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Individuals with ultrarare disorders pose a structural challenge for healthcare systems since expert clinical knowledge is required to establish diagnoses. In TRANSLATE NAMSE, a 3-year prospective study, we evaluated a novel diagnostic concept based on multidisciplinary expertise in Germany. Here we present the systematic investigation of the phenotypic and molecular genetic data of 1,577 patients who had undergone exome sequencing and were partially analyzed with next-generation phenotyping approaches. Molecular genetic diagnoses were established in 32% of the patients totaling 370 distinct molecular genetic causes, most with prevalence below 1:50,000. During the diagnostic process, 34 novel and 23 candidate genotype-phenotype associations were identified, mainly in individuals with neurodevelopmental disorders. Sequencing data of the subcohort that consented to computer-assisted analysis of their facial images with GestaltMatcher could be prioritized more efficiently compared with approaches based solely on clinical features and molecular scores. Our study demonstrates the synergy of using next-generation sequencing and phenotyping for diagnosing ultrarare diseases in routine healthcare and discovering novel etiologies by multidisciplinary teams., (© 2024. The Author(s).)

Background: In basilar artery occlusion stroke, the impact of the collateral circulation on infarct progression in the context of endovascular treatment is yet poorly studied., Aim: This study investigates the impact of the posterior circulation collateral score (PCCS) on functional outcome according to the extent of early ischemic changes and treatment. We hypothesized that the presence of collaterals, quantified by the PCCS, mediates the effect of endovascular treatment on functional outcome in patients with acute basilar artery occlusion., Methods: In this multicenter observational study, patients with basilar artery occlusion and admission computed tomography were analyzed. At baseline, Posterior circulation Acute Stroke Prognosis Early Computed Tomography score (pcASPECTS) was assessed and PCCS was quantified using an established 10-point grading system. Logistic regression analyses were performed to identify factors associated with good functional outcome (modified Rankin Scale scores 0-2 at day 90)., Results: A total of 151 patients were included, of which 112 patients (74%) underwent endovascular treatment. In patients with a better PCCS (>5), the rate of good outcome was significantly higher (55% vs. 11%; p = 0.001). After adjusting for PCCS, vessel recanalization was significantly associated with improved functional outcome (aOR: 4.53, 95%CI: 1.25-16.4, p = 0.02), while there was no association between recanalization status and outcome in univariable analysis. Patients with low pcASPECTS generally showed very poor outcomes (mean modified Rankin Scale score 5.3, 95%CI: 4.9-5.8)., Conclusion: PCCS modified the effect of recanalization on functional outcome, particularly in patients with less pronounced ischemic changes in admission computed tomography. These results should be validated to improve patient selection for endovascular treatment in basilar artery occlusion, particularly in uncertain indications, or to triage patients at risk for very poor outcomes.

Purpose: Evidence regarding the effect of mechanical thrombectomy (MT) of basilar artery occlusion (BAO) stroke is yet sparse. As successful recanalization has been suggested as major determinant of outcome, the early identification of modifiable factors associated with successful recanalization could be of importance to improve functional outcome. Hyperglycemia has been associated with enhanced thrombin generation and unfavorably altered clot features., Objective: We hypothesized that serum baseline glucose is associated with likelihood of vessel recanalization mediated by collateral quality and clot burden in BAO stroke., Methods: BAO stroke patients who received multimodal CT on admission were analyzed. The association of vessel recanalization defined using modified Thrombolysis in cerebral infarction scale (mTICI) scores 2b-3, and baseline imaging and clinical parameters were tested in logistic regression analyses. Collateral quality and clot burden were evaluated using the Basilar Artery on CT-Angiography (BATMAN) score., Results: Out of 117 BAO patients, 91 patients (78%) underwent MT. In 70 patients (77%), successful recanalization could be achieved (mTICI 2b/3). In multivariable logistic regression analysis, only a higher BGL (aOR 0.97, 95% CI 0.96-0.99, p = 0.03) and higher BATMAN score (aOR 1.77, 95% CI 1.11-2.82, p = 0.02) were independently associated with vessel recanalization. Application of alteplase, or time from symptom onset-imaging revealed no independent association with recanalization status., Conclusion: Higher BGL was significantly associated with reduced likelihood for recanalization success besides BATMAN score as a measure of collateral quality and clot burden. BGL could be tested as a modifiable parameter to increase likelihood for recanalization in BAO stroke, aiming to improve functional outcome., (© 2022. The Author(s).)

A categorical approach to the study of amygdala volumes in specific neuropsychiatric disorders leads to contradictory findings. In an alternative dimensional approach, we tested the hypothesis that amygdala volume loss represents specific dimensions of affective syndromes in patients with epilepsy. One hundred sixty patients with chronic therapy-refractory epilepsy were carefully diagnosed for psychiatric symptoms. Fifty-three patients without any lifetime psychopathology (n=24), with dysphoric disorder of epilepsy (n=12), or with major depressive disorder (n=17) were included. Amygdala and hippocampal volumes were measured using established protocols. Amygdala volumes were significantly reduced in patients with dysphoric disorder of epilepsy and correlated significantly with core symptoms of dysphoric disorder of epilepsy, that is, emotional instability, dysphoria, irritability, and aggression. Our finding supports a dimensional concept of the meaning of brain alterations and validates the clinical concept of dysphoric disorder of epilepsy.