TY - JOUR A1 - Vitale, Maria Rosaria A1 - Zöller, Johanna Eva Maria A1 - Jansch, Charline A1 - Janz, Anna A1 - Edenhofer, Frank A1 - Klopocki, Eva A1 - van den Hove, Daniel A1 - Vanmierlo, Tim A1 - Rivero, Olga A1 - Kasri, Nael Nadif A1 - Ziegler, Georg Christoph A1 - Lesch, Klaus-Peter T1 - Generation of induced pluripotent stem cell (iPSC) lines carrying a heterozygous (UKWMPi002-A-1) and null mutant knockout (UKWMPi002-A-2) of Cadherin 13 associated with neurodevelopmental disorders using CRISPR/Cas9 JF - Stem Cell Research N2 - Fibroblasts isolated from a skin biopsy of a healthy 46-year-old female were infected with Sendai virus containing the Yamanaka factors to produce transgene-free human induced pluripotent stem cells (iPSCs). CRISPR/Cas9 was used to generate isogenic cell lines with a gene dose-dependent deficiency of CDH13, a risk gene associated with neurodevelopmental and psychiatric disorders. Thereby, a heterozygous CDH13 knockout (CDH13\(^{+/-}\)) and a CDH13 null mutant (CDH13\(^{-/-}\)) iPSC line was obtained. All three lines showed expression of pluripotency-associated markers, the ability to differentiate into cells of the three germ layers in vitro, and a normal female karyotype. KW - CRISPR-Cas Systems KW - cadherins KW - female KW - heterozygote KW - humans KW - Induced Pluripotent Stem Cells KW - middle aged KW - neurodevelopmental disorders / genetics Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-260331 VL - 51 ER - TY - JOUR A1 - Köping, Maria A1 - Shehata-Dieler, Wafaa A1 - Cebulla, Mario A1 - Rak, Kristen A1 - Oder, Daniel A1 - Müntze, Jonas A1 - Nordbeck, Peter A1 - Wanner, Christoph A1 - Hagen, Rudolf A1 - Schraven, Sebastian T1 - Cardiac and renal dysfunction is associated with progressive hearing loss in patients with Fabry disease JF - PLoS ONE N2 - Background Fabry disease (FD) is an X-linked recessive hereditary lysosomal storage disorder which results in the accumulation of globotriaosylceramid (Gb3) in tissues of kidney and heart as well as central and peripheral nervous system. Besides prominent renal and cardiac organ involvement, cochlear symptoms like high-frequency hearing loss and tinnitus are frequently found with yet no comprehensive data available in the literature. Objective To examine hearing loss in patients with FD depending on cardiac and renal function. Material and methods Single-center study with 68 FD patients enrolled between 2012 and 2016 at the Department of Oto-Rhino-Laryngology, Plastic, Aesthetic and Reconstructive Head and Neck Surgery of the University of Würzburg. Every subject underwent an oto-rhino-laryngological examination as well as behavioral, electrophysiological and electroacoustical audiological testing. High-frequency thresholds were evaluated by using a modified PTA\(_{6}\) (0.5, 1, 2, 4, 6, 8) and HF-PTA (6, 8 kHz). Renal function was measured by eGFR, cardiac impairment was graduated by NYHA class. Results Sensorineural hearing loss was detected in 58.8% of the cohort, which occurred typically in sudden episodes and affected especially high frequencies. Hearing loss is asymmetric, beginning unilaterally and affecting the contralateral ear later. Tinnitus was reported by 41.2%. Renal and cardiac impairment influenced the severity of hearing loss (p < 0.05). Conclusions High frequency hearing loss is a common problem in patients with FD. Although not life-threatening, it can seriously reduce quality of life and should be taken into account in diagnosis and therapy. Optimized extensive hearing assessment including higher frequency thresholds should be used. KW - cardiac dysfunction KW - renal dysfunction KW - Fabry disease KW - hearing loss Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-169961 VL - 12 IS - 11 ER - TY - JOUR A1 - Schiele, Miriam A. A1 - Ziegler, Christiane A1 - Kollert, Leonie A1 - Katzorke, Andrea A1 - Schartner, Christoph A1 - Busch, Yasmin A1 - Gromer, Daniel A1 - Reif, Andreas A1 - Pauli, Paul A1 - Deckert, Jürgen A1 - Herrmann, Martin J. A1 - Domschke, Katharina T1 - Plasticity of Functional MAOA Gene Methylation in Acrophobia JF - International Journal of Neuropsychopharmacology N2 - Epigenetic mechanisms have been proposed to mediate fear extinction in animal models. Here, MAOA methylation was analyzed via direct sequencing of sodium bisulfite-treated DNA extracted from blood cells before and after a 2-week exposure therapy in a sample of n = 28 female patients with acrophobia as well as in n = 28 matched healthy female controls. Clinical response was measured using the Acrophobia Questionnaire and the Attitude Towards Heights Questionnaire. The functional relevance of altered MAOA methylation was investigated by luciferase-based reporter gene assays. MAOA methylation was found to be significantly decreased in patients with acrophobia compared with healthy controls. Furthermore, MAOA methylation levels were shown to significantly increase after treatment and correlate with treatment response as reflected by decreasing Acrophobia Questionnaire/Attitude Towards Heights Questionnaire scores. Functional analyses revealed decreased reporter gene activity in presence of methylated compared with unmethylated pCpGfree_MAOA reporter gene vector constructs. The present proof-of-concept psychotherapy-epigenetic study for the first time suggests functional MAOA methylation changes as a potential epigenetic correlate of treatment response in acrophobia and fosters further investigation into the notion of epigenetic mechanisms underlying fear extinction. KW - monoamine oxidase A KW - anxiety KW - extinction KW - epigenetics KW - DNA methylation Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-228571 VL - 21 IS - 9 ER - TY - JOUR A1 - Ortiz, Alberto A1 - Abiose, Ademola A1 - Bichet, Daniel G. A1 - Cabrera, Gustavo A1 - Charrow, Joel A1 - Germain, Dominique P. A1 - Hopkin, Robert J. A1 - Jovanovic, Ana A1 - Linhart, Aleš A1 - Maruti, Sonia S. A1 - Mauer, Michael A1 - Oliveira, João P. A1 - Patel, Manesh R. A1 - Politei, Juan A1 - Waldek, Stephen A1 - Wanner, Christoph A1 - Yoo, Han-Wook A1 - Warnock, David G. T1 - Time to treatment benefit for adult patients with Fabry disease receiving agalsidase beta: data from the Fabry Registry JF - Journal of Medical Genetics N2 - Background Agalsidase beta is a form of enzyme replacement therapy for Fabry disease, a genetic disorder characterised by low alpha-galactosidase A activity, accumulation of glycosphingolipids and life-threatening cardiovascular, renal and cerebrovascular events. In clinical trials, agalsidase beta cleared glycolipid deposits from endothelial cells within 6 months; clearance from other cell types required sustained treatment. We hypothesised that there might be a 'lag time' to clinical benefit after initiating agalsidase beta treatment, and analysed the incidence of severe clinical events over time in patients receiving agalsidase beta. Methods The incidence of severe clinical events (renal failure, cardiac events, stroke, death) was studied in 1044 adult patients (641 men, 403 women) enrolled in the Fabry Registry who received agalsidase beta (average dose 1 mg/kg every 2 weeks) for up to 5 years. Results The incidence of all severe clinical events was 111 per 1000 person-years (95% CI 84 to 145) during the first 6 months. After 6 months, the incidence decreased and remained stable within the range of 40-58 events per 1000 patient-years. The largest decrease in incidence rates was among male patients and those aged >= 40 years when agalsidase beta was initiated. Conclusions Contrary to the expected increased incidence of severe clinical events with time, adult patients with Fabry disease had decreased incidence of severe clinical events after 6 months treatment with agalsidase beta 1 mg/kg every 2 weeks. KW - Enzyme replacement therapy KW - Natural-history data KW - Racial differences KW - Outcome survey KW - Galactosidase-A gene KW - Alpha-Galactosidase KW - Kidney function KW - Lag time Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-188241 VL - 53 IS - 7 ER - TY - JOUR A1 - Grünwald, Viktor A1 - Pink, Daniel A1 - Egerer, Gerlinde A1 - Schalk, Enrico A1 - Augustin, Marinela A1 - Deinzer, Christoph K. W. A1 - Kob, Viola A1 - Reichert, Dietmar A1 - Kebenko, Maxim A1 - Brandl, Stephan A1 - Hahn, Dennis A1 - Lindner, Lars H. A1 - Hoiczyk, Mathias A1 - Ringsdorf, Uta A1 - Hanker, Lars C. A1 - Hempel, Dirk A1 - De Rivas, Beatriz A1 - Wismann, Tobias A1 - Ivanyi, Philipp T1 - Trabectedin for patients with advanced soft tissue sarcoma: a non-interventional, prospective, multicenter, phase IV trial JF - Cancers N2 - This non-interventional, prospective phase IV trial evaluated trabectedin in patients with soft tissue sarcoma (STS) in real-life clinical practice across Germany. The primary endpoints were progression-free survival (PFS) rates at 3 and 6 months, as defined by investigators. Overall, 128 patients from 19 German sites were evaluated for efficacy and 130 for safety. Median age was 58.5 years (range: 23–84) and leiomyosarcoma was the most frequent histotype (n = 45; 35.2%). Trabectedin was mostly used as second/third-line treatment (n = 91; 71.1%). Median PFS was 5.2 months (95% CI: 3.3–6.7), with 60.7% and 44.5% of patients free from progression at 3 and 6 months, respectively. Median overall survival was 15.2 months (95% CI: 9.6–21.4). One patient achieved a complete and 14 patients a partial response, conferring an objective response rate of 11.7%. Decreases in white blood cells (27.0% of patients), platelets (16.2%) and neutrophils (13.1%) and increased alanine aminotransferase (10.8%) were the most common trabectedin-related grade 3/4 adverse drug reactions. Two deaths due to pneumonia and sepsis were considered trabectedin-related. Trabectedin confers clinically meaningful activity in patients with multiple STS histotypes, comparable to that previously observed in clinical trials and other non-interventional studies, and with a manageable safety profile. KW - trabectedin KW - STS KW - sarcoma KW - non-interventional KW - prospective Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-290898 SN - 2072-6694 VL - 14 IS - 21 ER - TY - JOUR A1 - Köping, Maria A1 - Shehata-Dieler, Wafaa A1 - Schneider, Dieter A1 - Cebulla, Mario A1 - Oder, Daniel A1 - Müntze, Jonas A1 - Nordbeck, Peter A1 - Wanner, Christoph A1 - Hagen, Rudolf A1 - Schraven, Sebastian P. T1 - Characterization of vertigo and hearing loss in patients with Fabry disease JF - Orphanet Journal of Rare Diseases N2 - Background Fabry Disease (FD) is an X-linked hereditary lysosomal storage disorder which leads to a multisystemic intralysosomal accumulation of globotriaosylceramid (Gb3). Besides prominent renal and cardiac organ involvement, patients commonly complain about vestibulocochlear symptoms like high-frequency hearing loss, tinnitus and vertigo. However, comprehensive data especially on vertigo remain scarce. The aim of this study was to examine the prevalence and characteristics of vertigo and hearing loss in patients with FD, depending on renal and cardiac parameters and get hints about the site and the pattern of the lesions. Methods Single-center study with 57 FD patients. Every patient underwent an oto-rhino-laryngological examination as well as videonystagmography and vestibular evoked myogenic potentials (VEMPs) and audiological measurements using pure tone audiometry and auditory brainstem response audiometry (ABR). Renal function was measured by eGFR, cardiac impairment was graduated by NYHA class. Results More than one out of three patients (35.1%) complained about hearing loss, 54.4% about vertigo and 28.1% about both symptom. In 74% a sensorineural hearing loss of at least 25 dB was found, ABR could exclude any retrocochlear lesion. Caloric testing showed abnormal values in 71.9%, VEMPs were pathological in 68%. A correlation between the side or the shape of hearing loss and pathological vestibular testing could not be revealed. Conclusions Hearing loss and vertigo show a high prevalence in FD. While hearing loss seems due to a cochlear lesion, peripheral vestibular as well as central nervous pathologies cause vertigo. Thus, both the site of lesion and the pathophysiological patterns seem to differ. KW - Fabry disease KW - vertigo KW - VEMP KW - cardiomyopathy KW - chronic kidney disease KW - lysosomal storage disorder Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-222818 VL - 13 ER - TY - JOUR A1 - Merz, Julia A1 - Dietz, Maximilian A1 - Vonhausen, Yvonne A1 - Wöber, Frederik A1 - Friedrich, Alexandra A1 - Sieh, Daniel A1 - Krummenacher, Ivo A1 - Braunschweig, Holger A1 - Moos, Michael A1 - Holzapfel, Marco A1 - Lambert, Christoph A1 - Marder, Todd B. T1 - Synthesis, Photophysical and Electronic Properties of New Red-to-NIR Emitting Donor-Acceptor Pyrene Derivatives JF - Chemistry - A European Journal N2 - We synthesized new pyrene derivatives with strong bis(para ‐methoxyphenyl)amine donors at the 2,7‐positions and n ‐azaacene acceptors at the K‐region of pyrene. The compounds possess a strong intramolecular charge transfer, leading to unusual properties such as emission in the red to NIR region (700 nm), which has not been reported before for monomeric pyrenes. Detailed photophysical studies reveal very long intrinsic lifetimes of >100 ns for the new compounds, which is typical for 2,7‐substituted pyrenes but not for K‐region substituted pyrenes. The incorporation of strong donors and acceptors leads to very low reduction and oxidation potentials, and spectroelectrochemical studies show that the compounds are on the borderline between localized Robin‐Day class‐II and delocalized Robin‐Day class‐III species. KW - orylation KW - K-region KW - luminescence KW - polycyclic aromatic hydrocarbons KW - redox Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-207486 VL - 26 IS - 2 ER - TY - JOUR A1 - Schischlevskij, Pavel A1 - Cordts, Isabell A1 - Günther, René A1 - Stolte, Benjamin A1 - Zeller, Daniel A1 - Schröter, Carsten A1 - Weyen, Ute A1 - Regensburger, Martin A1 - Wolf, Joachim A1 - Schneider, Ilka A1 - Hermann, Andreas A1 - Metelmann, Moritz A1 - Kohl, Zacharias A1 - Linker, Ralf A. A1 - Koch, Jan Christoph A1 - Stendel, Claudia A1 - Müschen, Lars H. A1 - Osmanovic, Alma A1 - Binz, Camilla A1 - Klopstock, Thomas A1 - Dorst, Johannes A1 - Ludolph, Albert C. A1 - Boentert, Matthias A1 - Hagenacker, Tim A1 - Deschauer, Marcus A1 - Lingor, Paul A1 - Petri, Susanne A1 - Schreiber-Katz, Olivia T1 - Informal caregiving in amyotrophic lateral sclerosis (ALS): a high caregiver burden and drastic consequences on caregivers' lives JF - Brain Sciences N2 - Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that causes progressive autonomy loss and need for care. This does not only affect patients themselves, but also the patients’ informal caregivers (CGs) in their health, personal and professional lives. The big efforts of this multi-center study were not only to evaluate the caregivers' burden and to identify its predictors, but it also should provide a specific understanding of the needs of ALS patients' CGs and fill the gap of knowledge on their personal and work lives. Using standardized questionnaires, primary data from patients and their main informal CGs (n = 249) were collected. Patients' functional status and disease severity were evaluated using the Barthel Index, the revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) and the King’s Stages for ALS. The caregivers' burden was recorded by the Zarit Burden Interview (ZBI). Comorbid anxiety and depression of caregivers were assessed by the Hospital Anxiety and Depression Scale. Additionally, the EuroQol Five Dimension Five Level Scale evaluated their health-related quality of life. The caregivers' burden was high (mean ZBI = 26/88, 0 = no burden, ≥24 = highly burdened) and correlated with patients' functional status (r\(_p\) = −0.555, p < 0.001, n = 242). It was influenced by the CGs' own mental health issues due to caregiving (+11.36, 95% CI [6.84; 15.87], p < 0.001), patients' wheelchair dependency (+9.30, 95% CI [5.94; 12.66], p < 0.001) and was interrelated with the CGs' depression (r\(_p\) = 0.627, p < 0.001, n = 234), anxiety (r\(_p\) = 0.550, p < 0.001, n = 234), and poorer physical condition (r\(_p\) = −0.362, p < 0.001, n = 237). Moreover, female CGs showed symptoms of anxiety more often, which also correlated with the patients' impairment in daily routine (r\(_s\) = −0.280, p < 0.001, n = 169). As increasing disease severity, along with decreasing autonomy, was the main predictor of caregiver burden and showed to create relevant (negative) implications on CGs' lives, patient care and supportive therapies should address this issue. Moreover, in order to preserve the mental and physical health of the CGs, new concepts of care have to focus on both, on not only patients but also their CGs and gender-associated specific issues. As caregiving in ALS also significantly influences the socioeconomic status by restrictions in CGs' work lives and income, and the main reported needs being lack of psychological support and a high bureaucracy, the situation of CGs needs more attention. Apart from their own multi-disciplinary medical and psychological care, more support in care and patient management issues is required. KW - amyotrophic lateral sclerosis (ALS) KW - informal caregiving KW - caregiver burden KW - functional status KW - decreasing autonomy KW - depression KW - anxiety KW - health-related quality of life KW - socioeconomic status KW - psychological support Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-240981 SN - 2076-3425 VL - 11 IS - 6 ER - TY - JOUR A1 - Kolokotronis, Konstantinos A1 - Pluta, Natalie A1 - Klopocki, Eva A1 - Kunstmann, Erdmute A1 - Messroghli, Daniel A1 - Maack, Christoph A1 - Tejman-Yarden, Shai A1 - Arad, Michael A1 - Rost, Simone A1 - Gerull, Brenda T1 - New Insights on Genetic Diagnostics in Cardiomyopathy and Arrhythmia Patients Gained by Stepwise Exome Data Analysis JF - Journal of Clinical Medicine N2 - Inherited cardiomyopathies are characterized by clinical and genetic heterogeneity that challenge genetic diagnostics. In this study, we examined the diagnostic benefit of exome data compared to targeted gene panel analyses, and we propose new candidate genes. We performed exome sequencing in a cohort of 61 consecutive patients with a diagnosis of cardiomyopathy or primary arrhythmia, and we analyzed the data following a stepwise approach. Overall, in 64% of patients, a variant of interest (VOI) was detected. The detection rate in the main sub-cohort consisting of patients with dilated cardiomyopathy (DCM) was much higher than previously reported (25/36; 69%). The majority of VOIs were found in disease-specific panels, while a further analysis of an extended panel and exome data led to an additional diagnostic yield of 13% and 5%, respectively. Exome data analysis also detected variants in candidate genes whose functional profile suggested a probable pathogenetic role, the strongest candidate being a truncating variant in STK38. In conclusion, although the diagnostic yield of gene panels is acceptable for routine diagnostics, the genetic heterogeneity of cardiomyopathies and the presence of still-unknown causes favor exome sequencing, which enables the detection of interesting phenotype–genotype correlations, as well as the identification of novel candidate genes. KW - cardiomyopathy KW - cardiogenetics KW - whole exome sequencing KW - targeted gene panel KW - candidate genes Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-236094 VL - 9 IS - 7 ER - TY - JOUR A1 - Peseschkian, Tara A1 - Cordts, Isabell A1 - Günther, René A1 - Stolte, Benjamin A1 - Zeller, Daniel A1 - Schröter, Carsten A1 - Weyen, Ute A1 - Regensburger, Martin A1 - Wolf, Joachim A1 - Schneider, Ilka A1 - Hermann, Andreas A1 - Metelmann, Moritz A1 - Kohl, Zacharias A1 - Linker, Ralf A. A1 - Koch, Jan Christoph A1 - Büchner, Boriana A1 - Weiland, Ulrike A1 - Schönfelder, Erik A1 - Heinrich, Felix A1 - Osmanovic, Alma A1 - Klopstock, Thomas A1 - Dorst, Johannes A1 - Ludolph, Albert C. A1 - Boentert, Matthias A1 - Hagenacker, Tim A1 - Deschauer, Marcus A1 - Lingor, Paul A1 - Petri, Susanne A1 - Schreiber-Katz, Olivia T1 - A nation-wide, multi-center study on the quality of life of ALS patients in Germany JF - Brain Sciences N2 - Improving quality of life (QoL) is central to amyotrophic lateral sclerosis (ALS) treatment. This Germany-wide, multicenter cross-sectional study analyses the impact of different symptom-specific treatments and ALS variants on QoL. Health-related QoL (HRQoL) in 325 ALS patients was assessed using the Amyotrophic Lateral Sclerosis Assessment Questionnaire 5 (ALSAQ-5) and EuroQol Five Dimension Five Level Scale (EQ-5D-5L), together with disease severity (captured by the revised ALS Functional Rating Scale (ALSFRS-R)) and the current care and therapies used by our cohort. At inclusion, the mean ALSAQ-5 total score was 56.93 (max. 100, best = 0) with a better QoL associated with a less severe disease status (β = −1.96 per increase of one point in the ALSFRS-R score, p < 0.001). “Limb-onset” ALS (lALS) was associated with a better QoL than “bulbar-onset” ALS (bALS) (mean ALSAQ-5 total score 55.46 versus 60.99, p = 0.040). Moreover, with the ALSFRS-R as a covariate, using a mobility aid (β = −7.60, p = 0.001), being tracheostomized (β = −14.80, p = 0.004) and using non-invasive ventilation (β = −5.71, p = 0.030) were associated with an improved QoL, compared to those at the same disease stage who did not use these aids. In contrast, antidepressant intake (β = 5.95, p = 0.007), and increasing age (β = 0.18, p = 0.023) were predictors of worse QoL. Our results showed that the ALSAQ-5 was better-suited for ALS patients than the EQ-5D-5L. Further, the early and symptom-specific clinical management and supply of assistive devices can significantly improve the individual HRQoL of ALS patients. Appropriate QoL questionnaires are needed to monitor the impact of treatment to provide the best possible and individualized care. KW - Amyotrophic Lateral Sclerosis (ALS) KW - Amyotrophic Lateral Sclerosis Assessment Questionnaire 5 (ALSAQ-5) KW - ALS treatment KW - “bulbar-onset” ALS (bALS) KW - “limb-onset” ALS (lALS) KW - EuroQol Five Dimension Five Level Scale (EQ-5D-5L) KW - health-related quality of life (HRQoL) KW - quality of life (QoL) KW - symptom-specific treatment KW - assistive devices Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-234147 SN - 2076-3425 VL - 11 IS - 3 ER -