@article{LendersHennermannKurschatetal.2016, author = {Lenders, Malte and Hennermann, Julia B. and Kurschat, Christine and Rolfs, Arndt and Canaan-K{\"u}hl, Sima and Sommer, Claudia and {\"U}{\c{c}}eyler, Nurcan and Kampmann, Christoph and Karabul, Nesrin and Giese, Anne-Katrin and Duning, Thomas and Stypmann, J{\"o}rg and Kr{\"a}mer, Johannes and Weidemann, Frank and Brand, Stefan-Martin and Wanner, Christoph and Brand, Eva}, title = {Multicenter Female Fabry Study (MFFS) - clinical survey on current treatment of females with Fabry disease}, series = {Orphanet Journal of Rare Diseases}, volume = {11}, journal = {Orphanet Journal of Rare Diseases}, number = {88}, doi = {10.1186/s13023-016-0473-4}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-166543}, year = {2016}, abstract = {Background The aim of the present study was to assess manifestations of and applied treatment concepts for females with Fabry disease (FD) according to the current European Fabry Guidelines. Methods Between 10/2008 and 12/2014, data from the most recent visit of 261 adult female FD patients from six German Fabry centers were retrospectively analyzed. Clinical presentation and laboratory data, including plasma lyso-Gb3 levels were assessed. Results Fifty-five percent of females were on enzyme replacement therapy (ERT), according to recent European FD guidelines. Thirty-three percent of females were untreated although criteria for ERT initiation were fulfilled. In general, the presence of left ventricular hypertrophy (LVH) seemed to impact more on ERT initiation than impaired renal function. In ERT-na{\"i}ve females RAAS blockers were more often prescribed if LVH was present rather than albuminuria. Affected females with missense mutations showed a similar disease burden compared to females with nonsense mutations. Elevated plasma lyso-Gb3 levels in ERT-na{\"i}ve females seem to be a marker of disease burden, since patients showed comparable incidences of organ manifestations even if they were ~8 years younger than females with normal lyso-Gb3 levels. Conclusion The treatment of the majority of females with FD in Germany is in line with the current European FD guidelines. However, a relevant number of females remain untreated despite organ involvement, necessitating a careful reevaluation of these females.}, language = {en} } @article{LendersWeidemannKurschatetal.2016, author = {Lenders, Malte and Weidemann, Frank and Kurschat, Christine and Canaan-K{\"u}hl, Sima and Duning, Thomas and Stypmann, J{\"o}rg and Schmitz, Boris and Reiermann, Stefanie and Kr{\"a}mer, Johannes and Blaschke, Daniela and Wanner, Christoph and Brand, Stefan-Martin and Brand, Eva}, title = {Alpha-Galactosidase A p.A143T, a non-Fabry disease-causing variant}, series = {Orphanet Journal of Rare Diseases}, volume = {11}, journal = {Orphanet Journal of Rare Diseases}, number = {54}, doi = {10.1186/s13023-016-0441-z}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-166559}, year = {2016}, abstract = {Background Fabry disease (FD) is an X-linked multisystemic disorder with a heterogeneous phenotype. Especially atypical or late-onset type 2 phenotypes present a therapeutical dilemma. Methods To determine the clinical impact of the alpha-Galactosidase A (GLA) p.A143T/ c.427G > A variation, we retrospectively analyzed 25 p.A143T patients in comparison to 58 FD patients with other missense mutations. Results p.A143T patients suffering from stroke/ transient ischemic attacks had slightly decreased residual GLA activities, and/or increased lyso-Gb3 levels, suspecting FD. However, most male p.A143T patients presented with significant residual GLA activity (~50 \% of reference), which was associated with normal lyso-Gb3 levels. Additionally, p.A143T patients showed less severe FD-typical symptoms and absent FD-typical renal and cardiac involvement in comparison to FD patients with other missense mutations. Two tested female p.A143T patients with stroke/TIA did not show skewed X chromosome inactivation. No accumulation of neurologic events in family members of p.A143T patients with stroke/transient ischemic attacks was observed. Conclusions We conclude that GLA p.A143T seems to be most likely a neutral variant or a possible modifier instead of a disease-causing mutation. Therefore, we suggest that p.A143T patients with stroke/transient ischemic attacks of unknown etiology should be further evaluated, since the diagnosis of FD is not probable and subsequent ERT or chaperone treatment should not be an unreflected option.}, language = {en} } @article{JanzWalzCirnuetal.2024, author = {Janz, Anna and Walz, Katharina and Cirnu, Alexandra and Surjanto, Jessica and Urlaub, Daniela and Leskien, Miriam and Kohlhaas, Michael and Nickel, Alexander and Brand, Theresa and Nose, Naoko and W{\"o}rsd{\"o}rfer, Philipp and Wagner, Nicole and Higuchi, Takahiro and Maack, Christoph and Dudek, Jan and Lorenz, Kristina and Klopocki, Eva and Erg{\"u}n, S{\"u}leyman and Duff, Henry J. and Gerull, Brenda}, title = {Mutations in DNAJC19 cause altered mitochondrial structure and increased mitochondrial respiration in human iPSC-derived cardiomyocytes}, series = {Molecular Metabolism}, volume = {79}, journal = {Molecular Metabolism}, issn = {2212-8778}, doi = {10.1016/j.molmet.2023.101859}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-350393}, year = {2024}, abstract = {Highlights • Loss of DNAJC19's DnaJ domain disrupts cardiac mitochondrial structure, leading to abnormal cristae formation in iPSC-CMs. • Impaired mitochondrial structures lead to an increased mitochondrial respiration, ROS and an elevated membrane potential. • Mutant iPSC-CMs show sarcomere dysfunction and a trend to more arrhythmias, resembling DCMA-associated cardiomyopathy. Background Dilated cardiomyopathy with ataxia (DCMA) is an autosomal recessive disorder arising from truncating mutations in DNAJC19, which encodes an inner mitochondrial membrane protein. Clinical features include an early onset, often life-threatening, cardiomyopathy associated with other metabolic features. Here, we aim to understand the metabolic and pathophysiological mechanisms of mutant DNAJC19 for the development of cardiomyopathy. Methods We generated induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) of two affected siblings with DCMA and a gene-edited truncation variant (tv) of DNAJC19 which all lack the conserved DnaJ interaction domain. The mutant iPSC-CMs and their respective control cells were subjected to various analyses, including assessments of morphology, metabolic function, and physiological consequences such as Ca\(^{2+}\) kinetics, contractility, and arrhythmic potential. Validation of respiration analysis was done in a gene-edited HeLa cell line (DNAJC19tv\(_{HeLa}\)). Results Structural analyses revealed mitochondrial fragmentation and abnormal cristae formation associated with an overall reduced mitochondrial protein expression in mutant iPSC-CMs. Morphological alterations were associated with higher oxygen consumption rates (OCRs) in all three mutant iPSC-CMs, indicating higher electron transport chain activity to meet cellular ATP demands. Additionally, increased extracellular acidification rates suggested an increase in overall metabolic flux, while radioactive tracer uptake studies revealed decreased fatty acid uptake and utilization of glucose. Mutant iPSC-CMs also showed increased reactive oxygen species (ROS) and an elevated mitochondrial membrane potential. Increased mitochondrial respiration with pyruvate and malate as substrates was observed in mutant DNAJC19tv HeLa cells in addition to an upregulation of respiratory chain complexes, while cellular ATP-levels remain the same. Moreover, mitochondrial alterations were associated with increased beating frequencies, elevated diastolic Ca\(^{2+}\) concentrations, reduced sarcomere shortening and an increased beat-to-beat rate variability in mutant cell lines in response to β-adrenergic stimulation. Conclusions Loss of the DnaJ domain disturbs cardiac mitochondrial structure with abnormal cristae formation and leads to mitochondrial dysfunction, suggesting that DNAJC19 plays an essential role in mitochondrial morphogenesis and biogenesis. Moreover, increased mitochondrial respiration, altered substrate utilization, increased ROS production and abnormal Ca\(^{2+}\) kinetics provide insights into the pathogenesis of DCMA-related cardiomyopathy.}, language = {en} } @article{WannerFeldtRasmussenJovanovicetal.2020, author = {Wanner, Christoph and Feldt-Rasmussen, Ulla and Jovanovic, Ana and Linhart, Aleš and Yang, Meng and Ponce, Elvira and Brand, Eva and Germain, Dominique P. and Hughes, Derralynn A. and Jefferies, John L. and Martins, Anna Maria and Nowak, Albina and Vujkovac, Bojan and Weidemann, Frank and West, Michael L. and Ortiz, Alberto}, title = {Cardiomyopathy and kidney function in agalsidase beta-treated female Fabry patients: a pre-treatment vs. post-treatment analysis}, series = {ESC Heart Failure}, volume = {7}, journal = {ESC Heart Failure}, number = {3}, doi = {10.1002/ehf2.12647}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-235963}, pages = {825-834}, year = {2020}, abstract = {Long-term treatment effect studies in large female Fabry patient groups are challenging to design because of phenotype heterogeneity and lack of appropriate comparison groups, and have not been reported. We compared long-term cardiomyopathy and kidney function outcomes after agalsidase beta treatment with preceding treatment-naive outcomes. Methods and results Self-controlled pretreatment and post-treatment comparison (piecewise mixed linear modelling) included Fabry female patients ≥18 years at treatment initiation who received agalsidase beta (0.9-1.1 mg/kg every other week) for ≥2 years, with ≥2 pretreatment and ≥2 post-treatment outcome measurements during 10-year follow-up. Left ventricular posterior wall thickness (LVPWT)/interventricular septal thickness (IVST) and estimated glomerular filtration rate (eGFR, Chronic Kidney Disease Epidemiology Collaboration creatinine equation) analyses included 42 and 86 patients, respectively, aged 50.0 and 46.3 years at treatment initiation, respectively. LVPWT and IVST increased pretreatment (follow-up 3.5 years) but stabilized during 3.6 years of treatment (LVPWT: n = 38, slope difference [95\% confidence interval (CI)] = - 0.41 [ - 0.68, - 0.15] mm/year, P\(_{pre-post difference}\)<0.01; IVST: n = 38, slope difference =-0.32 [-0.67, 0.02] mm/year, P\(_{pre-post difference}\) = 0.07). These findings were not modified by renal involvement or antiproteinuric agent use. Compared with the treatment-naive period (follow-up 3.6 years), eGFR decline remained modest and stabilized within normal ranges during 4.1 years of treatment (slope difference, 95\% CI: -0.13 [-1.15, 0.89] mL/min/1.73m\(^2\)/year, P\(_{pre-post difference}\) = 0.80). Conclusions Cardiac hypertrophy, progressing during pretreatment follow-up, appeared to stabilize during sustained agalsidase beta treatment. eGFR decline remained within normal ranges. This suggests that treatment may prevent further Fabry-related progression of cardiomyopathy in female patients and maintain normal kidney function.}, language = {en} } @article{KleijnWinfreeBartomeusetal.2015, author = {Kleijn, David and Winfree, Rachael and Bartomeus, Ignasi and Carvalheiro, Lu{\´i}sa G. and Henry, Mickael and Isaacs, Rufus and Klein, Alexandra-Maria and Kremen, Claire and M'Gonigle, Leithen K. and Rader, Romina and Ricketts, Taylor H. and Williams, Neal M. and Adamson, Nancy Lee and Ascher, John S. and B{\´a}ldi, Andr{\´a}s and Bat{\´a}ry, P{\´e}ter and Benjamin, Faye and Biesmeijer, Jacobus C. and Blitzer, Eleanor J. and Bommarco, Riccardo and Brand, Mariette R. and Bretagnolle, Vincent and Button, Lindsey and Cariveau, Daniel P. and Chifflet, R{\´e}my and Colville, Jonathan F. and Danforth, Bryan N. and Elle, Elizabeth and Garratt, Michael P. D. and Herzog, Felix and Holzschuh, Andrea and Howlett, Brad G. and Jauker, Frank and Jha, Shalene and Knop, Eva and Krewenka, Kristin M. and Le F{\´e}on, Violette and Mandelik, Yael and May, Emily A. and Park, Mia G. and Pisanty, Gideon and Reemer, Menno and Riedinger, Verena and Rollin, Orianne and Rundl{\"o}f, Maj and Sardi{\~n}as, Hillary S. and Scheper, Jeroen and Sciligo, Amber R. and Smith, Henrik G. and Steffan-Dewenter, Ingolf and Thorp, Robbin and Tscharntke, Teja and Verhulst, Jort and Viana, Blandina F. and Vaissi{\`e}re, Bernard E. and Veldtman, Ruan and Ward, Kimiora L. and Westphal, Catrin and Potts, Simon G.}, title = {Delivery of crop pollination services is an insufficient argument for wild pollinator conservation}, series = {Nature Communications}, volume = {6}, journal = {Nature Communications}, number = {7414}, doi = {10.1038/ncomms8414}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-151879}, year = {2015}, abstract = {There is compelling evidence that more diverse ecosystems deliver greater benefits to people, and these ecosystem services have become a key argument for biodiversity conservation. However, it is unclear how much biodiversity is needed to deliver ecosystem services in a cost- effective way. Here we show that, while the contribution of wild bees to crop production is significant, service delivery is restricted to a limited subset of all known bee species. Across crops, years and biogeographical regions, crop-visiting wild bee communities are dominated by a small number of common species, and threatened species are rarely observed on crops. Dominant crop pollinators persist under agricultural expansion and many are easily enhanced by simple conservation measures, suggesting that cost- effective management strategies to promote crop pollination should target a different set of species than management strategies to promote threatened bees. Conserving the biological diversity of bees therefore requires more than just ecosystem-service-based arguments.}, language = {en} } @article{vanderVeenVlietstravanDussenetal.2020, author = {van der Veen, Sanne J. and Vlietstra, Wytze J. and van Dussen, Laura and van Kuilenburg, Andr{\´e} B.P. and Dijkgraaf, Marcel G. W. and Lenders, Malte and Brand, Eva and Wanner, Christoph and Hughes, Derralynn and Elliott, Perry M. and Hollak, Carla E. M. and Langeveld, Mirjam}, title = {Predicting the development of anti-drug antibodies against recombinant alpha-galactosidase A in male patients with classical Fabry disease}, series = {International Journal of Molecular Sciences}, volume = {21}, journal = {International Journal of Molecular Sciences}, number = {16}, issn = {1422-0067}, doi = {10.3390/ijms21165784}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-285687}, year = {2020}, abstract = {Fabry Disease (FD) is a rare, X-linked, lysosomal storage disease that mainly causes renal, cardiac and cerebral complications. Enzyme replacement therapy (ERT) with recombinant alpha-galactosidase A is available, but approximately 50\% of male patients with classical FD develop inhibiting anti-drug antibodies (iADAs) that lead to reduced biochemical responses and an accelerated loss of renal function. Once immunization has occurred, iADAs tend to persist and tolerization is hard to achieve. Here we developed a pre-treatment prediction model for iADA development in FD using existing data from 120 classical male FD patients from three European centers, treated with ERT. We found that nonsense and frameshift mutations in the α-galactosidase A gene (p = 0.05), higher plasma lysoGb3 at baseline (p < 0.001) and agalsidase beta as first treatment (p = 0.006) were significantly associated with iADA development. Prediction performance of a Random Forest model, using multiple variables (AUC-ROC: 0.77) was compared to a logistic regression (LR) model using the three significantly associated variables (AUC-ROC: 0.77). The LR model can be used to determine iADA risk in individual FD patients prior to treatment initiation. This helps to determine in which patients adjusted treatment and/or immunomodulatory regimes may be considered to minimize iADA development risk.}, language = {en} } @article{GermainBrandBurlinaetal.2018, author = {Germain, Dominique P. and Brand, Eva and Burlina, Alessandro and Cecchi, Franco and Garman, Scott C. and Kempf, Judy and Laney, Dawn A. and Linhart, Aleš and Mar{\´o}di, L{\´a}szl{\´o} and Nicholls, Kathy and Ortiz, Alberto and Pieruzzi, Federico and Shankar, Suma P. and Waldek, Stephen and Wanner, Christoph and Jovanovic, Ana}, title = {Phenotypic characteristics of the p.Asn215Ser (p.N215S) GLA mutation in male and female patients with Fabry disease: A multicenter Fabry Registry study}, series = {Molecular Genetics \& Genomic Medicine}, volume = {6}, journal = {Molecular Genetics \& Genomic Medicine}, doi = {10.1002/mgg3.389}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-232976}, pages = {492-503}, year = {2018}, abstract = {Background The p.Asn215Ser or p.N215S GLA variant has been associated with late-onset cardiac variant of Fabry disease. Methods To expand on the scarce phenotype data, we analyzed natural history data from 125 p.N215S patients (66 females, 59 males) enrolled in the Fabry Registry (NCT00196742) and compared it with data from 401 patients (237 females, 164 males) harboring mutations associated with classic Fabry disease. We evaluated interventricular septum thickness (IVST), left ventricular posterior wall thickness (LVPWT), estimated glomerular filtration rate and severe clinical events. Results In p.N215S males, mildly abnormal mean IVST and LVPWT values were observed in patients aged 25-34 years, and values gradually increased with advancing age. Mean values were similar to those of classic males. In p.N215S females, these abnormalities occurred primarily in patients aged 55-64 years. Severe clinical events in p.N215S patients were mainly cardiac (males 31\%, females 8\%) while renal and cerebrovascular events were rare. Renal impairment occurred in 17\% of p.N215S males (mostly in patients aged 65-74 years), and rarely in females (3\%). Conclusion p.N215S is a disease-causing mutation with severe clinical manifestations found primarily in the heart. Cardiac involvement may become as severe as in classic Fabry patients, especially in males.}, language = {en} }