Wilichowski, Ekkehard

[["dc.bibliographiccitation.artnumber","10"],["dc.bibliographiccitation.journal","Molecular Cytogenetics"],["dc.bibliographiccitation.volume","2"],["dc.contributor.author","Auber, Bernd"],["dc.contributor.author","Bruemmer, Verena"],["dc.contributor.author","Zoll, Barbara"],["dc.contributor.author","Burfeind, Peter"],["dc.contributor.author","Boehm, Detlef"],["dc.contributor.author","Liehr, Thomas"],["dc.contributor.author","Brockmann, Knut"],["dc.contributor.author","Wilichowski, Ekkehard"],["dc.contributor.author","Argyriou, Loukas"],["dc.contributor.author","Bartels, Iris"],["dc.date.accessioned","2018-11-07T08:35:08Z"],["dc.date.available","2018-11-07T08:35:08Z"],["dc.date.issued","2009"],["dc.description.abstract","Background: Submicroscopic imbalances in the subtelomeric regions of the chromosomes are considered to play an important role in the aetiology of mental retardation (MR). The aim of the study was to evaluate a quantitative PCR (qPCR) protocol established by Boehm et al. (2004) in the clinical routine of subtelomeric testing. Results: 296 patients with MR and a normal karyotype (500-550 bands) were screened for subtelomeric imbalances by using qPCR combined with SYBR green detection. In total, 17 patients (5.8%) with 20 subtelomeric imbalances were identified. Six of the aberrations (2%) were classified as causative for the symptoms, because they occurred either de novo in the patients (5 cases) or the aberration were be detected in the patient and an equally affected parent (1 case). The extent of the deletions ranged from 1.8 to approximately 10 Mb, duplications were 1.8 to approximately 5 Mb in size. In 6 patients, the copy number variations (CNVs) were rated as benign polymorphisms, and the clinical relevance of these CNVs remains unclear in 5 patients (1.7%). Therefore, the overall frequency of clinically relevant imbalances ranges between 2% and 3.7% in our cohort."],["dc.identifier.doi","10.1186/1755-8166-2-10"],["dc.identifier.isi","000208460900009"],["dc.identifier.pmid","19284615"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/5765"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/17987"],["dc.notes.intern","Merged from goescholar"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Biomed Central Ltd"],["dc.relation.issn","1755-8166"],["dc.rights","CC BY 2.0"],["dc.rights.uri","https://creativecommons.org/licenses/by/2.0"],["dc.title","Identification of subtelomeric genomic imbalances and breakpoint mapping with quantitative PCR in 296 individuals with congenital defects and/or mental retardation"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.artnumber","64"],["dc.bibliographiccitation.issue","1"],["dc.bibliographiccitation.journal","Orphanet Journal of Rare Diseases"],["dc.bibliographiccitation.volume","16"],["dc.contributor.author","Reinert, Marie-Christine"],["dc.contributor.author","Pacheu-Grau, David"],["dc.contributor.author","Catarino, Claudia B."],["dc.contributor.author","Klopstock, Thomas"],["dc.contributor.author","Ohlenbusch, Andreas"],["dc.contributor.author","Schittkowski, Michael Peter"],["dc.contributor.author","Wilichowski, Ekkehard"],["dc.contributor.author","Rehling, Peter"],["dc.contributor.author","Brockmann, Knut"],["dc.date.accessioned","2021-04-14T08:28:08Z"],["dc.date.available","2021-04-14T08:28:08Z"],["dc.date.issued","2021"],["dc.date.updated","2022-07-29T12:17:42Z"],["dc.description.abstract","Background Leber hereditary optic neuropathy (LHON) is the most common mitochondrial disorder and characterized by acute or subacute painless visual loss. Environmental factors reported to trigger visual loss in LHON mutation carriers include smoking, heavy intake of alcohol, raised intraocular pressure, and some drugs, including several carbonic anhydrase inhibitors. The antiepileptic drug sulthiame (STM) is effective especially in focal seizures, particularly in benign epilepsy of childhood with centrotemporal spikes, and widely used in pediatric epileptology. STM is a sulfonamide derivate and an inhibitor of mammalian carbonic anhydrase isoforms I–XIV. Results We describe two unrelated patients, an 8-year-old girl and an 11-year-old boy, with cryptogenic focal epilepsy, who suffered binocular (subject #1) or monocular (subject #2) visual loss in close temporal connection with starting antiepileptic pharmacotherapy with STM. In both subjects, visual loss was due to LHON. We used real-time respirometry in fibroblasts derived from LHON patients carrying the same mitochondrial mutations as our two subjects to investigate the effect of STM on oxidative phosphorylation. Oxygen consumption rate in fibroblasts from a healthy control was not impaired by STM compared with a vehicle control. In contrast, fibroblasts carrying the m.14484T>C or the m.3460G>A LHON mutation displayed a drastic reduction of the respiration rate when treated with STM compared to vehicle control. Conclusions Our observations point to a causal relationship between STM treatment and onset or worsening of visual failure in two subjects with LHON rather than pure coincidence. We conclude that antiepileptic medication with STM may pose a risk for visual loss in LHON mutation carriers and should be avoided in these patients."],["dc.description.sponsorship","Open-Access-Publikationsfonds 2021"],["dc.identifier.citation","Orphanet Journal of Rare Diseases. 2021 Feb 04;16(1):64"],["dc.identifier.doi","10.1186/s13023-021-01690-y"],["dc.identifier.pmid","33541401"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/17726"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/82509"],["dc.identifier.url","https://mbexc.uni-goettingen.de/literature/publications/219"],["dc.identifier.url","https://sfb1286.uni-goettingen.de/literature/publications/102"],["dc.language.iso","en"],["dc.notes.intern","DOI Import GROB-399"],["dc.notes.intern","Merged from goescholar"],["dc.relation","EXC 2067: Multiscale Bioimaging"],["dc.relation","SFB 1286: Quantitative Synaptologie"],["dc.relation","SFB 1286 | A06: Mitochondrienfunktion und -umsatz in Synapsen"],["dc.relation.eissn","1750-1172"],["dc.relation.workinggroup","RG Rehling (Mitochondrial Protein Biogenesis)"],["dc.rights","CC BY 4.0"],["dc.rights.holder","The Author(s)"],["dc.rights.uri","https://creativecommons.org/licenses/by/4.0"],["dc.subject","Sulthiame"],["dc.subject","Carbonic anhydrase inhibitor"],["dc.subject","Adverse effects"],["dc.subject","Leber hereditary optic neuropathy"],["dc.subject","LHON"],["dc.subject","Oxygen consumption rate"],["dc.title","Sulthiame impairs mitochondrial function in vitro and may trigger onset of visual loss in Leber hereditary optic neuropathy"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.subtype","original_ja"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.artnumber","e13513"],["dc.bibliographiccitation.issue","10"],["dc.bibliographiccitation.journal","PLoS ONE"],["dc.bibliographiccitation.volume","5"],["dc.contributor.author","Brinckmann, Anja"],["dc.contributor.author","Weiss, Claudia"],["dc.contributor.author","Wilbert, Friederike"],["dc.contributor.author","von Moers, Arpad"],["dc.contributor.author","Zwirner, Angelika"],["dc.contributor.author","Stoltenburg-Didinger, Gisela"],["dc.contributor.author","Wilichowski, Ekkehard"],["dc.contributor.author","Schuelke, Markus"],["dc.date.accessioned","2018-11-07T08:37:56Z"],["dc.date.available","2018-11-07T08:37:56Z"],["dc.date.issued","2010"],["dc.description.abstract","Human patients with myoclonic epilepsy with ragged-red fibers (MERRF) suffer from regionalized pathology caused by a mutation in the mitochondrial DNA (m.8344A -> G). In MERRF-syndrome brain and skeletal muscles are predominantly affected, despite mtDNA being present in any tissue. In the past such tissue-specificity could not be explained by varying mtDNA mutation loads. In search for a region-specific pathology in human individuals we determined the mtDNA/nDNA ratios along with the mutation loads in 43 different post mortem tissue samples of a 16-year-old female MERRF patient and in four previously healthy victims of motor vehicle accidents. In brain and muscle we further determined the quantity of mitochondrial proteins (COX subunits II and IV), transcription factors (NRF1 and TFAM), and VDAC1 (Porin) as a marker for the mitochondrial mass. In the patient the mutation loads varied merely between 89-100%. However, mtDNA copy numbers were increased 3-7 fold in predominantly affected brain areas (e.g. hippocampus, cortex and putamen) and in skeletal muscle. Similar increases were absent in unaffected tissues (e.g. heart, lung, kidney, liver, and gastrointestinal organs). Such mtDNA copy number increase was not paralleled by an augmentation of mitochondrial mass in some investigated tissues, predominantly in the most affected tissue regions of the brain. We thus conclude that \"futile' stimulation of mtDNA replication per se or a secondary failure to increase the mitochondrial mass may contribute to the regionalized pathology seen in MERRF-syndrome."],["dc.identifier.doi","10.1371/journal.pone.0013513"],["dc.identifier.isi","000283216400018"],["dc.identifier.pmid","20976001"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/6120"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/18660"],["dc.notes.intern","Merged from goescholar"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Public Library Science"],["dc.relation.issn","1932-6203"],["dc.rights","CC BY 2.5"],["dc.rights.uri","https://creativecommons.org/licenses/by/2.5"],["dc.title","Regionalized Pathology Correlates with Augmentation of mtDNA Copy Numbers in a Patient with Myoclonic Epilepsy with Ragged-Red Fibers (MERRF-Syndrome)"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","616"],["dc.bibliographiccitation.issue","8"],["dc.bibliographiccitation.journal","Journal of Child Neurology"],["dc.bibliographiccitation.lastpage","619"],["dc.bibliographiccitation.volume","16"],["dc.contributor.author","Čačić, Melita"],["dc.contributor.author","Wilichowski, Ekkehard"],["dc.contributor.author","Mejaški-Bošnjak, Vlatka"],["dc.contributor.author","Fumić, Ksenija"],["dc.contributor.author","Lujić, Lucija"],["dc.contributor.author","Marusić, Branka"],["dc.contributor.author","Marina, Della"],["dc.contributor.author","Hanefeld, Folker"],["dc.date.accessioned","2019-07-09T11:42:13Z"],["dc.date.available","2019-07-09T11:42:13Z"],["dc.date.issued","2001"],["dc.description.abstract","We report a case of a neonate with sectional narrowing of the spinal cord on the level of T12 to L2 and a deformed vertebral body on a different level, L4. In previously described cases of sectional spinal dysgenesis, the vertebral and spinal cord malformations are usually found on the same level. Our case may represent a new variant of spinal dysgenesis."],["dc.identifier.doi","10.1177/088307380101600818"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/13077"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/58622"],["dc.notes.intern","Merged from goescholar"],["dc.publisher","Sage Publications"],["dc.publisher.place","Thousand Oaks"],["dc.title","Cytochrome c Oxidase Partial Deficiency-Associated Leigh Disease Presenting as an Extrapyramidal Syndrome"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.artnumber","55"],["dc.bibliographiccitation.issue","1"],["dc.bibliographiccitation.journal","Genome Medicine"],["dc.bibliographiccitation.volume","13"],["dc.contributor.author","Yap, Zheng Y."],["dc.contributor.author","Park, Yo H."],["dc.contributor.author","Wortmann, Saskia B."],["dc.contributor.author","Gunning, Adam C."],["dc.contributor.author","Ezer, Shlomit"],["dc.contributor.author","Lee, Sukyeong"],["dc.contributor.author","Duraine, Lita"],["dc.contributor.author","Wilichowski, Ekkehard"],["dc.contributor.author","Wilson, Kate"],["dc.contributor.author","Mayr, Johannes A."],["dc.contributor.author","Wagner, Matias"],["dc.contributor.author","Li, Hong"],["dc.contributor.author","Kini, Usha"],["dc.contributor.author","Black, Emily D."],["dc.contributor.author","Monaghan, Kristin G."],["dc.contributor.author","Lupski, James R."],["dc.contributor.author","Ellard, Sian"],["dc.contributor.author","Westphal, Dominik S."],["dc.contributor.author","Harel, Tamar"],["dc.contributor.author","Yoon, Wan H."],["dc.date.accessioned","2021-06-01T09:42:16Z"],["dc.date.accessioned","2022-08-16T12:48:31Z"],["dc.date.available","2021-06-01T09:42:16Z"],["dc.date.available","2022-08-16T12:48:31Z"],["dc.date.issued","2021-04-12"],["dc.date.updated","2022-07-29T12:18:07Z"],["dc.description.abstract","Abstract\r\n \r\n Background\r\n ATPase family AAA-domain containing protein 3A (ATAD3A) is a nuclear-encoded mitochondrial membrane-anchored protein involved in diverse processes including mitochondrial dynamics, mitochondrial DNA organization, and cholesterol metabolism. Biallelic deletions (null), recessive missense variants (hypomorph), and heterozygous missense variants or duplications (antimorph) in ATAD3A lead to neurological syndromes in humans.\r\n \r\n \r\n Methods\r\n To expand the mutational spectrum of ATAD3A variants and to provide functional interpretation of missense alleles in trans to deletion alleles, we performed exome sequencing for identification of single nucleotide variants (SNVs) and copy number variants (CNVs) in ATAD3A in individuals with neurological and mitochondrial phenotypes. A Drosophila Atad3a Gal4 knockin-null allele was generated using CRISPR-Cas9 genome editing technology to aid the interpretation of variants.\r\n \r\n \r\n Results\r\n We report 13 individuals from 8 unrelated families with biallelic ATAD3A variants. The variants included four missense variants inherited in trans to loss-of-function alleles (p.(Leu77Val), p.(Phe50Leu), p.(Arg170Trp), p.(Gly236Val)), a homozygous missense variant p.(Arg327Pro), and a heterozygous non-frameshift indel p.(Lys568del). Affected individuals exhibited findings previously associated with ATAD3A pathogenic variation, including developmental delay, hypotonia, congenital cataracts, hypertrophic cardiomyopathy, and cerebellar atrophy. Drosophila studies indicated that Phe50Leu, Gly236Val, Arg327Pro, and Lys568del are severe loss-of-function alleles leading to early developmental lethality. Further, we showed that Phe50Leu, Gly236Val, and Arg327Pro cause neurogenesis defects. On the contrary, Leu77Val and Arg170Trp are partial loss-of-function alleles that cause progressive locomotion defects and whose expression leads to an increase in autophagy and mitophagy in adult muscles.\r\n \r\n \r\n Conclusion\r\n Our findings expand the allelic spectrum of ATAD3A variants and exemplify the use of a functional assay in Drosophila to aid variant interpretation."],["dc.identifier.citation","Genome Medicine. 2021 Apr 12;13(1):55"],["dc.identifier.doi","10.1186/s13073-021-00873-3"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/17762"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/85195"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/112746"],["dc.language.iso","en"],["dc.notes.intern","DOI-Import GROB-425"],["dc.notes.intern","Merged from goescholar"],["dc.relation.eissn","1756-994X"],["dc.rights","CC BY 4.0"],["dc.rights.holder","The Author(s)"],["dc.rights.uri","https://creativecommons.org/licenses/by/4.0"],["dc.subject","ATAD3A"],["dc.subject","Mitochondria"],["dc.subject","Disease"],["dc.subject","Autosomal recessive"],["dc.subject","Autophagy"],["dc.subject","Neurogenesis"],["dc.subject","Drosophila"],["dc.subject","AAA+ protein"],["dc.title","Functional interpretation of ATAD3A variants in neuro-mitochondrial phenotypes"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.subtype","original_ja"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.artnumber","291"],["dc.bibliographiccitation.issue","1"],["dc.bibliographiccitation.journal","Trials"],["dc.bibliographiccitation.volume","19"],["dc.contributor.author","Crow, Rebecca A"],["dc.contributor.author","Hart, Kimberly A"],["dc.contributor.author","McDermott, Michael P"],["dc.contributor.author","Tawil, Rabi"],["dc.contributor.author","Martens, William B"],["dc.contributor.author","Herr, Barbara E"],["dc.contributor.author","McColl, Elaine"],["dc.contributor.author","Wilkinson, Jennifer"],["dc.contributor.author","Kirschner, Janbernd"],["dc.contributor.author","King, Wendy M"],["dc.contributor.author","Eagle, Michele"],["dc.contributor.author","Brown, Mary W"],["dc.contributor.author","Hirtz, Deborah"],["dc.contributor.author","Lochmuller, Hanns"],["dc.contributor.author","Straub, Volker"],["dc.contributor.author","Ciafaloni, Emma"],["dc.contributor.author","Shieh, Perry B"],["dc.contributor.author","Spinty, Stefan"],["dc.contributor.author","Childs, Anne-Marie"],["dc.contributor.author","Manzur, Adnan Y"],["dc.contributor.author","Morandi, Lucia"],["dc.contributor.author","Butterfield, Russell J"],["dc.contributor.author","Horrocks, Iain"],["dc.contributor.author","Roper, Helen"],["dc.contributor.author","Flanigan, Kevin M"],["dc.contributor.author","Kuntz, Nancy L"],["dc.contributor.author","Mah, Jean K"],["dc.contributor.author","Morrison, Leslie"],["dc.contributor.author","Darras, Basil T"],["dc.contributor.author","von der Hagen, Maja"],["dc.contributor.author","Schara, Ulrike"],["dc.contributor.author","Wilichowski, Ekkehard"],["dc.contributor.author","Mongini, Tiziana"],["dc.contributor.author","McDonald, Craig M"],["dc.contributor.author","Vita, Giuseppe"],["dc.contributor.author","Barohn, Richard J"],["dc.contributor.author","Finkel, Richard S"],["dc.contributor.author","Wicklund, Matthew"],["dc.contributor.author","McMillan, Hugh J"],["dc.contributor.author","Hughes, Imelda"],["dc.contributor.author","Pegoraro, Elena"],["dc.contributor.author","Bryan Burnette, W."],["dc.contributor.author","Howard, James F"],["dc.contributor.author","Thangarajh, Mathula"],["dc.contributor.author","Campbell, Craig"],["dc.contributor.author","Griggs, Robert C"],["dc.contributor.author","Bushby, Kate"],["dc.contributor.author","Guglieri, Michela"],["dc.date.accessioned","2019-07-09T11:45:29Z"],["dc.date.available","2019-07-09T11:45:29Z"],["dc.date.issued","2018"],["dc.description.abstract","Abstract Background Trials in rare diseases have many challenges, among which are the need to set up multiple sites in different countries to achieve recruitment targets and the divergent landscape of clinical trial regulations in those countries. Over the past years, there have been initiatives to facilitate the process of international study set-up, but the fruits of these deliberations require time to be operationally in place. FOR-DMD (Finding the Optimum Steroid Regimen for Duchenne Muscular Dystrophy) is an academic-led clinical trial which aims to find the optimum steroid regimen for Duchenne muscular dystrophy, funded by the National Institutes of Health (NIH) for 5 years (July 2010 to June 2015), anticipating that all sites (40 across the USA, Canada, the UK, Germany and Italy) would be open to recruitment from July 2011. However, study start-up was significantly delayed and recruitment did not start until January 2013. Method The FOR-DMD study is used as an example to identify systematic problems in the set-up of international, multi-centre clinical trials. The full timeline of the FOR-DMD study, from funding approval to site activation, was collated and reviewed. Systematic issues were identified and grouped into (1) study set-up, e.g. drug procurement; (2) country set-up, e.g. competent authority applications; and (3) site set-up, e.g. contracts, to identify the main causes of delay and suggest areas where anticipatory action could overcome these obstacles in future studies. Results Time from the first contact to site activation across countries ranged from 6 to 24 months. Reasons of delay were universal (sponsor agreement, drug procurement, budgetary constraints), country specific (complexity and diversity of regulatory processes, indemnity requirements) and site specific (contracting and approvals). The main identified obstacles included (1) issues related to drug supply, (2) NIH requirements regarding contracting with non-US sites, (3) differing regulatory requirements in the five participating countries, (4) lack of national harmonisation with contracting and the requirement to negotiate terms and contract individually with each site and (5) diversity of languages needed for study materials. Additionally, as with many academic-led studies, the FOR-DMD study did not have access to the infrastructure and expertise that a contracted research organisation could provide, organisations often employed in pharmaceutical-sponsored studies. This delay impacted recruitment, challenged the clinical relevance of the study outcomes and potentially delayed the delivery of the best treatment to patients. Conclusion Based on the FOR-DMD experience, and as an interim solution, we have devised a checklist of steps to not only anticipate and minimise delays in academic international trial initiation but also identify obstacles that will require a concerted effort on the part of many stakeholders to mitigate."],["dc.identifier.doi","10.1186/s13063-018-2645-0"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/15228"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/59241"],["dc.language.iso","en"],["dc.notes.intern","Merged from goescholar"],["dc.publisher","BioMed Central"],["dc.rights","CC BY 4.0"],["dc.rights.uri","https://creativecommons.org/licenses/by/4.0"],["dc.title","A checklist for clinical trials in rare disease: obstacles and anticipatory actions—lessons learned from the FOR-DMD trial"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.artnumber","105"],["dc.bibliographiccitation.issue","1"],["dc.bibliographiccitation.journal","Orphanet Journal of Rare Diseases"],["dc.bibliographiccitation.volume","14"],["dc.contributor.author","Dittrich, Sven"],["dc.contributor.author","Graf, Erika"],["dc.contributor.author","Trollmann, Regina"],["dc.contributor.author","Neudorf, Ulrich"],["dc.contributor.author","Schara, Ulrike"],["dc.contributor.author","Heilmann, Antje"],["dc.contributor.author","von der Hagen, Maja"],["dc.contributor.author","Stiller, Brigitte"],["dc.contributor.author","Kirschner, Janbernd"],["dc.contributor.author","Pozza, Robert Dalla"],["dc.contributor.author","Müller-Felber, Wolfgang"],["dc.contributor.author","Weiss, Katja"],["dc.contributor.author","von Au, Katja"],["dc.contributor.author","Khalil, Markus"],["dc.contributor.author","Motz, Reinald"],["dc.contributor.author","Korenke, Christoph"],["dc.contributor.author","Lange, Martina"],["dc.contributor.author","Wilichowski, Ekkehard"],["dc.contributor.author","Pattathu, Joseph"],["dc.contributor.author","Ebinger, Friedrich"],["dc.contributor.author","Wiechmann, Nicola"],["dc.contributor.author","Schröder, Rolf"],["dc.date.accessioned","2019-07-09T11:51:41Z"],["dc.date.available","2019-07-09T11:51:41Z"],["dc.date.issued","2019"],["dc.description.abstract","BACKGROUND: X-linked Duchenne muscular dystrophy (DMD), the most frequent human hereditary skeletal muscle myopathy, inevitably leads to progressive dilated cardiomyopathy. We assessed the effect and safety of a combined treatment with the ACE-inhibitor enalapril and the β-blocker metoprolol in a German cohort of infantile and juvenile DMD patients with preserved left ventricular function. METHODS TRIAL DESIGN: Sixteen weeks single-arm open run-in therapy with enalapril and metoprolol followed by a two-arm 1:1 randomized double-blind placebo-controlled treatment in a multicenter setting. INCLUSION CRITERIA: DMD boys aged 10-14 years with left ventricular fractional shortening [LV-FS] ≥ 30% in echocardiography. Primary endpoint: time from randomization to first occurrence of LV-FS < 28%. Secondary: changes of a) LV-FS from baseline, b) blood pressure, c), heart rate and autonomic function in ECG and Holter-ECG, e) cardiac biomarkers and neurohumeral serum parameters, f) quality of life, and g) adverse events. RESULTS: From 3/2010 to 12/2013, 38 patients from 10 sites were centrally randomized after run-in, with 21 patients continuing enalapril and metoprolol medication and 17 patients receiving placebo. Until end of study 12/2015, LV-FS < 28% was reached in 6/21 versus 7/17 patients. Cox regression adjusted for LV-FS after run-in showed a statistically non-significant benefit for medication over placebo (hazard ratio: 0.38; 95% confidence interval: 0.12 to 1.22; p = 0.10). Analysis of secondary outcome measures revealed a time-dependent deterioration of LV-FS with no statistically significant differences between the two study arms. Blood pressure, maximal heart rate and mean-NN values were significantly lower at the end of open run-in treatment compared to baseline. Outcome analysis 19 months after randomization displayed significantly lower maximum heart rate and higher noradrenalin and renin values in the intervention group. No difference between treatments was seen for quality of life. As a single, yet important adverse event, the reversible deterioration of walking abilities of one DMD patient during the run-in period was observed. CONCLUSIONS: Our analysis of enalapril and metoprolol treatment in DMD patients with preserved left ventricular function is suggestive to delay the progression of the intrinsic cardiomyopathy to left ventricular failure, but did not reach statistical significance, probably due to insufficient sample size."],["dc.identifier.doi","10.1186/s13023-019-1066-9"],["dc.identifier.pmid","31077250"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/16170"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/59989"],["dc.language.iso","en"],["dc.notes.intern","Merged from goescholar"],["dc.rights","CC BY 4.0"],["dc.rights.uri","https://creativecommons.org/licenses/by/4.0"],["dc.subject.ddc","610"],["dc.title","Effect and safety of treatment with ACE-inhibitor Enalapril and β-blocker metoprolol on the onset of left ventricular dysfunction in Duchenne muscular dystrophy - a randomized, double-blind, placebo-controlled trial"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.artnumber","384"],["dc.bibliographiccitation.issue","1"],["dc.bibliographiccitation.journal","Orphanet Journal of Rare Diseases"],["dc.bibliographiccitation.volume","17"],["dc.contributor.author","Pechmann, Astrid"],["dc.contributor.author","Behrens, Max"],["dc.contributor.author","Dörnbrack, Katharina"],["dc.contributor.author","Tassoni, Adrian"],["dc.contributor.author","Wenzel, Franziska"],["dc.contributor.author","Stein, Sabine"],["dc.contributor.author","Vogt, Sibylle"],["dc.contributor.author","Zöller, Daniela"],["dc.contributor.author","Bernert, Günther"],["dc.contributor.author","Hagenacker, Tim"],["dc.contributor.author","Zobel, Joachim"],["dc.contributor.author","Hahn, Andreas"],["dc.contributor.author","von Moers, Arpad"],["dc.contributor.author","Wilichowski, Ekkehard"],["dc.contributor.authorgroup","SMArtCARE study group"],["dc.date.accessioned","2022-12-01T08:31:23Z"],["dc.date.available","2022-12-01T08:31:23Z"],["dc.date.issued","2022"],["dc.date.updated","2022-10-30T04:18:38Z"],["dc.description.abstract","Abstract\r\n \r\n Background\r\n The development and approval of disease modifying treatments have dramatically changed disease progression in patients with spinal muscular atrophy (SMA). Nusinersen was approved in Europe in 2017 for the treatment of SMA patients irrespective of age and disease severity. Most data on therapeutic efficacy are available for the infantile-onset SMA. For patients with SMA type 2 and type 3, there is still a lack of sufficient evidence and long-term experience for nusinersen treatment. Here, we report data from the SMArtCARE registry of non-ambulant children with SMA type 2 and typen 3 under nusinersen treatment with a follow-up period of up to 38 months.\r\n \r\n \r\n Methods\r\n SMArtCARE is a disease-specific registry with data on patients with SMA irrespective of age, treatment regime or disease severity. Data are collected during routine patient visits as real-world outcome data. This analysis included all non-ambulant patients with SMA type 2 or 3 below 18 years of age before initiation of treatment. Primary outcomes were changes in motor function evaluated with the Hammersmith Functional Motor Scale Expanded (HFMSE) and the Revised Upper Limb Module (RULM).\r\n \r\n \r\n Results\r\n Data from 256 non-ambulant, pediatric patients with SMA were included in the data analysis. Improvements in motor function were more prominent in upper limb: 32.4% of patients experienced clinically meaningful improvements in RULM and 24.6% in HFMSE. 8.6% of patients gained a new motor milestone, whereas no motor milestones were lost. Only 4.3% of patients showed a clinically meaningful worsening in HFMSE and 1.2% in RULM score.\r\n \r\n \r\n Conclusion\r\n Our results demonstrate clinically meaningful improvements or stabilization of disease progression in non-ambulant, pediatric patients with SMA under nusinersen treatment. Changes were most evident in upper limb function and were observed continuously over the follow-up period. Our data confirm clinical trial data, while providing longer follow-up, an increased number of treated patients, and a wider range of age and disease severity."],["dc.description.sponsorship"," Biogen http://dx.doi.org/10.13039/100005614"],["dc.description.sponsorship","Novartis Gene Therapies"],["dc.description.sponsorship","Universitätsklinikum Freiburg"],["dc.identifier.citation","Orphanet Journal of Rare Diseases. 2022 Oct 23;17(1):384"],["dc.identifier.doi","10.1186/s13023-022-02547-8"],["dc.identifier.pii","2547"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/118161"],["dc.language.iso","en"],["dc.notes.intern","DOI-Import GROB-621"],["dc.relation.eissn","1750-1172"],["dc.rights","CC BY 4.0"],["dc.rights.holder","The Author(s)"],["dc.rights.uri","https://creativecommons.org/licenses/by/4.0"],["dc.subject","Spinal muscular atrophy"],["dc.subject","Nusinersen"],["dc.subject","Sitter"],["dc.subject","Later-onset"],["dc.subject","SMArtCARE"],["dc.title","Improved upper limb function in non-ambulant children with SMA type 2 and 3 during nusinersen treatment: a prospective 3-years SMArtCARE registry study"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]