Publications by authors named "Andreas Ziegler"

405 Publications

Gene replacement therapy with onasemnogene abeparvovec in children with spinal muscular atrophy aged 24 months or younger and bodyweight up to 15 kg: an observational cohort study.

Lancet Child Adolesc Health 2021 Oct 28. Epub 2021 Oct 28.

Department of Pediatric Neurology, Charité-Universitätsmedizin Berlin, Berlin, Germany; Center for Chronically Sick Children, Charité-Universitätsmedizin Berlin, Berlin, Germany; Institute of Cell Biology and Neurobiology, Charité-Universitätsmedizin Berlin, Berlin, Germany. Electronic address:

Background: Given the novelty of gene replacement therapy with onasemnogene abeparvovec in spinal muscular atrophy, efficacy and safety data are limited, especially for children older than 24 months, those weighing more than 8·5 kg, and those who have received nusinersen. We aimed to provide real-world data on motor function and safety after gene replacement therapy in different patient subgroups.

Methods: We did a protocol-based, multicentre prospective observational study between Sept 21, 2019, and April 20, 2021, in 18 paediatric neuromuscular centres in Germany and Austria. All children with spinal muscular atrophy types 1 and 2 receiving onasemnogene abeparvovec were included in our cohort, and there were no specific exclusion criteria. Motor function was assessed at the time of gene replacement therapy and 6 months afterwards, using the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) and Hammersmith Functional Motor Scale-Expanded (HFMSE) scores. Additionally, in children pretreated with nusinersen, motor function was assessed before and after treatment switch. Off-target adverse events were analysed with a focus on liver function, thrombocytopaenia, and potential cardiotoxicity.

Findings: 76 children (58 pretreated with nusinersen and 18 who were nusinersen naive) with spinal muscular atrophy were treated with onasemnogene abeparvovec at a mean age of 16·8 months (range 0·8-59·0, IQR 9-23) and a mean weight of 9·1 kg (range 4·0-15·0, IQR 7·4-10·6). In 60 patients with available data, 49 had a significant improvement on the CHOP-INTEND score (≥4 points) and HFMSE score (≥3 points). Mean CHOP INTEND scores increased significantly in the 6 months after therapy in children younger than 8 months (n=16; mean change 13·8 [SD 8·5]; p<0·0001) and children aged between 8 and 24 months (n=34; 7·7 [SD 5·2]; p<0·0001), but not in children older than 24 months (n=6; 2·5 [SD 5·2]; p=1·00). In the 45 children pretreated with nusinersen and had available data, CHOP INTEND score increased by 8·8 points (p=0·0003) at 6 months after gene replacement therapy. No acute complications occurred during infusion of onasemnogene abeparvovec, but 56 (74%) patients had treatment-related side-effects. Serious adverse events occurred in eight (11%) children. Liver enzyme elevation significantly increased with age and weight at treatment. Six (8%) patients developed acute liver dysfunction. Other adverse events included pyrexia (n=47 [62%]), vomiting or loss of appetite (41 [54%]), and thrombocytopenia (n=59 [78%]). Prednisolone treatment was significantly prolonged with a mean duration of 15·7 weeks (IQR 9-19), mainly due to liver enzyme elevation. Cardiac adverse events were rare; only two patients had abnormal echocardiogram and echocardiography findings.

Interpretation: This study provides class IV evidence that children with spinal muscular atrophy aged 24 months or younger and patients pretreated with nusinersen significantly benefit from gene replacement therapy, but adverse events can be severe and need to be closely monitored.

Funding: None.

Translation: For the German translation of the abstract see Supplementary Materials section.
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http://dx.doi.org/10.1016/S2352-4642(21)00287-XDOI Listing
October 2021

H-NMR-based metabolic profiling identifies non-invasive diagnostic and predictive urinary fingerprints in 5q spinal muscular atrophy.

Orphanet J Rare Dis 2021 10 20;16(1):441. Epub 2021 Oct 20.

Division of Child Neurology and Metabolic Medicine, Center for Child and Adolescent Medicine, Heidelberg University Hospital, Im Neuenheimer Feld 430, 69120, Heidelberg, Germany.

Background: 5q spinal muscular atrophy (SMA) is a disabling and life-limiting neuromuscular disease. In recent years, novel therapies have shown to improve clinical outcomes. Yet, the absence of reliable biomarkers renders clinical assessment and prognosis of possibly already affected newborns with a positive newborn screening result for SMA imprecise and difficult. Therapeutic decisions and stratification of individualized therapies remain challenging, especially in symptomatic children. The aim of this proof-of-concept and feasibility study was to explore the value of H-nuclear magnetic resonance (NMR)-based metabolic profiling in identifying non-invasive diagnostic and prognostic urinary fingerprints in children and adolescents with SMA.

Results: Urine samples were collected from 29 treatment-naïve SMA patients (5 pre-symptomatic, 9 SMA 1, 8 SMA 2, 7 SMA 3), 18 patients with Duchenne muscular dystrophy (DMD) and 444 healthy controls. Using machine-learning algorithms, we propose a set of prediction models built on urinary fingerprints that showed potential diagnostic value in discriminating SMA patients from controls and DMD, as well as predictive properties in separating between SMA types, allowing predictions about phenotypic severity. Interestingly, preliminary results of the prediction models suggest additional value in determining biochemical onset of disease in pre-symptomatic infants with SMA identified by genetic newborn screening and furthermore as potential therapeutic monitoring tool.

Conclusions: This study provides preliminary evidence for the use of H-NMR-based urinary metabolic profiling as diagnostic and prognostic biomarker in spinal muscular atrophy.
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http://dx.doi.org/10.1186/s13023-021-02075-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8527822PMC
October 2021

Bi-allelic variants in SPATA5L1 lead to intellectual disability, spastic-dystonic cerebral palsy, epilepsy, and hearing loss.

Am J Hum Genet 2021 10;108(10):2006-2016

Institute of Human Genetics, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, 81675 Munich, Germany.

Spermatogenesis-associated 5 like 1 (SPATA5L1) represents an orphan gene encoding a protein of unknown function. We report 28 bi-allelic variants in SPATA5L1 associated with sensorineural hearing loss in 47 individuals from 28 (26 unrelated) families. In addition, 25/47 affected individuals (53%) presented with microcephaly, developmental delay/intellectual disability, cerebral palsy, and/or epilepsy. Modeling indicated damaging effect of variants on the protein, largely via destabilizing effects on protein domains. Brain imaging revealed diminished cerebral volume, thin corpus callosum, and periventricular leukomalacia, and quantitative volumetry demonstrated significantly diminished white matter volumes in several individuals. Immunofluorescent imaging in rat hippocampal neurons revealed localization of Spata5l1 in neuronal and glial cell nuclei and more prominent expression in neurons. In the rodent inner ear, Spata5l1 is expressed in the neurosensory hair cells and inner ear supporting cells. Transcriptomic analysis performed with fibroblasts from affected individuals was able to distinguish affected from controls by principal components. Analysis of differentially expressed genes and networks suggested a role for SPATA5L1 in cell surface adhesion receptor function, intracellular focal adhesions, and DNA replication and mitosis. Collectively, our results indicate that bi-allelic SPATA5L1 variants lead to a human disease characterized by sensorineural hearing loss (SNHL) with or without a nonprogressive mixed neurodevelopmental phenotype.
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http://dx.doi.org/10.1016/j.ajhg.2021.08.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8546233PMC
October 2021

The epidermis cells of mandible teeth in the terrestrial isopod Porcellio scaber: Differentiations for mineralisation with calcium phosphate and carbonate.

Arthropod Struct Dev 2021 Nov 6;65:101101. Epub 2021 Sep 6.

Central Facility for Electron Microscopy, University of Ulm, Albert-Einstein-Allee 11, 89069 Ulm, Germany.

Generally, the mineralisation of the crustacean cuticle occurs when the cuticle has expanded after moulting. However, in the partes incisivae of Porcellio scaber, cuticle mineralisation with calcium phosphate already occurs before the moult. We investigated the ultrastructure and distribution of organelles within the epidermis cells and searched for calcium-containing organelles using EDX and EFTEM analysis. We found two different cell types. Calcium carbonate-secreting C-cells, which resemble the epithelial cells of the general integument, and the P-cells, which, as an unusual feature, have cell extensions up to 400 μm long. During secretion of the partes incisivae, these extensions end at the unmineralised tip and the phosphate-containing middle region. Their cell bodies contain most of the mitochondria located in basal folds and a high amount of endoplasmic reticulum. The cell extensions contain many microtubules, endoplasmic reticulum, large and small vesicles and densely stained rod-shaped cisternae. The rod-shaped cisternae and the endoplasmic reticulum contain calcium. During cuticle mineralisation, vesicles, which probably belong to the endo-lysosomal system, contain calcium and phosphorus. They occur at some distance and close to the cuticle. The mineral in these vesicles has a similar composition to that within the cuticle, suggesting that they play a role in cuticle mineralisation.
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http://dx.doi.org/10.1016/j.asd.2021.101101DOI Listing
November 2021

A Modular Approach to Combine Postmarket Clinical Follow-Up Studies and Postmarket Surveillance Studies.

Methods Inf Med 2021 09 27;60(3-04):116-122. Epub 2021 Aug 27.

Amedon GmbH, Lübeck, Germany.

Background: The European Medical Device Regulation 2017/745 (MDR) has its date of application in May 2021. This new legislation has refined and expanded the need of manufacturers to have a postmarket surveillance (PMS) system. According to this legislation, a postmarket clinical follow-up (PMCF) plan is also required. Manufacturers of high-risk medical devices are obliged to conduct both PMCF and PMS studies. There is thus the need to generate evidence from clinical data.

Objectives: The conduct of several studies for PMS and PMCF can be cumbersome. We therefore aim to present a modular approach to combine PMS and PMCF studies into a single study.

Materials And Methods: We extracted the topics listed in the MDR, especially Annex XV, Section 3, the Good Clinical Practice for medical devices (EN 14155:2020, Annex A). In addition, we added topics according to the SPIRIT and the SPIRIT-PRO statement and created a draft clinical investigation plan (CIP).

Results: The CIP template is provided as part of the manuscript. The modular concept has passed the required regulatory and legal requirements for one specific study.

Conclusion: A modular approach for combining PMCF and PMS studies in a single CIP has been developed and implemented, and it is ready for use. The provided CIP template should enable other researchers and groups to adopt this concept according to their needs.
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http://dx.doi.org/10.1055/s-0041-1735165DOI Listing
September 2021

The dorsal tergite cuticle of Ultrastructure, mineral distribution, calcite microstructure and texture.

J Struct Biol X 2021 10;5:100051. Epub 2021 Jul 10.

Central Facility for Electron Microscopy, University of Ulm, Albert-Einstein-Allee 11, 89069 Ulm, Germany.

Among the terrestrial Crustacea, isopods have most successfully established themselves in a large variety of terrestrial habitats. As in most Crustacea, their cuticle consists of a hierarchically organised organic phase of chitin-protein fibrils, containing calcium carbonate and some calcium phosphate. In previous studies, we examined the tergite cuticle of which lives on seashores and burrows into moist sand. In this study, we investigate the closely related species which is completely terrestrial and lives in leaf litter and humus and burrows into the soil. To get deeper insights in relation between the structure of the organic and mineral phase in species living in diverse habitats, we have investigated the structure, and the chemical and crystallographic properties of the tergite cuticle using various preparation techniques, and microscopic and analytical methods. The results reveal long and short epicuticular sensilla with brushed tips on the tergite surface that do not occur in As in a distal exocuticle, which contains a low number of organic fibres, contains calcite while the subjacent layers of the exo- and endocuticle contain amorphous calcium carbonate. The distal exocuticle contains a polygonal pattern of mineral initiation sites that correspond to interprismatic septa described for decapod crabs. The shape and position of calcite units do not follow the polygonal pattern of the septa. The results indicate that the calcite units form by crystallisation from an amorphous phase that progresses from both margins of the septa to the centres of the polygons.
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http://dx.doi.org/10.1016/j.yjsbx.2021.100051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8313847PMC
July 2021

Diagnostic Validation of a High-Sensitivity Cardiac Troponin I Assay.

Clin Chem 2021 Sep;67(9):1230-1239

Department of Cardiology, University Heart and Vascular Center Hamburg, Hamburg, Germany.

Background: Emergency departments worldwide are increasingly adopting rapid diagnosis of patients with suspected myocardial infarction (MI) based on high-sensitivity troponin. We set out to assess the diagnostic accuracy of a high-sensitivity cardiac troponin I (hs-cTnI) assay in a prospective study.

Methods: In a cohort study including 1800 patients presenting with suspected acute MI, we developed and temporally validated a 0/1 h diagnostic algorithm using the Siemens Atellica IM hs-cTnI assay. The algorithm was established in the first 928 patients and validated in the following 872 patients.

Results: The derived algorithm consisted of a baseline rule-out of non-ST-segment elevation MI using a cutoff <3 ng/L in patients with symptom onset ≥3 h or an admission troponin I level <6 ng/L with a Δ change of <3 ng/L from 0 h to 1 h. For rule-in, an admission troponin I level ≥120 ng/L or an increase within the first hour ≥12 ng/L was required. Application of the algorithm to the validation cohort showed a negative predictive value of 99.8% (95% CI, 98.7%-100.0%), sensitivity of 99.1% (95% CI, 95.1%-100.0%), and 48.3% of patients ruled out, whereas 15.1% were ruled in with a positive predictive value of 68.0% (95% CI, 59.1%-75.9%) and specificity of 94.4% (95% CI, 92.5%-96.0%). The diagnostic performance was comparable to guideline-recommended application of an established hs-cTnI assay in a rapid 0/1 h strategy.

Conclusions: The Siemens hs-cTnI assay is well suited for application in rapid diagnostic stratification of patients with suspected MI.

Study Registration: www.clinicaltrials.gov (NCT02355457).
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http://dx.doi.org/10.1093/clinchem/hvab070DOI Listing
September 2021

Biallelic and monoallelic variants in PLXNA1 are implicated in a novel neurodevelopmental disorder with variable cerebral and eye anomalies.

Genet Med 2021 09 30;23(9):1715-1725. Epub 2021 May 30.

Department of Medical Genetics, Centre for Applied Neurogenetics, University of British Columbia, Vancouver, BC, Canada.

Purpose: To investigate the effect of PLXNA1 variants on the phenotype of patients with autosomal dominant and recessive inheritance patterns and to functionally characterize the zebrafish homologs plxna1a and plxna1b during development.

Methods: We assembled ten patients from seven families with biallelic or de novo PLXNA1 variants. We describe genotype-phenotype correlations, investigated the variants by structural modeling, and used Morpholino knockdown experiments in zebrafish to characterize the embryonic role of plxna1a and plxna1b.

Results: Shared phenotypic features among patients include global developmental delay (9/10), brain anomalies (6/10), and eye anomalies (7/10). Notably, seizures were predominantly reported in patients with monoallelic variants. Structural modeling of missense variants in PLXNA1 suggests distortion in the native protein. Our zebrafish studies enforce an embryonic role of plxna1a and plxna1b in the development of the central nervous system and the eye.

Conclusion: We propose that different biallelic and monoallelic variants in PLXNA1 result in a novel neurodevelopmental syndrome mainly comprising developmental delay, brain, and eye anomalies. We hypothesize that biallelic variants in the extracellular Plexin-A1 domains lead to impaired dimerization or lack of receptor molecules, whereas monoallelic variants in the intracellular Plexin-A1 domains might impair downstream signaling through a dominant-negative effect.
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http://dx.doi.org/10.1038/s41436-021-01196-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8460429PMC
September 2021

[Home infusion therapy for Pompe disease: Recommendations for German-speaking countries].

Fortschr Neurol Psychiatr 2021 Apr 27. Epub 2021 Apr 27.

Friedrich-Baur- Institut der Neurologischen Klinik , Klinikum der Universität München, Deutschland.

Background: Pompe disease is a lysosomal multisystem disorder with predominant proximal myopathy. Treatment with enzyme replacement therapy (ERT) is available requiring life-long biweekly infusions of recombinant α-glucosidase. To minimize the burden of ERT patients ask for home infusion therapy.

Aims And Methods: Pompe disease experts from Germany, Austria, and Switzerland discussed in two consensus meetings in 2019 and 2020 requirements for home infusion therapy, adequate execution of treatment, and the legal situation for delegating physicians.

Results And Discussion: Home infusion therapy is principally feasible for patients with Pompe disease if certain preconditions are fulfilled, but the decision to implement has to be made on an individual basis. The treating physician delegates the execution of ERT to nursing staff but retains full legal responsibility. Home infusion therapy has to be carried out by specially trained and qualified staff. Infusion-related risks comprise mainly allergic reactions, and adequate medical treatment must be warranted. In German-speaking countries, clear rules for conducting home infusion therapy are needed to reduce psychosocial stress for patients with Pompe disease, and providing legal certainty for delegating physicians.
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http://dx.doi.org/10.1055/a-1482-6041DOI Listing
April 2021

Response to letter: A decision for life - Treatment decisions in newly diagnosed families with spinal muscular atrophy.

Eur J Paediatr Neurol 2021 Jan 14;30:103-104. Epub 2020 Dec 14.

Dubowitz Neuromuscular Centre, UCL Great Ormond Street Institute of Child Health, And NIHR Biomedical Research Centre, Great Ormond Street Hospital for Children, London, UK. Electronic address:

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http://dx.doi.org/10.1016/j.ejpn.2020.12.005DOI Listing
January 2021

[Home infusion therapy for Pompe disease: Recommendations for German-speaking countries].

Fortschr Neurol Psychiatr 2021 Dec 9;89(12):630-636. Epub 2021 Feb 9.

Friedrich-Baur- Institut der Neurologischen Klinik , Klinikum der Universität München, Deutschland.

Background: Pompe disease is a lysosomal multisystem disorder with predominant proximal myopathy. Treatment with enzyme replacement therapy (ERT) is available requiring life-long biweekly infusions of recombinant α-glucosidase. To minimize the burden of ERT patients ask for home infusion therapy.

Aims And Methods: Pompe disease experts from Germany, Austria, and Switzerland discussed in two consensus meetings in 2019 and 2020 requirements for home infusion therapy, adequate execution of treatment, and the legal situation for delegating physicians.

Results And Discussion: Home infusion therapy is principally feasible for patients with Pompe disease if certain preconditions are fulfilled, but the decision to implement has to be made on an individual basis. The treating physician delegates the execution of ERT to nursing staff but retains full legal responsibility. Home infusion therapy has to be carried out by specially trained and qualified staff. Infusion-related risks comprise mainly allergic reactions, and adequate medical treatment must be warranted. In German-speaking countries, clear rules for conducting home infusion therapy are needed to reduce psychosocial stress for patients with Pompe disease, and providing legal certainty for delegating physicians.
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http://dx.doi.org/10.1055/a-1365-8977DOI Listing
December 2021

Focus on time: dynamic imaging reveals stretch-dependent cell relaxation and nuclear deformation.

Biophys J 2021 03 30;120(5):764-772. Epub 2021 Jan 30.

University Hospital Balgrist, University of Zurich, Zurich, Switzerland; Institute for Biomechanics, ETH Zurich, Zurich, Switzerland; BCMaterials, Basque Center for Materials, Applications and Nanostructures, UPV/EHU Science Park, Leioa, Spain; Ikerbasque, Basque Foundation for Science, Bilbao, Spain. Electronic address:

Among the stimuli to which cells are exposed in vivo, it has been shown that tensile deformations induce specific cellular responses in musculoskeletal, cardiovascular, and stromal tissues. However, the early response of cells to sustained substrate-based stretch has remained elusive because of the short timescale at which it occurs. To measure the tensile mechanical properties of adherent cells immediately after the application of substrate deformations, we have developed a dynamic traction force microscopy method that enables subsecond temporal resolution imaging of transient subcellular events. The system employs a novel, to our knowledge, tracking approach with minimal computational overhead to compensate substrate-based, stretch-induced motion/drift of stretched single cells in real time, allowing capture of biophysical phenomena on multiple channels by fluorescent multichannel imaging on a single camera, thus avoiding the need for beam splitting with the associated loss of light. Using this tool, we have characterized the transient subcellular forces and nuclear deformations of single cells immediately after the application of equibiaxial strain. Our experiments reveal significant differences in the cell relaxation dynamics and in the intracellular propagation of force to the nuclear compartment in cells stretched at different strain rates and exposes the need for time control for the correct interpretation of dynamic cell mechanics experiments.
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http://dx.doi.org/10.1016/j.bpj.2021.01.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8008268PMC
March 2021

Gene-Targeted Therapies and Palliative Care in Children with Spinal Muscular Atrophy Type I: No Intrinsic Contradiction.

J Palliat Med 2021 02;24(2):162-163

Zentrum für Kinder- und Jugendmedizin Heidelberg, Sektion Neuropädiatrie und Stoffwechselmedizin, Universitätsklinikum Heidelberg, Heidelberg, Germany.

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http://dx.doi.org/10.1089/jpm.2020.0505DOI Listing
February 2021

Empirical analysis of the text structure of original research articles in medical journals.

PLoS One 2020 8;15(10):e0240288. Epub 2020 Oct 8.

Medizincampus Davos, Davos, Switzerland.

Successful publishing of an article depends on several factors, including the structure of the main text, the so-called introduction, methods, results and discussion structure (IMRAD). The first objective of our work is to provide recent results on the number of paragraphs (pars.) per section used in articles published in major medical journals. Our second objective is the investigation of other structural elements, i.e., number of tables, figures and references and the availability of supplementary material. We analyzed data from randomly selected original articles published in years 2005, 2010 and 2015 from the journals The BMJ, The Journal of the American Medical Association, The Lancet, The New England Journal of Medicine and PLOS Medicine. Per journal and year 30 articles were investigated. Random effect meta-analyses were performed to provide pooled estimates. The effect of time was analyzed by linear mixed models. All articles followed the IMRAD structure. The number of pars. per section increased for all journals over time with 1.08 (95% confidence interval (CI): 0.70-1.46) pars. per every two years. The largest increase was observed for the methods section (0.29 pars. per year; 95% confidence interval (CI): 0.19-0.39). PLOS Medicine had the highest number of pars. The number of tables did not change, but number of figures and references increased slightly. Not only the standard IMRAD structure should be used to increase the likelihood for publication of an article but also the general layout of the target journal. Supplementary material has become standard. If no journal-specific information is available, authors should use 3/10/9/8 pars. for the introduction/methods/results/discussion sections.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0240288PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7544105PMC
December 2020

Defining the clinical, molecular and imaging spectrum of adaptor protein complex 4-associated hereditary spastic paraplegia.

Brain 2020 10;143(10):2929-2944

Division of Neurology, Department of Pediatrics, University of Iowa Carver College of Medicine, Iowa City, IA, USA.

Bi-allelic loss-of-function variants in genes that encode subunits of the adaptor protein complex 4 (AP-4) lead to prototypical yet poorly understood forms of childhood-onset and complex hereditary spastic paraplegia: SPG47 (AP4B1), SPG50 (AP4M1), SPG51 (AP4E1) and SPG52 (AP4S1). Here, we report a detailed cross-sectional analysis of clinical, imaging and molecular data of 156 patients from 101 families. Enrolled patients were of diverse ethnic backgrounds and covered a wide age range (1.0-49.3 years). While the mean age at symptom onset was 0.8 ± 0.6 years [standard deviation (SD), range 0.2-5.0], the mean age at diagnosis was 10.2 ± 8.5 years (SD, range 0.1-46.3). We define a set of core features: early-onset developmental delay with delayed motor milestones and significant speech delay (50% non-verbal); intellectual disability in the moderate to severe range; mild hypotonia in infancy followed by spastic diplegia (mean age: 8.4 ± 5.1 years, SD) and later tetraplegia (mean age: 16.1 ± 9.8 years, SD); postnatal microcephaly (83%); foot deformities (69%); and epilepsy (66%) that is intractable in a subset. At last follow-up, 36% ambulated with assistance (mean age: 8.9 ± 6.4 years, SD) and 54% were wheelchair-dependent (mean age: 13.4 ± 9.8 years, SD). Episodes of stereotypic laughing, possibly consistent with a pseudobulbar affect, were found in 56% of patients. Key features on neuroimaging include a thin corpus callosum (90%), ventriculomegaly (65%) often with colpocephaly, and periventricular white-matter signal abnormalities (68%). Iron deposition and polymicrogyria were found in a subset of patients. AP4B1-associated SPG47 and AP4M1-associated SPG50 accounted for the majority of cases. About two-thirds of patients were born to consanguineous parents, and 82% carried homozygous variants. Over 70 unique variants were present, the majority of which are frameshift or nonsense mutations. To track disease progression across the age spectrum, we defined the relationship between disease severity as measured by several rating scales and disease duration. We found that the presence of epilepsy, which manifested before the age of 3 years in the majority of patients, was associated with worse motor outcomes. Exploring genotype-phenotype correlations, we found that disease severity and major phenotypes were equally distributed among the four subtypes, establishing that SPG47, SPG50, SPG51 and SPG52 share a common phenotype, an 'AP-4 deficiency syndrome'. By delineating the core clinical, imaging, and molecular features of AP-4-associated hereditary spastic paraplegia across the age spectrum our results will facilitate early diagnosis, enable counselling and anticipatory guidance of affected families and help define endpoints for future interventional trials.
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http://dx.doi.org/10.1093/brain/awz307DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7780481PMC
October 2020

Intracellular calcium phosphate deposits contribute to transcellular calcium transport within the hepatopancreas of Porcellio scaber.

J Struct Biol 2020 11 4;212(2):107613. Epub 2020 Sep 4.

Central Facility for Electron Microscopy, University of Ulm, Albert-Einstein-Allee 11, 89069 Ulm, Germany.

Like in most Crustacea, the cuticle of terrestrial isopods is hardened by a calcareous mineral phase. This rigid cuticle is frequently shed during a process called moulting. To reduce calcium loss, Porcellio scaber eats the shed cuticle, the exuviae, and absorb the calcium from it through large tubular diverticula of the intestine, called the mid gut glands or hepatopancreas. After moulting the absorbed calcium should be transported immediately into the hemolymph from which it is used to rapidly mineralize the new cuticle. This suggests that the hepatopancreas epithelium transports calcium from the lumen to the hemolymph. We used TEM, energy-filtered TEM and electron-probe X-ray microanalysis to analyse the distribution of elevated calcium within the hepatopancreas cells of P. scaber. We used animals in the postmoult stage that have eaten their exuviae and, as a control, those that have not ingested the exuviae. To minimize calcium loss within the samples, we used high pressure frozen and freeze substituted samples and propane-1-3-diol as floatation medium for thin-sectioning. The results reveal intracellular dense deposits containing calcium, phosphorus and oxygen at the apical microvillus membrane, within the cytoplasm, attached to vesicles and to the basolateral membrane, as well as extracellular between cells and the basal lamina. Control animals were devoid of these deposits. The results indicate that calcium from the exuviae is absorbed and transported across the epithelium into the hemolymph. We propose that during transport, intracellular calcium is bound to phosphate avoiding toxic effects of high concentrations of ionized calcium.
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http://dx.doi.org/10.1016/j.jsb.2020.107613DOI Listing
November 2020

Maintenance of muscle strength following a one-year resistance training program in older adults.

Exp Gerontol 2020 10 8;139:111049. Epub 2020 Aug 8.

Institute of Sports Medicine Copenhagen, Department of Orthopaedic Surgery M81 and Center for Translational Research, Bispebjerg and Frederiksberg Hospital, Nielsine Nielsensvej 11, 2400 Copenhagen NV, Denmark; Center for Healthy Aging, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen N, Denmark.

Background: Muscle mass, strength and function declines with advancing age. Strength training (ST) improves these parameters in older adults, but the gains often disappear after completion of a short-term intervention. The purpose of the present study was to investigate muscle mass, -strength and -function one year after the completion of a successful long-term (12 months) supervised ST program in older adults.

Method: Men and women (n = 419, age: 62-70 years) completed one year of supervised heavy resistance training (HRT, n = 143) or moderate intensity resistance training (MIT, n = 144) and were compared to a non-exercising control group (CON, n = 132). At 1-year follow-up, 398 participants returned for measurements of muscle power, -strength and -mass, physical function, body composition, hippocampus volume and physical/mental well-being. The results were compared to pre-training (baseline) and post-training (1-year) values. Further, the participants from the two previous training groups (HRT + MIT, n = 265) were divided into 1) those who on their own continued the ST program (>9 months) the year after completion of the supervised ST program (CONTIN, n = 65) and 2) those who stopped during the follow-up year (<9 months) (STOP, n = 200).

Results: Out of all the improvements obtained after the 1-year training intervention, only knee extensor muscle strength in HRT was preserved at 1-year follow-up (p < 0.0001), where muscle strength was 7% higher than baseline. Additionally, the decrease in muscle strength over the second year was lower in CONTIN than in STOP with decreases of 1% and 6%, respectively (p < 0.05). Only in CONTIN was the muscle strength still higher at 1-year follow-up compared with baseline with a 14% increase (p < 0.0001). The heavy strength training induced increase in whole-body lean mass was erased at 1-year follow-up. However, there was a tendency for maintenance of the cross-sectional area of m. vastus lateralis from baseline to 1-year follow-up in HRT compared with CON (p = 0.06). Waist circumference decreased further over the second year in CONTIN, whereas it increased in STOP (p < 0.05).

Conclusion: Even though long-term strength training effectively improved muscle function and other health parameters in older adults, only knee extensor muscle strength was preserved one year after completion of heavy (but not moderate intensity) resistance training. Continuation of strength training resulted in better maintenance of muscle strength and health, which indicates that it is required to continue with physical activity to benefit from the long-term effects of strength training upon muscle function and health in older men and women.
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http://dx.doi.org/10.1016/j.exger.2020.111049DOI Listing
October 2020

European ad-hoc consensus statement on gene replacement therapy for spinal muscular atrophy.

Eur J Paediatr Neurol 2020 Sep 9;28:38-43. Epub 2020 Jul 9.

Dubowitz Neuromuscular Centre, UCL Great Ormond Street Institute of Child Health, and NIHR Biomedical Research Centre, Great Ormond Street Hospital for Children, London, UK. Electronic address:

Spinal muscular atrophy (SMA) used to be one of the most common genetic causes of infant mortality. New disease modifying treatments have changed the disease trajectories and most impressive results are seen if treatment is initiated in the presymptomatic phase of the disease. Very recently, the European Medicine Agency approved Onasemnogene abeparvovec (Zolgensma®) for the treatment of patients with SMA with up to three copies of the SMN2 gene or the clinical presentation of SMA type 1. While this broad indication provides new opportunities, it also triggers discussions on the appropriate selection of patients in the context of limited available evidence. To aid the rational use of Onasemnogene abeparvovec for the treatment of SMA, a group of European neuromuscular experts presents in this paper eleven consensus statements covering qualification, patient selection, safety considerations and long-term monitoring.
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http://dx.doi.org/10.1016/j.ejpn.2020.07.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7347351PMC
September 2020

Functional adaptations in the tergite cuticle of the desert isopod Hemilepistus reaumuri (Milne-Edwards, 1840).

J Struct Biol 2020 10 7;212(1):107570. Epub 2020 Jul 7.

Central Facility for Electron Microscopy, University of Ulm, Albert-Einstein-Allee 11, 89069 Ulm, Germany. Electronic address:

To survive in its extreme habitat, the cuticle of the burrowing desert isopod Hemilepistus reaumuri requires properties distinct from isopods living in moist or mesic habitats. In particular, the anterior tergites are exposed to high mechanical loads and temperatures when individuals guard the entrance of their burrow. We have, therefore, investigated the architecture, composition, calcite texture and local mechanical properties of the tergite cuticle, with particular emphasis on large anterior cuticle tubercles and differences between the anterior and posterior tergite. Unexpectedly, structure and thickness of the epicuticle resemble those in mesic isopod species. The anterior tergite has a thicker endocuticle and a higher local stiffness than the posterior tergite. Calcite distribution in the cuticle is unusual, because in addition to the exocuticle the endocuticle distally also contains calcite. The calcite consists of a distal layer of dense and highly co-oriented crystal-units, followed proximally by irregularly distributed and, with respect to each other, misoriented calcite crystallites. The calcite layer at the tip of the tubercle is thicker relative to the tubercle slopes, and its crystallites are more misoriented to each other. A steep decrease of local stiffness and hardness is observed within a distal region of the cuticle, likely caused by a successive increase in the ACC/calcite ratio rather than changes in the degree of mineralisation. Comparison of the results with other isopods reveals a much lower ACC/calcite ratio in H. reaumuri and a correlation between the degree of terrestriality of isopod species and the magnesium content of the cuticle.
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http://dx.doi.org/10.1016/j.jsb.2020.107570DOI Listing
October 2020

CASPR2 autoimmunity in children expanding to mild encephalopathy with hypertension.

Neurology 2020 06 18;94(22):e2290-e2301. Epub 2020 May 18.

From the Division of Pediatric Epileptology (S. Syrbe), Centre for Paediatrics and Adolescent Medicine, University Hospital Heidelberg, Germany; Division of Pediatric Neurology (G.M.S., R.S.), University Children's Hospital Zurich; Department of Neurology (J.B., R.I.F.), University & University Hospitals of Geneva, Switzerland; Division of Pediatric Neurology (I.B.), Developmental Neurology and Social Pediatrics, Department of Pediatrics and Epilepsy Center for Children, Adolescents and Adults, University Hospital LMU Munich; Laboratory Krone (C.I.B., C.G.B.), Bad Salzuflen; Department of Pediatrics and Pediatric Neurology (P.H.), Faculty of Medicine, Georg August University, Goettingen; Department of Child Neurology (J.K., A.W.), University Children's Hospital, Tuebingen; Epilepsy Center Bethel (T.P., C.G.B.), Krankenhaus Mara, Bielefeld, Germany; Clinic of Immunology (E.P.-M.), University Hospital Zurich; Kantonsspital Graubünden (S. Schmid, S. Strozzi), Chur; Pediatric Nephrology Unit (M.W.), University Children's Hospital Zurich, Switzerland; Division of Child Neurology and Metabolic Medicine (A.Z.), Centre for Paediatrics and Adolescent Medicine, University Hospital Heidelberg; Institute of Clinical Chemistry (K.-P.W., F.L.), Neuroimmunology Section, University Hospital Schleswig-Holstein Kiel/Lübeck; Department of Neurology (K.-P.W.), University of Lübeck; and Department of Neurology (F.L.), Christian-Albrechts-University Kiel, Germany.

Objective: To delineate autoimmune disease in association with contactin-associated protein 2 (CASPR2) antibodies in childhood, we reviewed the clinical phenotype of children with CASPR2 antibodies.

Methods: Retrospective assessment of patients recruited through laboratories specialized in autoimmune CNS disease.

Results: Ten children with serum CASPR2 antibodies were identified (age at manifestation 18 months to 17 years). Eight children with CASPR2 antibody titers from ≥1:160 to 1:5,120 had complex autoimmune diseases with an age-dependent clinical phenotype. Two children with structural epilepsy due to CNS malformations harbored nonspecific low-titer CASPR2 antibodies (serum titers 1:80). The clinical symptoms of the 8 children with high-titer CASPR2 antibodies were general weakness (8/8), sleep dysregulation (8/8), dysautonomia (8/8) encephalopathy (7/8), neuropathic pain (7/8), neuromyotonia (3/8), and flaccid paresis (3/8). Adolescents (3/8) showed pain, neuromyotonia, and encephalopathy, whereas younger children (5/8) displayed severe hypertension, encephalopathy, and hormonal dysfunction mimicking a systemic disease. No tumors were identified. Motor symptoms remitted with immunotherapy. Mild behavioral changes persisted in 1 child, and autism spectrum disorder was diagnosed during follow-up in a young boy.

Conclusion: High-titer CASPR2 antibodies are associated with Morvan syndrome in children as young as 2 years. However, CASPR2 autoimmunity mimics systemic disease and hypertensive encephalopathy in children younger than 7 years. The outcome following immunotherapy was mostly favorable; long-term behavioral impairment may occur in younger children.
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http://dx.doi.org/10.1212/WNL.0000000000009523DOI Listing
June 2020

[Recommendations for gene therapy of spinal muscular atrophy with onasemnogene abeparvovec-AVXS-101 : Consensus paper of the German representatives of the Society for Pediatric Neurology (GNP) and the German treatment centers with collaboration of the medical scientific advisory board of the German Society for Muscular Diseases (DGM)].

Nervenarzt 2020 Jun;91(6):518-529

Abteilung Neuropädiatrie und Sozialpädiatrisches Zentrum, Zentrum für Kinderheilkunde, Universitätsklinikum Bonn, Bonn, Deutschland.

Background: Spinal muscular atrophy (SMA) is a severe, life-limiting neurodegenerative disease. A disease-modifying and approved therapy with nusinersen has been available in Germany since July 2017. Gene therapies offer another promising treatment option through a once in a lifetime administration. In May 2019 a gene replacement therapy for the treatment of SMA was approved for the first time by the U.S. Food and Drug Administration (FDA). An application for approval in Europe has been submitted and is currently pending.

Objective: This consensus paper was compiled at the invitation of the German Society for Muscular Diseases (DGM) with the participation of all potential German neuromuscular treatment centers, the German section of the Society for Pediatric Neurology (GNP) and with the involvement of the medical scientific advisory board of the DGM. The aim was to define and establish the necessary prerequisites for a safe and successful application of the new gene replacement therapy in clinical practice.

Conclusion: Gene replacement therapy with onasemnogene abeparvovec has the potential to significantly influence the course of SMA. Long-term data on sustainability of effects and possible adverse effects of gene replacement therapy are not yet available. The application of this innovative therapy must be carried out in specialized and appropriately qualified treatment centers under strict safety conditions. This article makes suggestions for the necessary framework conditions and gives recommendations for a systematic pretreatment and posttreatment assessment schedule under gene therapy. The effectiveness and safety of the therapy should be systematically documented in an industry-independent and disease-specific register.
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http://dx.doi.org/10.1007/s00115-020-00919-8DOI Listing
June 2020

The influence of prolonged strength training upon muscle and fat in healthy and chronically diseased older adults.

Exp Gerontol 2020 07 8;136:110939. Epub 2020 Apr 8.

Institute of Sports Medicine Copenhagen, Department of Orthopaedic Surgery M81 and Centre for Translational Research, Bispebjerg and Frederiksberg Hospital, Bispebjerg Bakke 23, 2400 Copenhagen, NV, Denmark; Center for Healthy Aging, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen, N, Denmark.

Background: Physical muscle function and brain hippocampus size declines with age, accelerating after the age of 60. Strength training over a few months improves physical function, but less is known about how long-term strength training affects physical function and hippocampus volume. Therefore, we aimed to investigate the effect of 1-year strength training of two different intensities upon muscle mass, function, and hippocampus volume in retirement-age individuals.

Methods: In this multidisciplinary randomized controlled trial (clinicaltrials.gov: NCT02123641), participants were allocated to either a) supervised, heavy resistance training (HRT, n = 149, 3/wk), b) moderate intensity resistance training (MIT, n = 154, 3/wk) or c) non-exercise activities (CON, n = 148). 451 participants were randomized (62-70 yrs., women 61%, ≈80% with a chronic medical disease) and 419 were included in the intention-to-treat analysis (n = 143, 144 and 132; HRT, MIT and CON). Changes in muscle power (primary outcome), strength and size, physical function, body composition, hippocampus volume and physical/mental well-being were analyzed.

Findings: Of the participants (HRT + MIT), 83% completed training at least 2/week. Leg extensor power was unchanged in all groups, but strength training had a positive effect on isometric knee extensor strength in both groups, whereas an increased muscle mass, cross-sectional area of vastus lateralis muscle, a decreased whole-body fat percentage, visceral fat content and an improved mental health (SF-36) occurred in HRT only. Further, chair-stand performance improved in all groups, whereas hippocampus volume decreased in all groups over time with no influence of strength training.

Interpretation: Together, the results indicate that leg extensor power did not respond to long-term supervised strength training, but this type of training in a mixed group of healthy and chronically diseased elderly individuals can be implemented with good compliance and induces consistent changes in physiological parameters of muscle strength, muscle mass and abdominal fat.
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July 2020

Osteosynthesis of the Mandibular Condyle With Magnesium-Based Biodegradable Headless Compression Screws Show Good Clinical Results During a 1-Year Follow-Up Period.

J Oral Maxillofac Surg 2021 Mar 3;79(3):637-643. Epub 2020 Mar 3.

Resident, Department of Oral Maxillofacial Surgery, University Hospital Carl Gustav Carus, Dresden, Germany.

Purpose: The use of titanium-based implants in mandibular condyle fractures can require implant removal because of screw penetration through the condylar surface. The use of biodegradable implants can avoid a second operation for implant removal and the associated possible complications. We investigated the clinical and radiologic outcomes of osteosynthesis of mandibular condyle fractures (MCFs) with biodegradable magnesium-based compression screws.

Materials And Methods: We performed a retrospective observational study of 6 patients who had been treated at our department. We recorded the changes in jaw movements over time, occlusion, and possible complications at defined intervals of 1, 3, 6, and 12 months postoperatively. We also compared the preoperative computed tomography (CT) scans with the postoperative cone-beam CT (CBCT) scans at 6 and 12 months postoperatively to evaluate mandibular condyle healing and screw degradation.

Results: Of the 6 patients, 4 were men and 2 were women, with a mean age of 43.2 years (range, 30 to 66 years). All 6 patients had unilateral MCFs. All the patients showed well-restored function of the temporomandibular joint with significant improvement in mouth opening (46.17 ± 6.49 mm), right (10.67 ± 1.03 mm) and left (10.67 ± 1.97 mm) laterotrusion, and protrusion (10.17 ± 1.33 mm) distances to physiologic values. The CBCT scans showed the remodeling processes of the mandibular condyle and a few radiolucencies indicating the magnesium-based screws. Although penetration of 1 screw tip through the condylar surface had occurred, no implant removal was necessary owing to biodegradation of the implant.

Conclusions: The results of the present study have shown that biodegradable magnesium-based compression screws provide good clinical results and avoid implant removal.
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http://dx.doi.org/10.1016/j.joms.2020.02.025DOI Listing
March 2021

Nusinersen in adults with 5q spinal muscular atrophy: a non-interventional, multicentre, observational cohort study.

Lancet Neurol 2020 04 18;19(4):317-325. Epub 2020 Mar 18.

Department of Neurology, Ulm University, Ulm, Germany; German Center for Neurodegenerative Diseases Ulm, Ulm, Germany.

Background: Nusinersen is approved for the treatment of 5q spinal muscular atrophy of all types and stages in patients of all ages. Although clinical trials have shown improvements in motor function in infants and children treated with the drug, data for adults are scarce. We aimed to assess the safety and efficacy of nusinersen in adults with 5q spinal muscular atrophy.

Methods: We did an observational cohort study at ten academic clinical sites in Germany. Patients with genetically confirmed 5q spinal muscular atrophy (age 16-65 years) with a homozygous deletion of exons 7, 8, or both, or with compound heterozygous mutations were eligible for inclusion and received nusinersen treatment in accordance with the label for a minimum treatment time of 6 months to a follow-up of up to 14 months. The primary outcome was the change in the total Hammersmith Functional Motor Scale Expanded (HFMSE) score, assessed at months 6, 10, and 14, and based on pre-post comparisons. This study is registered with the German Clinical Trials Register (number DRKS00015702).

Findings: Between July 13, 2017, and May 1, 2019, 173 patients were screened, of whom 139 (80%) were eligible for data analysis. Of these, 124 (89%) were included in the 6-month analysis, 92 (66%) in the 10-month analysis, and 57 (41%) in the 14-month analysis; patients with missing baseline HFMSE scores were excluded from these analyses. Mean HFMSE scores were significantly increased compared with baseline at 6 months (mean difference 1·73 [95% CI 1·05-2·41], p<0·0001), 10 months (2·58 [1·76-3·39], p<0·0001), and 14 months (3·12 [2·06-4·19], p<0·0001). Clinically meaningful improvements (≥3 points increase) in HFMSE scores were seen in 35 (28%) of 124 patients at 6 months, 33 (35%) of 92 at 10 months, and 23 (40%) of 57 at 14 months. To 14-month follow-up, the most frequent adverse effects among 173 patients were headache (61 [35%] patients), back pain (38 [22%]), and nausea (19 [11%]). No serious adverse events were reported.

Interpretation: Despite the limitations of the observational study design and a slow functional decline throughout the natural disease course, our data provide evidence for the safety and efficacy of nusinersen in the treatment of adults with 5q spinal muscular atrophy, with clinically meaningful improvements in motor function in a real-world cohort.

Funding: None.
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http://dx.doi.org/10.1016/S1474-4422(20)30037-5DOI Listing
April 2020

Conformational Plasticity of HLA-B27 Molecules Correlates Inversely With Efficiency of Negative T Cell Selection.

Front Immunol 2020 11;11:179. Epub 2020 Feb 11.

Ziegler Biosolutions, Waldshut-Tiengen, Germany.

The development of autoimmune disorders is incompletely understood. Inefficient thymic T cell selection against self-peptides presented by major histocompatibility antigens (HLA in humans) may contribute to the emergence of auto-reactive effector cells, and molecular mimicry between foreign and self-peptides could promote T cell cross-reactivity. A pair of class I subtypes, HLA-B2705 and HLA-B2709, have previously been intensely studied, because they are distinguished from each other only by a single amino acid exchange at the floor of the peptide-binding groove, yet are differentially associated with the autoinflammatory disorder ankylosing spondylitis. Using X-ray crystallography in combination with ensemble refinement, we find that the non-disease-associated subtype HLA-B2709, when presenting the self-peptide pGR (RRRWHRWRL), exhibits elevated conformational dynamics, and the complex can also be recognized by T cells. Both features are not observed in case of the sequence-related self-peptide pVIPR (RRKWRRWHL) in complex with this subtype, and T cell cross-reactivity between pGR, pVIPR, and the viral peptide pLMP2 (RRRWRRLTV) is only rarely observed. The disease-associated subtype HLA-B2705, however, exhibits extensive conformational flexibility in case of the three complexes, all of which are also recognized by frequently occurring cross-reactive T cells. A comparison of the structural and dynamic properties of the six HLA-B27 complexes, together with their individual ability to interact with T cells, permits us to correlate the flexibility of HLA-B27 complexes with effector cell reactivity. The results suggest the existence of an inverse relationship between conformational plasticity of peptide-HLA-B27 complexes and the efficiency of negative selection of self-reactive cells within the thymus.
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http://dx.doi.org/10.3389/fimmu.2020.00179DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7027375PMC
February 2021

Axenfeld-Rieger Anomaly and Neuropsychiatric Problems-More than Meets the Eye.

Neuropediatrics 2020 06 11;51(3):192-197. Epub 2020 Feb 11.

Division of Pediatric Epileptology, Centre for Paediatrics and Adolescent Medicine, University Hospital Heidelberg, Heidelberg, Germany.

Objective: The main purpose of this article is to demonstrate the co-occurrence of Axenfeld-Rieger anomaly and neuropsychiatric problems as clinical signs of genetically determined cerebral small vessel disease in two patients.

Case Study: We report on two adolescent individuals with ocular anterior segment dysgenesis (Axenfeld-Rieger anomaly) presenting with neuropsychiatric symptoms. Both patients underwent cerebral magnetic resonance imaging showing white matter T2-hyperintensities involving different brain regions, suspective of cerebral small vessel disease. Genetic analysis revealed pathogenic mutations in the gene (patient 1) and the gene (patient 2), respectively.

Conclusion: We report on the co-occurrence of ocular anterior segment dysgenesis (Axenfeld-Rieger anomaly) and neuropsychiatric symptoms as clinical signs of genetically determined cerebral small vessel disease in two patients. In both patients, the cerebral lesions involved the frontotemporal regions, brain regions that control social behavior as well as executive and cognitive function, highlighting the fact that neuropsychiatric symptoms may be early clinical presentations of cerebral small vessel disease. We further provide a review of monogenic causes of pediatric cerebral small vessel disease, emphasizing the links to childhood-onset neuropsychiatric disease.
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http://dx.doi.org/10.1055/s-0039-3402037DOI Listing
June 2020

Statistical analysis plan for the randomized controlled trial CardioCare MV investigating a novel integrated care concept (NICC) for patients suffering from chronic cardiovascular disease.

Trials 2020 Feb 3;21(1):131. Epub 2020 Feb 3.

Universitätsmedizin Rostock, Ernst-Heydemann-Str. 8, 18057, Rostock, Germany.

Background: Cardiovascular diseases are the major cause of death globally and represent a major economic burden on health care systems. For patients with heart failure, atrial fibrillation or therapy-resistant hypertension, we have developed a novel integrated care concept (NICC) which combines telemedicine with intensive support by a care center, including a call center, an integrated care network including inpatient and outpatient care providers and guideline therapy for patients (Schmidt et al. 2018 Trials 19:120). Here, we describe challenges and solutions in patient recruitment and provide the statistical analysis plan.

Methods: The study CardioCare MV is a prospective, randomized, controlled, parallel-group, open-label, bi-center trial with two groups for comparing NICC with standard of care (SoC). Because of issues with patient enrollment we adapted the study plan after consultation with the Ethics Committee and the funding agency. We altered the analysis strategy for the primary endpoints, which led to a change in the required sample size. We also changed the access points to patients from inpatient hospitals specialized in the treatment of patients with cardiovascular disease to specialized practices.

Results: Recruitment of patients started on 1 December 2017, and first patient in was on 4 December 2017. Recruitment was completed on 15 August 2019 as planned according to the amended study plan. The follow-up period will end in August 2020. A total of 964 patients was enrolled into the trial. The statistical analysis plan was finalized prior to last patient in. Results will be available by the end of 2020.

Discussion: The trial will inform care providers whether quality of care can be improved by an integrated care concept providing telemedicine through a round-the-clock call center approach. We expect that cost of the NICC will be lower than standard care because of reduced hospitalizations. The trial will guide additional research to disentangle the effects of this complex intervention.

Trial Registration: DRKS, ID: DRKS00013124. Registered on 5 October 2017 ClinicalTrials.gov, ID: NCT03317951. Registered on 17 October 2017.
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http://dx.doi.org/10.1186/s13063-020-4052-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6998105PMC
February 2020

Cerebrospinal fluid proteomic profiling in nusinersen-treated patients with spinal muscular atrophy.

J Neurochem 2020 06 19;153(5):650-661. Epub 2020 Feb 19.

Department of Neurology, Heidelberg University Hospital, Heidelberg, Germany.

Promising results from recent clinical trials on the approved antisense oligonucleotide nusinersen in pediatric patients with 5q-linked spinal muscular atrophy (SMA) still have to be confirmed in adult patients but are hindered by a lack of sensitive biomarkers that indicate an early therapeutic response. Changes in the overall neurochemical composition of cerebrospinal fluid (CSF) under therapy may yield additive diagnostic and predictive information. With this prospective proof-of-concept and feasibility study, we evaluated non-targeted CSF proteomic profiles by mass spectrometry along with basic CSF parameters of 10 adult patients with SMA types 2 or 3 before and after 10 months of nusinersen therapy, in comparison with 10 age- and gender-matched controls. These data were analyzed by bioinformatics and correlated with clinical outcomes assessed by the Hammersmith Functional Rating Scale Expanded (HFMSE). CSF proteomic profiles of SMA patients differed from controls. Two groups of SMA patients were identified based on unsupervised clustering. These groups differed in age and expression of proteins related to neurodegeneration and neuroregeneration. Intraindividual CSF differences in response to nusinersen treatment varied between patients who clinically improved and those who did not. Data are available via ProteomeXchange with identifier PXD016757. Comparative CSF proteomic analysis in adult SMA patients before and after treatment with nusinersen-identified subgroups and treatment-related changes and may therefore be suitable for diagnostic and predictive analyses.
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http://dx.doi.org/10.1111/jnc.14953DOI Listing
June 2020

Diagnostic utility of small fiber analysis in skin biopsies from children with chronic pain.

Muscle Nerve 2020 02 9;61(2):173-181. Epub 2019 Dec 9.

Institute of Neuropathology, Justus-Liebig-University Giessen, Giessen, Germany.

Introduction: Small fiber neuropathies (SFN) are associated with a reduction in quality of life. In adults, epidermal nerve fiber density (END) analysis is recommended for the diagnosis of SFN. In children, END assessment is not often performed. We analyzed small nerve fiber innervation to elucidate the potential diagnostic role of skin biopsies in young patients with pain.

Methods: Epidermal nerve fiber density and sudomotor neurite density (SND) were assessed in skin biopsies from 26 patients aged 7 to 20 years (15 female patients) with unexplained chronic pain. The results were compared with clinical data.

Results: Epidermal nerve fiber density was abnormal in 50% and borderline in 35% of patients. An underlying medical condition was found in 42% of patients, including metabolic, autoimmune, and genetic disorders.

Discussion: Reduction of epidermal nerve fibers can be associated with treatable conditions. Therefore, the analysis of END in children with pain may help to uncover a possible cause and guide potential treatment options.
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http://dx.doi.org/10.1002/mus.26766DOI Listing
February 2020

Pulsed Electromagnetic Field Therapy Improves Osseous Consolidation after High Tibial Osteotomy in Elderly Patients-A Randomized, Placebo-Controlled, Double-Blind Trial.

J Clin Med 2019 Nov 17;8(11). Epub 2019 Nov 17.

Siegfried Weller Institute for Trauma Research, Department of Trauma and Reconstructive Surgery, BG Unfallklinik Tübingen, Eberhard Karls Universität Tübingen, Schnarrenbergstr. 95, D-72076 Tübingen, Germany.

Extremely low-frequency pulsed electromagnetic field (ELF-PEMF) therapy is proposed to support bone healing after injuries and surgical procedures, being of special interest for elderly patients. This study aimed at investigating the effect of a specific ELF-PEMF, recently identified to support osteoblast function in vitro, on bone healing after high tibial osteotomy (HTO). Patients who underwent HTO were randomized to ELF-PEMF or placebo treatment, both applied by optically identical external devices 7 min per day for 30 days following surgery. Osseous consolidation was evaluated by post-surgical X-rays (7 and 14 weeks). Serum markers were quantified by ELISA. Data were compared by a two-sided t-test (α = 0.05). Device readouts showed excellent therapy compliance. Baseline parameters, including age, sex, body mass index, wedge height and blood cell count, were comparable between both groups. X-rays revealed faster osseous consolidation for ELF-PEMF compared to placebo treatment, which was significant in patients ≥50 years (∆ = 0.68%/week; = 0.003). Findings are supported by post-surgically increased bone-specific alkaline phosphatase serum levels following ELF-PEMF, compared to placebo (∆ = 2.2 µg/L; = 0.029) treatment. Adverse device effects were not reported. ELF-PEMF treatment showed a tendency to accelerate osseous consolidation after HTO. This effect was stronger and more significant for patients ≥50 years. This ELF-PEMF treatment might represent a promising adjunct to conventional therapy supporting osseous consolidation in elderly patients.
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http://dx.doi.org/10.3390/jcm8112008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6912342PMC
November 2019
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