespite the consensus on the necessity of revascularizing surgery in Moyamoya angiopathy in Asia, the indication in Caucasian Moyamoya patients is discussed controversially.ObjectiveThe safety of revascularizing surgery in Europe should be clarified.MethodsThis study retrospectively analyzed the rate of complications as well as clinical symptoms within the first 3 months after bypass surgery between superficial temporal artery and middle cerebral artery (STA–MCA).Results64 direct bypass procedures in 45 patients (95.5% Caucasians) were analyzed. The magnetic resonance imaging at day 6 showed subdural hematoma in 60.3%. The mean diameter of these hematomas on magnetic resonance imaging was 5.1 mm (SD 3.4 mm) and increased in 25% at follow-up. No difference was found between those patients with early (day 1) or late (day 7) restarts of antiplatelet therapy. Magnetic resonance imaging at day 6 revealed hyperperfusion syndrome after six of 64 procedures (9.3%). Three of these six had clinical symptoms; two-thirds were transient within seconds. Magnetic resonance imaging depicted stroke after seven procedures (10.9%). Five of these seven patients had no new symptoms. Altogether, after ten procedures (15%), patients complained about clinical symptoms. These were all transient. No new transient ischemic attacks occurred during the 3 month follow-up and no new lesions were detected in magnetic resonance imaging. Only two patients underwent surgery for asymptomatic subdural hematoma. All other subdural hematomas resolved spontaneously.ConclusionRevasculating surgery is a safe procedure in Caucasian patients with Moyamoya angiopathy. The observed complications have a good prognosis.

•In the PCNSV group, only the HLA-A*69 variant was found more often than expected statistically.•No other HLA associations were found.•The results of this study indicate a potential association of HLA marker with PCNSV in European patients. The etiology and genetic susceptibility of primary central nervous system vasculitis (PCNSV) are still unclear. We analyzed the DNA of 25 Caucasian patients with PCNSV for human leucocyte antigen genes HLA-A, HLA-B, HLA-DRB1, and HLA-DQB1, respectively. HLA-frequencies of the 25 patients with PCNSV were compared with HLA-frequencies of matched Caucasian controls. No statistically significant associations were found for HLA-B, HLA-DR1 and HLA-DQB1 variant. In the PCNSV group, only the HLA-A*69 variant was found more often than expected statistically. The results of this study indicate a potential association of HLA marker with PCNSV in Caucasian patients. Further studies are needed to elucidate the role of genes within the human major histocompatibility complex in the pathogenesis of this angiopathy.

Moyamoya angiopathy is a progressive cerebral vasculopathy. The p.R4810K substitution in RNF213 has previously been linked to moyamoya disease in Asian populations. When associated with other medical conditions, such as neurofibromatosis type 1, this vasculopathy is frequently reported as moyamoya syndrome. Intriguingly, most cases of moyamoya-complicated neurofibromatosis type 1 have been described in Caucasians, inverting the population ratio observed in Asians, although prevalence of neurofibromatosis type 1 is constant worldwide. Our aim was to investigate whether, among Caucasians, additive genetic factors may contribute to the occurrence of moyamoya in neurofibromatosis type 1. Whole exome sequencing was carried out on an Italian family with moyamoya-complicated neurofibromatosis type 1 to identify putative genetic modifiers independent of the NF1 locus and potentially involved in moyamoya pathogenesis. Results were validated in an unrelated family of German ancestry. We identified the p.P186S substitution (rs35857561) in MRVI1 that segregated with moyamoya syndrome in both the Italian and German family. The rs35857561 polymorphism in MRVI1 may be a genetic susceptibility factor for moyamoya in European patients with neurofibromatosis type 1. MRVI1 is a functional partner of ITPR1, PRKG1 and GUCY1A3, which are involved in response to nitric oxide. Mutations in GUCY1A3 have been recently linked to a recessive syndromic form of moyamoya with esophageal achalasia.

Moyamoya angiopathy (MMA) is a cerebral angiopathy affecting the terminal part of internal carotid arteries. Its prevalence is 10 times higher in Japan and Korea than in Europe. In East Asian countries, moyamoya is strongly associated to the R4810K variant in the RNF213 gene that encodes for a protein containing a RING-finger and two AAA+ domains. This variant has never been detected in Caucasian MMA patients, but several rare RNF213 variants have been reported in Caucasian cases. Using a collapsing test based on exome data from 68 European MMA probands and 573 ethnically matched controls, we showed a significant association between rare missense RNF213 variants and MMA in European patients (odds ratio (OR)=2.24, 95% confidence interval (CI)=(1.19-4.11), P=0.01). Variants specific to cases had higher pathogenicity predictive scores (median of 24.2 in cases versus 9.4 in controls, P=0.029) and preferentially clustered in a C-terminal hotspot encompassing the RING-finger domain of RNF213 (P<10 ). This association was even stronger when restricting the analysis to childhood-onset and familial cases (OR=4.54, 95% CI=(1.80-11.34), P=1.1 × 10 ). All clinically affected relatives who were genotyped were carriers. However, the need for additional factors to develop MMA is strongly suggested by the fact that only 25% of mutation carrier relatives were clinically affected.

Background Moyamoya disease (MMD) is a rare disorder causing ischemic and hemorrhagic juvenile stroke. It is associated with the founder susceptibility variant p.R4810K in the RNF213 gene in East Asia. Our aim was to enhance understanding of MMD in so far poorly characterized Southeast Asians and exploring differences with Caucasian Europeans. Methods By retrospective analysis of medical records and systematic database search on PubMed for all published cases, we identified Southeast Asian patients with MMD. We extracted and pooled proportions using fixed-effects models. Our own cohort was tested for the East Asian RNF213 founder variant p.R4810K. One of our Southeast Asian patients underwent post-mortem histopathological examination. Results The study cohort comprised 32 Southeast Asians. Mean age at onset in the entire cohort was 32.5 ± 20.3 years ( n  = 24), 43.4 ± 8.7 years in patients admitted to our center ( n  = 11), and 23.4 ± 22.4 years in patients from the international literature ( n  = 13). Female-to-male ratio was 1.6:1. MMD predominantly affected bilateral anterior intracranial vessels. Cerebral ischemia outnumbered transient ischemic attacks (TIAs) and intracranial hemorrhage. TIAs, arterial hypertension and obesity were significantly less frequent in Southeast Asian patients compared to Caucasian Europeans. p.R4810K was absent in all examined Southeast Asians despite of typical histopathological signs of MMD in one autopsy case. Conclusion Clinical and histopathological manifestations of MMD in Southeast Asians are similar to those in Caucasian Europeans. The genotype of MMD in Southeast Asians differs from that of most East Asian patients.

Absence seizures (ASs) are characterized by pathological electrographic oscillations in the cerebral cortex and thalamus, which are called spike-and-wave discharges (SWDs). Subcortical structures, such as the cerebellum, may well contribute to the emergence of ASs, but the cellular and molecular underpinnings remain poorly understood. Here we show that the genetic ablation of P/Q-type calcium channels in cerebellar granule cells (quirky) or Purkinje cells (purky) leads to recurrent SWDs with the purky model showing the more severe phenotype. The quirky mouse model showed irregular action potential firing of their cerebellar nuclei (CN) neurons as well as rhythmic firing during the wave of their SWDs. The purky model also showed irregular CN firing, in addition to a reduced firing rate and rhythmicity during the spike of the SWDs. In both models, the incidence of SWDs could be decreased by increasing CN activity via activation of the G q -coupled designer receptor exclusively activated by designer drugs (DREADDs) or via that of the G q -coupled metabotropic glutamate receptor 1. In contrast, the incidence of SWDs was increased by decreasing CN activity via activation of the inhibitory G i/o -coupled DREADD. Finally, disrupting CN rhythmic firing with a closed-loop channelrhodopsin-2 stimulation protocol confirmed that ongoing SWDs can be ceased by activating CN neurons. Together, our data highlight that P/Q-type calcium channels in cerebellar granule cells and Purkinje cells can be relevant for epileptogenesis, that G q -coupled activation of CN neurons can exert anti-epileptic effects and that precisely timed activation of the CN can be used to stop ongoing SWDs.