Publications by authors named "Christian Thiel"

201 Publications

Glycosyltransferase POMGNT1 deficiency strengthens N-cadherin-mediated cell-cell adhesion.

J Biol Chem 2021 Feb 18:100433. Epub 2021 Feb 18.

Centre for Organismal Studies (COS), Glycobiology, Heidelberg University, Heidelberg, Germany. Electronic address:

Defects in protein O-mannosylation lead to severe congenital muscular dystrophies collectively known as α-dystroglycanopathy. A hallmark of these diseases is the loss of the O-mannose-bound matriglycan on α-dystroglycan, which reduces cell adhesion to the extracellular matrix. Mutations in protein O-mannose β1,2-N-acetylglucosaminyltransferase 1 (POMGNT1), which is crucial for the elongation of O-mannosyl glycans, have mainly been associated with muscle-eye-brain (MEB) disease. In addition to defects in cell-extracellular matrix adhesion, aberrant cell-cell adhesion has occasionally been observed in response to defects in POMGNT1. However, specific molecular consequences of POMGNT1 deficiency on cell-cell adhesion are largely unknown. We used POMGNT1 knock-out HEK293T cells and fibroblasts from a MEB patient to gain deeper insight into the molecular changes in POMGNT1 deficiency. Biochemical and molecular biological techniques combined with proteomics, glycoproteomics and glycomics revealed that a lack of POMGNT1 activity strengthens cell-cell adhesion. We demonstrate that the altered intrinsic adhesion properties are due to an increased abundance of N-cadherin (N-Cdh). In addition, site-specific changes in the N-glycan structures in the extracellular domain of N-Cdh were detected, which positively impact on homotypic interactions. Moreover, in POMGNT1-deficient cells, ERK1/2 and p38 signaling pathways are activated and transcriptional changes that are comparable to the epithelial-mesenchymal transition (EMT) are triggered, defining a possible molecular mechanism underlying the observed phenotype. Our study indicates that changes in cadherin-mediated cell-cell adhesion and other EMT-related processes may contribute to the complex clinical symptoms of MEB or α-dystroglycanopathy in general, and suggests that the impact of changes in O-mannosylation on N-glycosylation has been underestimated.
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http://dx.doi.org/10.1016/j.jbc.2021.100433DOI Listing
February 2021

Making sense of missense variants in TTN-related congenital myopathies.

Acta Neuropathol 2021 Mar 15;141(3):431-453. Epub 2021 Jan 15.

Randall Centre for Cell and Molecular Biophysics, Muscle Biophysics, King's College London BHF Centre of Research Excellence, London, UK.

Mutations in the sarcomeric protein titin, encoded by TTN, are emerging as a common cause of myopathies. The diagnosis of a TTN-related myopathy is, however, often not straightforward due to clinico-pathological overlap with other myopathies and the prevalence of TTN variants in control populations. Here, we present a combined clinico-pathological, genetic and biophysical approach to the diagnosis of TTN-related myopathies and the pathogenicity ascertainment of TTN missense variants. We identified 30 patients with a primary TTN-related congenital myopathy (CM) and two truncating variants, or one truncating and one missense TTN variant, or homozygous for one TTN missense variant. We found that TTN-related myopathies show considerable overlap with other myopathies but are strongly suggested by a combination of certain clinico-pathological features. Presentation was typically at birth with the clinical course characterized by variable progression of weakness, contractures, scoliosis and respiratory symptoms but sparing of extraocular muscles. Cardiac involvement depended on the variant position. Our biophysical analyses demonstrated that missense mutations associated with CMs are strongly destabilizing and exert their effect when expressed on a truncating background or in homozygosity. We hypothesise that destabilizing TTN missense mutations phenocopy truncating variants and are a key pathogenic feature of recessive titinopathies that might be amenable to therapeutic intervention.
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http://dx.doi.org/10.1007/s00401-020-02257-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7882473PMC
March 2021

Early-onset parkinsonism in PPP2R5D-related neurodevelopmental disorder.

Eur J Med Genet 2021 Jan 15;64(1):104123. Epub 2020 Dec 15.

Institute of Human Genetics, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg FAU, Erlangen, Germany. Electronic address:

PPP2R5D-related neurodevelopmental disorder (NDD) is a rare autosomal-dominant disease with developmental delay and mild to severe intellectual disability. So far, fewer than 30 affected individuals with mostly recurrent, de novo missense variants in PPP2R5D were reported. Recently, parkinsonism with an onset between 20 and 40 years was reported in four adult individuals with the same p.(Glu200Lys) variant in PPP2R5D. By trio exome sequencing we now identified the variant p.(Glu198Lys) in a 29 year old woman presenting with typical clinical manifestations of PPP2R5D-related neurodevelopmental disorder and additionally with motor decline and levodopa responsive, early-onset parkinsonism from her mid-twenties on. Accordingly, a clear reduction of dopamine transporter in the striatum on both sides was revealed by brain scintigraphy. Our findings further expand the molecular and clinical spectrum of PPP2R5D-related NDD and confirm the association with parkinsonism in early adulthood. This has marked implications for prognosis of PPP2R5D-related NDDs and for the therapeutic management of motor decline and parkinson-like symptoms in affected individuals.
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http://dx.doi.org/10.1016/j.ejmg.2020.104123DOI Listing
January 2021

Effects of a movement control and tactile acuity training in patients with nonspecific chronic low back pain and control impairment - a randomised controlled pilot study.

BMC Musculoskelet Disord 2020 Nov 30;21(1):794. Epub 2020 Nov 30.

Department of Applied Health Sciences, University of Applied Sciences Bochum, Gesundheitscampus 6-8, 44801, Bochum, Germany.

Background: Nonspecific chronic low back pain (NSCLBP) is a heterogeneous condition that is associated with complex neuromuscular adaptations. Exercise is a widely administered treatment, but its effects are small to moderate. Tailoring patient-specific exercise treatments based on subgroup classification may improve patient outcomes.

Objective: In this randomised controlled pilot study, our objective was to compare the feasibility and possible effects of a specific sensorimotor treatment (SMT) with those of a general exercise (GE) programme on patients with NSCLBP and control impairment (CI).

Methods: Patients with NSCLBP and CI were randomised into an SMT or a GE programme spanning 6 sessions each. The feasibility criteria included the study design, assessments, interventions and magnitudes of effects, and costs. Adverse events were documented. Primary (pain, physical function, and quality of life) and secondary outcomes were assessed three times: twice at baseline (t1a and t1b) to estimate parameter stability and once after the intervention (t2).

Results: Two-hundred and twenty-seven patients were screened to include 34 participants with NSCLBP and CI. Both treatment programmes and the assessments seemed feasible because their durations and contents were perceived as adequate. The total cost per participant was €321. Two adverse events occurred (one not likely related to the SMT, one likely related to the GE intervention). The SMT showed a tendency for superior effects in terms of pain severity (SMT t1a 3.5, t2 1.1; GE t1a 3.0, t2 2.0), pain interference (SMT t1a 1.9, t2 0.4; GE t1a 1.5, t2 0.9), physical component of quality of life (SMT t1a 39, t2 46; GE t1a 45, t2 48), and movement control.

Conclusions: The SMT approach proposed in this study is feasible and should be tested thoroughly in future studies, possibly as an addition to GE. To ensure the detection of differences in pain severity between SMT and GE in patients with NSCLBP with 80% power, future studies should include 110 patients. If the current results are confirmed, SMT should be considered in interventions for patients with NSCLBP and CI.

Trial Registration: Registered in the German Register for Clinical Trials (Trial registration date: November 11, 2016; Trial registration number: DRKS00011063 ; URL of trial registry record); retrospectively registered.
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http://dx.doi.org/10.1186/s12891-020-03727-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7702711PMC
November 2020

Fatal outcome after heart surgery in PMM2-CDG due to a rare homozygous gene variant with double effects.

Mol Genet Metab Rep 2020 Dec 7;25:100673. Epub 2020 Nov 7.

Centre for Child and Adolescent Medicine, Department I, University Hospital Heidelberg, Heidelberg, Germany.

Variants in Phosphomannomutase 2 (PMM2) lead to PMM2-CDG, the most frequent congenital disorder of glycosylation (CDG). We here describe the disease course of a ten-month old patient who presented with the classical PMM2-CDG symptoms as cerebellar hypoplasia, retinitis pigmentosa, seizures, short stature, hepato- and splenomegaly, anaemia, recurrent vomiting and inverted mamillae. A severe form of tetralogy of Fallot was diagnosed and corrective surgery was performed at the age of 10 months. At the end of the cardiopulmonary bypass, a sudden oedematous reaction of the myocardium accompanied by biventricular pump failure was observed immediately after heparin antagonization with protamine sulfate. The patient died seven days after surgery, since myocardial function did not recover on ECMO support. We here describe the first patient carrying the homozygous variant g.18313A > T in the gene (NG_009209.1) that either can lead to c.394A > T (p.I132F) or even loss of 100 bp due to exon 5 skipping (c.348_447del; p.G117Rfs*4) which is comparable to a null allele. Proliferation and doubling time of the patient's fibroblasts were affected. In addition, we show that the induction of cellular stress by elevating the cell culture temperature to 40 °C led to a decrease of the patients' transcript as well as PMM2 protein levels and subsequently to a significant loss of residual activity. We assume that metabolic stressful processes occurring after cardiac surgery led to the drop of the patient's PMM activity below a life-sustaining niveau which paved the way for the fatal outcome.
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http://dx.doi.org/10.1016/j.ymgmr.2020.100673DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7658698PMC
December 2020

Lack of Desmin in Mice Causes Structural and Functional Disorders of Neuromuscular Junctions.

Front Mol Neurosci 2020 26;13:567084. Epub 2020 Oct 26.

Institute of Biochemistry, Friedrich-Alexander-University of Erlangen-Nürnberg, Erlangen, Germany.

Desmin, the major intermediate filament (IF) protein in muscle cells, interlinks neighboring myofibrils and connects the whole myofibrillar apparatus to myonuclei, mitochondria, and the sarcolemma. However, desmin is also known to be enriched at postsynaptic membranes of neuromuscular junctions (NMJs). The pivotal role of the desmin IF cytoskeletal network is underscored by the fact that over 120 mutations of the human gene cause hereditary and sporadic myopathies and cardiomyopathies. A subgroup of human desminopathies comprises autosomal recessive cases resulting in the complete abolition of desmin protein. In these patients, who display a more severe phenotype than the autosomal dominant cases, it has been reported that some individuals also suffer from a myasthenic syndrome in addition to the classical occurrence of myopathy and cardiomyopathy. Since further studies on the NMJ pathology are hampered by the lack of available human striated muscle biopsy specimens, we exploited homozygous desmin knock-out mice which closely mirror the striated muscle pathology of human patients lacking desmin protein. Here, we report on the impact of the lack of desmin on the structure and function of NMJs and the transcription of genes coding for postsynaptic proteins. Desmin knock-out mice display a fragmentation of NMJs in soleus, but not in the extensor digitorum longus muscle. Moreover, soleus muscle fibers show larger NMJs. Further, transcription levels of acetylcholine receptor (AChR) genes are increased in muscles from desmin knock-out mice, especially of the AChRγ subunit, which is known as a marker of muscle fiber regeneration. Electrophysiological recordings depicted a pathological decrement of nerve-dependent endplate potentials and an increased rise time of the nerve-independent miniature endplate potentials. The latter appears related to the fragmentation of NMJs in desmin knockout mice. Our study highlights the essential role of desmin for the structural and functional integrity of mammalian NMJs.
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http://dx.doi.org/10.3389/fnmol.2020.567084DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7649329PMC
October 2020

An investigation of the measurement properties of the de Morton Mobility Index for measuring mobility capacity in hospital patients with Parkinson's disease.

Clin Rehabil 2020 Nov 11:269215520966472. Epub 2020 Nov 11.

Division of Physiotherapy, Department of Applied Health Sciences, Hochschule für Gesundheit (University of Applied Sciences), Bochum, Germany.

Objective: To examine the measurement properties of the de Morton Mobility Index (DEMMI), a performance-based clinical outcome assessment of mobility capacity, in hospital patients with Parkinson's disease.

Design: Cross-sectional study.

Participants: Hospital patients with Parkinson's disease.

Main Outcome Measure(s): Structural validity and unidimensionality (Rasch analysis), construct validity, internal consistency reliability, and inter-rater reliability of the de Morton Mobility Index (scale range: 0-100 points) were established. The minimal detectable change, the 95% limits of agreement and possible floor and ceiling effects were calculated to indicate interpretability.

Results: We analysed validity ( = 100; mean age: 70 years; 71% male) and reliability ( = 47; mean age: 71 years; 68% male) in two samples. The mean Hoehn and Yahr stage was 3.2 and the mean disease duration was 12 years in both samples. Rasch analysis indicated unidimensionality with an overall fit to the model (chi-square = 21.49,  = 0.122). Seventy-three percent of hypotheses on construct validity were confirmed. Internal consistency reliability (Cronbach's alpha = 0.91) and inter-rater reliability (intraclass correlation coefficient = 0.88; 95% confidence interval: 0.80 to 0.93) were sufficient. The minimal detectable change with 90% confidence was 17.5 points and the limits of agreement were 31%. No floor or ceiling effects were observed. The mean administration time was 6.6 minutes.

Conclusion: This study provides evidence of unidimensionality, sufficient internal consistency reliability, inter-rater reliability, construct validity, and feasibility of the de Morton Mobility Index in hospital patients with Parkinson's disease.

Trial Registration: German Clinical Trials Register (DRKS00004681). Registered May 6, 2013.
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http://dx.doi.org/10.1177/0269215520966472DOI Listing
November 2020

Impact of the COVID-19 pandemic on an interdisciplinary endoscopy unit in a German "hotspot" area: a single center experience.

Surg Endosc 2020 Nov 2. Epub 2020 Nov 2.

Department of Gastroenterology, Hepatology, Gastrointestinal Oncology, Geriatrics and Infectious Diseases, University Hospital Tübingen, Otfried-Müller-Strasse 10, 72076, Tübingen, Germany.

Background And Study Aims: Since December 2019, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative pathogen of coronavirus disease 2019 (COVID-19), has posed a pandemic threat to global health and has challenged health care system in all affected countries.

Patients And Methods: This is a combined study including a descriptive part about the changes in the daily work routine of an Interdisciplinary Endoscopic Unit (IEU) and a prospective analysis of patients tested positive for SARS-CoV-2 who required endoscopic interventions. Conclusively, we present the finding of a point-prevalence analysis in the staff of the IEU.

Results: We present effects of the COVID-19-related restructuring of processes in our interdisciplinary endoscopy unit (IEU) with respect to cancelation of examinations, relocation of staff to other departments, impact of SARS-CoV-2 on medical staff of the IEU, and supply of protective clothing. Additionally, we analyzed the cohort of COVID-19 patients: Sixteen endoscopic interventions were done in ten patients. In all patients with confirmed infection with SARS-CoV-2, emergency endoscopies were required for relevant bleeding situations. Re-endoscopies were required only in critically ill COVID-19 patients.

Conclusions: The restructuring of processes in the IEU was feasible in short time, effective, and can also be applied broadly at least in developed countries [Garbe et al. in Gastroenterology 159:778-780, 2020; Repici A, Pace F, Gabbiadini R, Colombo M, Hassan C, Dinelli M, Group IG-CW, Maselli R, Spadaccini M, Mutignani M, Gabbrielli A, Signorelli C, Spada C, Leoni P, Fabbri C, Segato S, Gaffuri N, Mangiavillano B, Radaelli F, Salerno R, Bargiggia S, Maroni L, Benedetti A, Occhipinti P, De Grazia F, Ferraris L, Cengia G, Greco S, Alvisi C, Scarcelli A, De Luca L, Cereatti F, Testoni PA, Mingotto R, Aragona G, Manes G, Beretta P, Amvrosiadis G, Cennamo V, Lella F, Missale G, Lagoussis P, Triossi O, Giovanardi M, De Roberto G, Cantu P, Buscarini E, Anderloni A, Carrara S, Fugazza A, Galtieri PA, Pellegatta G, Antonelli G, Rosch T, Sharma P (2020) Endoscopy units and the COVID-19 Outbreak: a Multi-Center Experience from Italy. Gastroenterology;]. The endoscopy-related rate of SARS-CoV-2 infection of staff is low, but supply of protective equipment is crucial for this. Endoscopic procedures in COVID-19 patients were not directly related to SARS-CoV-2 infection, but to other underlying diseases or typical complications of long-term ICU treatment.
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http://dx.doi.org/10.1007/s00464-020-08119-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7605334PMC
November 2020

A novel splice variant expands the LAMC3-associated cortical phenotype to frontal only polymicrogyria and adult-onset epilepsy.

Am J Med Genet A 2020 11 9;182(11):2761-2764. Epub 2020 Sep 9.

Institute of Human Genetics, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany.

Bi-allelic loss-of-function variants in LAMC3, encoding extracellular matrix protein laminin gamma 3, represent a rare cause of occipital polymicrogyria with epilepsy, developmental delay and cognitive impairment. So far, only five families have been reported. We now identified a novel, homozygous splice variant in LAMC3 in an individual with an unusual manifestation of cortical malformation. She presented with polymicrogyria in the frontal but not the occipital lobes, with adult-onset seizures and normal psychomotor development and cognition. Additionally, ictal asystole, requiring implantation of a pacemaker, and nonepileptic seizures occurred. This case expands the spectrum of LAMC3-associated cortical malformation phenotypes to frontal only polymicrogyria and adult-onset of epilepsy.
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http://dx.doi.org/10.1002/ajmg.a.61846DOI Listing
November 2020

Electric light commercial vehicles: Are they the sleeping giant of electromobility?

Transp Res D Transp Environ 2020 Sep 10;86:102421. Epub 2020 Jul 10.

European Commission, Joint Research Centre (JRC), Ispra, Italy.

Transport emissions need to be drastically decreased in order to put Europe on a path towards a long-term climate neutrality. Commercial transport, and especially last mile delivery is expected to grow because of the rise of e-commerce. In this frame, electric light commercial vehicles (eLCVs) can be a promising low-emission solution. Literature holistically analysing the potential of eLCVs as well as related support policies is sparse. This paper attempts to close this research gap. To this aim, the total cost of ownership (TCO) comparisons for eLCVs and benchmark vehicles are performed and support measures that target the improvement of the eLCV TCO are analysed. Various eLCV deployment scenarios until 2030 are explored and their impact on carbon dioxide (CO) and other pollutant emissions as well as pollutant concentrations are calculated. It is found that while in several European Union (EU) countries eLCVs are already cost competitive, because of fiscal support, some remaining market barriers need to be overcome to pave the way to mass market deployment of eLCVs. High penetration of eLCVs alone can lead to a reduction of total transport CO emissions by more than 3% by 2030. For pollutant emissions, such as nitrogen oxide (NO) and particulate matter (PM), the reduction would be equal or even higher. In the case of PM, this can translate to reductions in concentrations by nearly 2% in several urban areas by 2030. Carefully designed support policies could help to ensure that the potential of eLCVs as a low-emission alternative is fully leveraged in the EU.
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http://dx.doi.org/10.1016/j.trd.2020.102421DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7347503PMC
September 2020

Myeloperoxidase Modulates Inflammation in Generalized Pustular Psoriasis and Additional Rare Pustular Skin Diseases.

Am J Hum Genet 2020 09 5;107(3):527-538. Epub 2020 Aug 5.

Institute of Human Genetics, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen 91054, Germany. Electronic address:

Generalized pustular psoriasis (GPP) is a severe multi-systemic inflammatory disease characterized by neutrophilic pustulosis and triggered by pro-inflammatory IL-36 cytokines in skin. While 19%-41% of affected individuals harbor bi-allelic mutations in IL36RN, the genetic cause is not known in most cases. To identify and characterize new pathways involved in the pathogenesis of GPP, we performed whole-exome sequencing in 31 individuals with GPP and demonstrated effects of mutations in MPO encoding the neutrophilic enzyme myeloperoxidase (MPO). We discovered eight MPO mutations resulting in MPO -deficiency in neutrophils and monocytes. MPO mutations, primarily those resulting in complete MPO deficiency, cumulatively associated with GPP (p = 1.85E-08; OR = 6.47). The number of mutant MPO alleles significantly differed between 82 affected individuals and >4,900 control subjects (p = 1.04E-09); this effect was stronger when including IL36RN mutations (1.48E-13) and correlated with a younger age of onset (p = 0.0018). The activity of four proteases, previously implicated as activating enzymes of IL-36 precursors, correlated with MPO deficiency. Phorbol-myristate-acetate-induced formation of neutrophil extracellular traps (NETs) was reduced in affected cells (p = 0.015), and phagocytosis assays in MPO-deficient mice and human cells revealed altered neutrophil function and impaired clearance of neutrophils by monocytes (efferocytosis) allowing prolonged neutrophil persistence in inflammatory skin. MPO mutations contribute significantly to GPP's pathogenesis. We implicate MPO as an inflammatory modulator in humans that regulates protease activity and NET formation and modifies efferocytosis. Our findings indicate possible implications for the application of MPO inhibitors in cardiovascular diseases. MPO and affected pathways represent attractive targets for inducing resolution of inflammation in neutrophil-mediated skin diseases.
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http://dx.doi.org/10.1016/j.ajhg.2020.07.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7477008PMC
September 2020

International consensus guidelines for phosphoglucomutase 1 deficiency (PGM1-CDG): Diagnosis, follow-up, and management.

J Inherit Metab Dis 2021 Jan 15;44(1):148-163. Epub 2020 Sep 15.

Department of Clinical Genomics and Laboratory of Medical Pathology, Mayo Clinic, Rochester, Minnesota, USA.

Phosphoglucomutase 1 (PGM1) deficiency is a rare genetic disorder that affects glycogen metabolism, glycolysis, and protein glycosylation. Previously known as GSD XIV, it was recently reclassified as a congenital disorder of glycosylation, PGM1-CDG. PGM1-CDG usually manifests as a multisystem disease. Most patients present as infants with cleft palate, liver function abnormalities and hypoglycemia, but some patients present in adulthood with isolated muscle involvement. Some patients develop life-threatening cardiomyopathy. Unlike most other CDG, PGM1-CDG has an effective treatment option, d-galactose, which has been shown to improve many of the patients' symptoms. Therefore, early diagnosis and initiation of treatment for PGM1-CDG patients are crucial decisions. In this article, our group of international experts suggests diagnostic, follow-up, and management guidelines for PGM1-CDG. These guidelines are based on the best available evidence-based data and experts' opinions aiming to provide a practical resource for health care providers to facilitate successful diagnosis and optimal management of PGM1-CDG patients.
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http://dx.doi.org/10.1002/jimd.12286DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7855268PMC
January 2021

A Global Cndp1-Knock-Out Selectively Increases Renal Carnosine and Anserine Concentrations in an Age- and Gender-Specific Manner in Mice.

Int J Mol Sci 2020 Jul 10;21(14). Epub 2020 Jul 10.

Centre for Paediatric and Adolescent Medicine, University of Heidelberg, 69120 Heidelberg, Germany.

Carnosinase 1 (CN1) is encoded by the gene and degrades carnosine and anserine, two natural histidine-containing dipeptides. In vitro and in vivo studies suggest carnosine- and anserine-mediated protection against long-term sequelae of reactive metabolites accumulating, e.g., in diabetes mellitus. We have characterized the metabolic impact of CN1 in 11- and 55-week-old -knockout (-KO) mice and litter-matched wildtypes (WT). In -KO mice, renal carnosine and anserine concentrations were gender-specifically increased 2- to 9-fold, respectively in the kidney and both most abundant in the renal cortex, but remained unchanged in all other organs and in serum. Renal oxidized/reduced glutathione concentrations, renal morphology and function were unaltered. In -KO mice at week 11, renal asparagine, serine and glutamine levels and at week 55, renal arginine concentration were reduced. Renal heat-shock-protein 70 () mRNA declined with age in WT but not in -KO mice, transcription factor heat-shock-factor 1 was higher in 55-week-old KO mice. Fasting blood glucose concentrations decreased with age in WT mice, but were unchanged in mice. Blood glucose response to intraperitoneal insulin was gender- but not genotype-dependent, the response to intraperitoneal glucose injection was similar in all groups. A global -KO selectively, age- and gender-specifically, increases renal carnosine and anserine concentrations, alters renal amino acid- and HSP70 profile and modifies systemic glucose homeostasis. Increase of the natural occurring carnosine and anserine levels in the kidney by modulation of CN1 represents a promising therapeutic approach to mitigate or prevent chronic kidney diseases such as diabetic nephropathy.
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http://dx.doi.org/10.3390/ijms21144887DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7402351PMC
July 2020

A case of severe autosomal recessive spinocerebellar ataxia type 18 with a novel nonsense variant in GRID2.

Eur J Med Genet 2020 Sep 2;63(9):103998. Epub 2020 Jul 2.

Institute of Human Genetics, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg FAU, Erlangen, Germany. Electronic address:

Autosomal-recessive spinocerebellar ataxia type 18 (SCAR18) is a rare neurologic disorder. It is caused by bi-allelic aberrations in the GRID2 gene, encoding an ionotropic glutamate receptor. In total, 20 affected individuals with mainly homozygous/compound heterozygous intragenic deletions/duplications, two different missense variants and one nonsense variant in GRID2 have been reported, so far. SCAR18 is characterized by delayed psychomotor development, intellectual disability, severely impaired gait due to cerebellar ataxia, ocular movement abnormalities, and cerebellar atrophy in brain imaging. By trio exome sequencing, we now identified a novel homozygous nonsense variant (c.568C > T; p.Gln190*) in GRID2 in a four year old female from a consanguineous family who presented with a particularly severe manifestation of SCAR18. The girl was born after an uneventful pregnancy and showed early-onset, profoundly delayed psychomotor development with no achieved psychomotor milestones at age 4 years. Additionally, she presented with severe muscular hypotonia, progressive truncal and appendicular ataxia, binocular vertical nystagmus, central hearing loss and incomplete loss of sight. She was dystrophic, interacted only very little and had behavioral anomalies such as eating hair and bruxism. Brain imaging showed cerebellar hypoplasia, extended cerebrospinal fluid spaces and beginning reduction of cerebral volume. Our findings further delineate the mutational and clinical spectrum of GRID2-associated spinocerebellar ataxia type 18 and indicate that homozygous nonsense variants are possibly associated with the severe end of the SCAR18 phenotypic spectrum.
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http://dx.doi.org/10.1016/j.ejmg.2020.103998DOI Listing
September 2020

Frailty Phenotype Prevalence in Community-Dwelling Older Adults According to Physical Activity Assessment Method.

Clin Interv Aging 2020 9;15:343-355. Epub 2020 Mar 9.

Department of Applied Health Sciences, Division of Physiotherapy, Hochschule für Gesundheit (University of Applied Sciences), Bochum, Germany.

Introduction: Studies have described varying prevalences of frailty as determined by Fried's frailty phenotype. Comparability may be limited due to frailty phenotype modifications, especially the low physical activity criterion.

Purpose: This study aimed to determine the variability of frailty phenotype prevalence according to the physical activity assessment method.

Patients And Methods: In a cross-sectional analysis, frailty phenotype prevalence was assessed in community-dwelling older adults. The low physical activity criterion of the frailty phenotype was determined by using five different questionnaires and an accelerometer, and three different cut-point models.

Results: In 47 participants, frailty phenotype prevalence varied between 14.9% and 31.9%, depending on the model used to assess physical activity.

Conclusion: The method of physical activity assessment and the choice of cut-points for low physical activity considerably impact frailty phenotype prevalence. More efforts to standardize and adhere to the low physical activity criterion seem warranted. The calculation of correction factors between commonly used sets of low physical activity criteria might allow better comparisons of published prevalence rates.
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http://dx.doi.org/10.2147/CIA.S238204DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7069579PMC
August 2020

Camptocormia as the presenting symptom in sporadic late onset nemaline myopathy: a case report.

BMC Musculoskelet Disord 2019 Nov 20;20(1):553. Epub 2019 Nov 20.

Institute of Neuropathology, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Schwabachanlage 6, 91054, Erlangen, Germany.

Background: Camptocormia has been reported in a plethora of diseases comprising disorders of the central nervous system, the peripheral nervous system, and the neuromuscular junction as well as hereditary and acquired myopathies. In sporadic late onset nemaline myopathy concomitant axial myopathy is common, but reports about camptocormia as the only presenting symptom in this condition are very rare. Notably, sporadic late onset nemaline myopathy is a potentially treatable condition in particular when associated with monoclonal gammopathy of unknown significance, HIV or rheumatological disorders.

Case Presentation: We report the case of a 62-year-old female patient, who presented with slowly progressive camptocormia. Comprehensive work-up including neurological work-up, laboratory tests, MR-imaging, muscle biopsy and genetic testing led to the diagnosis of sporadic late onset nemaline myopathy.

Conclusions: Our case report highlights that sporadic late onset nemaline myopathy has to be considered in patients presenting with isolated camptocormia and comprehensive work-up of camptocormia is mandatory to ascertain the individual diagnosis, especially in consideration of treatable conditions.
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http://dx.doi.org/10.1186/s12891-019-2942-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6868766PMC
November 2019

A mutation in mannose-phosphate-dolichol utilization defect 1 reveals clinical symptoms of congenital disorders of glycosylation type I and dystroglycanopathy.

JIMD Rep 2019 Nov 30;50(1):31-39. Epub 2019 Sep 30.

Department of Neurology, Donders Institute for Brain, Cognition and Behavior Radboud University Medical Center Nijmegen The Netherlands.

Congenital disorders of glycosylation type I (CDG-I) are inborn errors of metabolism, generally characterized by multisystem clinical manifestations, including developmental delay, hepatopathy, hypotonia, and skin, skeletal, and neurological abnormalities. Among others, dolichol-phosphate-mannose (DPM) is the mannose donor for N-glycosylation as well as O-mannosylation. DOLK-CDG, DPM1-CDG, DPM2-CDG, and DPM3-CDG are defects in the DPM synthesis showing both CDG-I abnormalities and reduced O-mannosylation of alpha-dystroglycan (αDG), which leads to muscular dystrophy-dystroglycanopathy. Mannose-phosphate-dolichol utilization defect 1 (MPDU1) plays a role in the utilization of DPM. Here, we report two MPDU1-CDG patients without skin involvement, but with massive dilatation of the biliary duct system and dystroglycanopathy characteristics including hypotonia, elevated creatine kinase, dilated cardiomyopathy, buphthalmos, and congenital glaucoma. Biochemical analyses revealed elevated disialotransferrin in serum, and analyses in fibroblasts showed shortened lipid linked oligosaccharides and DPM, and reduced O-mannosylation of αDG. Thus, MPDU1-CDG can be added to the list of disorders with overlapping biochemical and clinical abnormalities of CDG-I and dystroglycanopathy.

Synopsis: Mannose-phosphate-dolichol utilization defect 1 patients can have overlapping biochemical and clinical abnormalities of congenital disorders of glycosylation type I and dystroglycanopathy.
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http://dx.doi.org/10.1002/jmd2.12060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6850978PMC
November 2019

De novo and inherited variants in ZNF292 underlie a neurodevelopmental disorder with features of autism spectrum disorder.

Genet Med 2020 03 14;22(3):538-546. Epub 2019 Nov 14.

Division of Genetic Medicine, Department of Pediatrics, University of Washington School of Medicine, Seattle, WA, USA.

Purpose: Intellectual disability (ID) and autism spectrum disorder (ASD) are genetically heterogeneous neurodevelopmental disorders. We sought to delineate the clinical, molecular, and neuroimaging spectrum of a novel neurodevelopmental disorder caused by variants in the zinc finger protein 292 gene (ZNF292).

Methods: We ascertained a cohort of 28 families with ID due to putatively pathogenic ZNF292 variants that were identified via targeted and exome sequencing. Available data were analyzed to characterize the canonical phenotype and examine genotype-phenotype relationships.

Results: Probands presented with ID as well as a spectrum of neurodevelopmental features including ASD, among others. All ZNF292 variants were de novo, except in one family with dominant inheritance. ZNF292 encodes a highly conserved zinc finger protein that acts as a transcription factor and is highly expressed in the developing human brain supporting its critical role in neurodevelopment.

Conclusion: De novo and dominantly inherited variants in ZNF292 are associated with a range of neurodevelopmental features including ID and ASD. The clinical spectrum is broad, and most individuals present with mild to moderate ID with or without other syndromic features. Our results suggest that variants in ZNF292 are likely a recurrent cause of a neurodevelopmental disorder manifesting as ID with or without ASD.
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http://dx.doi.org/10.1038/s41436-019-0693-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7060121PMC
March 2020

The lysosomal transporter MFSD1 is essential for liver homeostasis and critically depends on its accessory subunit GLMP.

Elife 2019 10 29;8. Epub 2019 Oct 29.

Institute of Biochemistry, Christian-Albrechts-University Kiel, Kiel, Germany.

Lysosomes are major sites for intracellular, acidic hydrolase-mediated proteolysis and cellular degradation. The export of low-molecular-weight catabolic end-products is facilitated by polytopic transmembrane proteins mediating secondary active or passive transport. A number of these lysosomal transporters, however, remain enigmatic. We present a detailed analysis of MFSD1, a hitherto uncharacterized lysosomal family member of the major facilitator superfamily. MFSD1 is not N-glycosylated. It contains a dileucine-based sorting motif needed for its transport to lysosomes. knockout mice develop splenomegaly and severe liver disease. Proteomics of isolated lysosomes from knockout mice revealed GLMP as a critical accessory subunit for MFSD1. MFSD1 and GLMP physically interact. GLMP is essential for the maintenance of normal levels of MFSD1 in lysosomes and vice versa. knockout mice mimic the phenotype of knockout mice. Our data reveal a tightly linked MFSD1/GLMP lysosomal membrane protein transporter complex.
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http://dx.doi.org/10.7554/eLife.50025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6819133PMC
October 2019

Unsuccessful intravenous D-mannose treatment in PMM2-CDG.

Orphanet J Rare Dis 2019 10 22;14(1):231. Epub 2019 Oct 22.

Department of General Pediatrics, Adolescent Medicine and Neonatology, Faculty of Medicine, Medical Center - University of Freiburg, Mathildenstraße 1, 79106, Freiburg, Germany.

Background: PMM2-CDG (Phosphomannomutase 2 - Congenital disorder of glycosylation-Ia; CDG-Ia) is the most common glycosylation defect, often presenting as a severe multisystem disorder that can be fatal within the first years of life. While mannose treatment has been shown to correct glycosylation in vitro and in vivo in mice, no convincing effects have been observed in short-term treatment trials in single patients so far.

Results: We report on a boy with a severe PMM2-CDG who received a continuous intravenous mannose infusion over a period of 5 months during the first year of life in a dose of 0.8 g/kg/day. N-glycosylation of serum glycoproteins and mannose concentrations in serum were studied regularly. Unfortunately, no biochemical or clinical improvement was observed, and the therapy was terminated at age 9 months.

Conclusion: Postnatal intravenous D-mannose treatment seems to be ineffective in PMM2-CDG.
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http://dx.doi.org/10.1186/s13023-019-1213-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6805611PMC
October 2019

Implementation of Urgent Start Peritoneal Dialysis Reduces Hemodialysis Catheter Use and Hospital Stay in Patients with Unplanned Dialysis Start.

Kidney Blood Press Res 2019 16;44(6):1383-1391. Epub 2019 Oct 16.

Department of Internal Medicine, Division of Diabetology, Endocrinology and Nephrology, University Hospital Tübingen, Tübingen, Germany.

Background: Unplanned start of renal replacement therapy is common in patients with end-stage renal disease and often accomplished by hemodialysis (HD) using a central venous catheter (CVC). Urgent start using peritoneal dialysis (PD) could be an alternative for some of the patients; however, this requires a hospital-based PD center that offers a structured urgent start PD (usPD) program.

Methods: In this prospective study, we describe the implementation of an usPD program at our university hospital by structuring the process from presentation to PD catheter implantation and start of PD within a few days. For clinical validation, we compared the patient flow before (2013-2015) and after (2016-2018) availability of usPD.

Results: In the 3 years before the availability of usPD, 14% (n = 12) of incident PD patients (n = 87) presented in an unplanned situation and were initially treated with HD using a CVC. In the 3 years after implementation of the usPD program, 18% (n = 18) of all incident PD patients (n = 103) presented in an unplanned situation of whom n = 12 (12%) were treated with usPD and n = 6 (6%) with initial HD. usPD significantly reduced the use of HD by 57% (p = 0.0005). Hospital stay was similar in patients treated with usPD (median 9 days) compared to those with elective PD (8 days), and significantly lower than in patients with initial HD (26 days, p = 0.0056).

Conclusions: Implementation of an usPD program reduces HD catheter use and hospital stay in the unplanned situation.
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http://dx.doi.org/10.1159/000503288DOI Listing
June 2020

ADP-dependent glucokinase regulates energy metabolism via ER-localized glucose sensing.

Sci Rep 2019 10 3;9(1):14248. Epub 2019 Oct 3.

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

Modulation of energy metabolism to a highly glycolytic phenotype, i.e. Warburg effect, is a common phenotype of cancer and activated immune cells allowing increased biomass-production for proliferation and cell division. Endoplasmic reticulum (ER)-localized ADP-dependent glucokinase (ADPGK) has been shown to play a critical role in T cell receptor activation-induced remodeling of energy metabolism, however the underlying mechanisms remain unclear. Therefore, we established and characterized in vitro and in vivo models for ADPGK-deficiency using Jurkat T cells and zebrafish. Upon activation, ADPGK knockout Jurkat T cells displayed increased cell death and ER stress. The increase in cell death resulted from a metabolic catastrophe and knockout cells displayed severely disturbed energy metabolism hindering induction of Warburg phenotype. ADPGK knockdown in zebrafish embryos led to short, dorsalized body axis induced by elevated apoptosis. ADPGK hypomorphic zebrafish further displayed dysfunctional glucose metabolism. In both model systems loss of ADPGK function led to defective N- and O-glycosylation. Overall, our data illustrate that ADPGK is part of a glucose sensing system in the ER modulating metabolism via regulation of N- and O-glycosylation.
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http://dx.doi.org/10.1038/s41598-019-50566-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6776650PMC
October 2019

Prenatal diagnosis of HNF1B-associated renal cysts: Is there a need to differentiate intragenic variants from 17q12 microdeletion syndrome?

Prenat Diagn 2019 11 25;39(12):1136-1147. Epub 2019 Oct 25.

Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany.

Objective: 17q12 microdeletions containing HNF1B and intragenic variants within this gene are associated with variable developmental, endocrine, and renal anomalies, often already noted prenatally as hyperechogenic/cystic kidneys. Here, we describe prenatal and postnatal phenotypes of seven individuals with HNF1B aberrations and compare their clinical and genetic data to those of previous studies.

Methods: Prenatal sequencing and postnatal chromosomal microarray analysis were performed in seven individuals with renal and/or neurodevelopmental phenotypes. We evaluated HNF1B-related clinical features from 82 studies and reclassified 192 reported intragenic HNF1B variants.

Results: In a prenatal case, we identified a novel in-frame deletion p.(Gly239del) within the HNF1B DNA-binding domain, a mutational hot spot as demonstrated by spatial clustering analysis and high computational prediction scores. The six postnatally diagnosed individuals harbored 17q12 microdeletions. Literature screening revealed variable reporting of HNF1B-associated clinical traits. Overall, both mutation groups showed a high phenotypic heterogeneity. The reclassification of all previously reported intragenic HNF1B variants provided an up-to-date overview of the mutational spectrum.

Conclusions: We highlight the value of prenatal HNF1B screening in renal developmental diseases. Standardized clinical reporting and systematic classification of HNF1B variants are necessary for a more accurate risk quantification of prenatal and postnatal clinical features, improving genetic counseling and prenatal decision making.
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http://dx.doi.org/10.1002/pd.5556DOI Listing
November 2019

An augmented prescribed exercise program (APEP) to improve mobility of older acute medical patients - a randomized, controlled pilot and feasibility trial.

BMC Geriatr 2019 08 30;19(1):240. Epub 2019 Aug 30.

Department of Applied Health Sciences, Division of Physiotherapy, Hochschule für Gesundheit (University of Applied Sciences), Gesundheitscampus 6-8, 44801, Bochum, Germany.

Background: There is inconclusive evidence for the effectiveness of additional exercise in older hospital patients. The aims of this study were (1) to assess the feasibility of an augmented prescribed exercise program (APEP) in older acute medical patients and (2) to measure the potential effects of APEP on mobility capacity in order to assess the feasibility of a large full-scale study.

Methods: We conducted a single-center, prospective, parallel-group, single-blinded, randomized (1:1) controlled pilot and feasibility trial. Participants were recruited from acute geriatric wards of a general hospital. Key inclusion criteria were: age ≥ 65 years and walking ability. Key exclusion criteria were severe cognitive impairment and medical restriction for physical exercise interventions. Both groups received usual care, including physiotherapy. Intervention group participants were scheduled for additional exercise sessions (20-30 min, 4-5x/week). Feasibility of the trial design was assessed along pre-defined criteria for process, resources and management. Feasibility of the APEP intervention was analyzed by means of adherence, compliance and safety. Outcomes were measured at baseline and prior to hospital discharge. The primary outcome was mobility capacity (de Morton Mobility Index; DEMMI). Secondary outcomes were walking ability, physical endurance, fear of falling, frailty and length of stay.

Results: Thirty-five participants were recruited (recruitment rate 20.3%). We lost 7 participants to follow-up (retention rate: 80%). Intervention group participants (n = 17) each participated in 5.3 ± 2.2 additional exercise sessions (mean duration: 23.2 ± 4.0 min; mean adherence rate 78% ± 26%). No severe adverse events occurred during study assessments or APEP sessions. There were no statistically significant differences in mean change scores in any outcome measure. A sample of 124 participants would be required to detect a difference of 4 DEMMI points (ES = 0.45) with a power of 80%.

Conclusions: This small feasibility RCT indicates that an APEP intervention may be safe and feasible in older acute medical patients. APEP may possibly induce small to moderate effects on mobility, but the clinical relevance of these effects may be limited. These results inform the planning of a larger-scale phase III study.

Trial Registration: German Clinical Trials Register ( DRKS00011262 ). Registered 27 October 2016.
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http://dx.doi.org/10.1186/s12877-019-1246-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6716827PMC
August 2019

Prevalence of frailty in older adults in outpatient physiotherapy in an urban region in the western part of Germany: a cross-sectional study.

BMJ Open 2019 06 21;9(6):e027768. Epub 2019 Jun 21.

Department of Applied Health Sciences, Hochschule für Gesundheit Bochum, Bochum, Germany.

Objective: To investigate the prevalence of frailty in older people in outpatient physiotherapy services in an urban region in the western part of Germany.

Design: Cross-sectional study.

Setting: Outpatient physiotherapy clinics were recruited in the municipal area of the city of Bochum, Germany, and selected randomly.

Participants: Older adults aged 65 years and older seeking outpatient physiotherapy.

Primary And Secondary Outcome Measures: Prevalence of frailty was assessed based on the frailty phenotype model of physical frailty and the accumulation of deficit model, expressed as a Frailty Index. Prevalence was calculated for the whole sample and according to age-related, sex-related and diagnosis-related subgroups.

Results: A total of 258 participants (74±6 years, 62% female) from 11 out of 130 (8%) different physiotherapy clinics were included. Participants' main indication for physiotherapy was an orthopaedic or surgical condition (75%). According to the model of a physical frailty phenotype, 17.8% (95% CI 13.2 to 22.5) participants were frail and 43.4% (95% CI 37.4 to 49.5) were prefrail. The Frailty Index identified 31.0% (95% CI 25.4 to 36.7) of individuals as frail. In both models, prevalence increased with age and was higher in women than in men. Slow gait speed (34%), reduced muscle strength (34%) and exhaustion (28%) were the most prevalent indicators of physical frailty.

Conclusions: Frailty is comparatively common in older patients attending physiotherapy care in Germany, with one out of three individuals being frail and every second individual being physically frail or prefrail.

Trial Registration Number: DRKS00009384; Results.
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http://dx.doi.org/10.1136/bmjopen-2018-027768DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6597098PMC
June 2019

Beating Yourself: How Do Runners Improve Their Own Records?

Int J Sports Physiol Perform 2019 Oct 15:1-4. Epub 2019 Oct 15.

Background: Pacing studies suggest the distribution of effort for optimizing performance. Cross-sectional studies of 1-mile world records (WRs) suggest that WR progression includes a smaller coefficient of variation of velocity.

Purpose: This study evaluates whether intraindividual pacing used by elite runners to break their own WR (1 mile, 5 km, and 10 km) is related to the evolution of pacing strategy. We provide supportive data from analysis in subelite runners.

Methods: Men's WR performances (with 400-m or 1-km splits) in 1 mile, 5 km, and 10 km were retrieved from the IAAF database (from 1924 to present). Data were analyzed relative to pacing pattern when a runner improved their own WR. Similar analyses are presented for 10-km performance in subelite runners before and after intensified training.

Results: WR performance was improved in 1 mile (mean [SD]: 3:59.4 [11.2] to 3:57.2 [8.6]), 5 km (13:27 [0:33] to 13:21 [0:33]), and 10 km (28:35 [1:27] to 28:21 [1:21]). The average coefficient of variation did not change in the 1 mile (3.4% [1.8%] to 3.6% [1.6%]), 5 km (2.4% [0.9%] to 2.2% [0.8%]), or 10 km (1.4% [0.1%] to 1.5% [0.6%]) with improved WR. When velocity was normalized to the percentage mean velocity for each race, the pacing pattern was almost identical. Very similar patterns were observed in subelite runners in the 10 km. When time improved from 49:20 (5:30) to 45:56 (4:58), normalized velocity was similar, terminal RPE increased (8.4 [1.6] to 9.1 [0.8]), coefficient of variation was unchanged (4.4% [1.1%] to 4.8% [2.1%]), and VO2max increased (49.8 [7.4] to 55.3 [8.8] mL·min-1·kg-1).

Conclusion: The results suggest that when runners break their own best performances, they employ the same pacing pattern, which is different from when WRs are improved in cross-sectional data.
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http://dx.doi.org/10.1123/ijspp.2019-0261DOI Listing
October 2019

PEDIA: prioritization of exome data by image analysis.

Genet Med 2019 12 5;21(12):2807-2814. Epub 2019 Jun 5.

Institute of Genomic Statistics and Bioinformatics, University of Bonn, Bonn, Germany.

Purpose: Phenotype information is crucial for the interpretation of genomic variants. So far it has only been accessible for bioinformatics workflows after encoding into clinical terms by expert dysmorphologists.

Methods: Here, we introduce an approach driven by artificial intelligence that uses portrait photographs for the interpretation of clinical exome data. We measured the value added by computer-assisted image analysis to the diagnostic yield on a cohort consisting of 679 individuals with 105 different monogenic disorders. For each case in the cohort we compiled frontal photos, clinical features, and the disease-causing variants, and simulated multiple exomes of different ethnic backgrounds.

Results: The additional use of similarity scores from computer-assisted analysis of frontal photos improved the top 1 accuracy rate by more than 20-89% and the top 10 accuracy rate by more than 5-99% for the disease-causing gene.

Conclusion: Image analysis by deep-learning algorithms can be used to quantify the phenotypic similarity (PP4 criterion of the American College of Medical Genetics and Genomics guidelines) and to advance the performance of bioinformatics pipelines for exome analysis.
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http://dx.doi.org/10.1038/s41436-019-0566-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6892739PMC
December 2019

Novel variants and clinical symptoms in four new ALG3-CDG patients, review of the literature, and identification of AAGRP-ALG3 as a novel ALG3 variant with alanine and glycine-rich N-terminus.

Hum Mutat 2019 07 8;40(7):938-951. Epub 2019 May 8.

Center for Child and Adolescent Medicine, Department Pediatrics I, University of Heidelberg, Heidelberg, Germany.

ALG3-CDG is one of the very rare types of congenital disorder of glycosylation (CDG) caused by variants in the ER-mannosyltransferase ALG3. Here, we summarize the clinical, biochemical, and genetic data of four new ALG3-CDG patients, who were identified by a type I pattern of serum transferrin and the accumulation of Man GlcNAc -PP-dolichol in LLO analysis. Additional clinical symptoms observed in our patients comprise sensorineural hearing loss, right-descending aorta, obstructive cardiomyopathy, macroglossia, and muscular hypertonia. We add four new biochemically confirmed variants to the list of ALG3-CDG inducing variants: c.350G>C (p.R117P), c.1263G>A (p.W421*), c.1037A>G (p.N346S), and the intron variant c.296+4A>G. Furthermore, in Patient 1 an additional open-reading frame of 141 bp (AAGRP) in the coding region of ALG3 was identified. Additionally, we show that control cells synthesize, to a minor degree, a hybrid protein composed of the polypeptide AAGRP and ALG3 (AAGRP-ALG3), while in Patient 1 expression of this hybrid protein is significantly increased due to the homozygous variant c.160_196del (g.165C>T). By reviewing the literature and combining our findings with previously published data, we further expand the knowledge of this rare glycosylation defect.
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http://dx.doi.org/10.1002/humu.23764DOI Listing
July 2019