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1. Novel likely pathogenic variants in TMEM126A identified in non-syndromic autosomal recessive optic atrophy: two case reports

Author: Katja Kloth, Matthis Synofzik, Christoph Kernstock, Simone Schimpf-Linzenbold, Frank Schuettauf, Axel Neu, Bernd Wissinger, and Nicole Weisschuh
Subjects: Optic atrophy, Autosomal recessive, TMEM126A, Internal medicine, RC31-1245, Genetics, QH426-470
Abstract: Abstract Background Reports on autosomal recessive optic atrophy (arOA) are sparse and so far, only one gene has been specifically associated with non-syndromic arOA, namely TMEM126A. To date, all reports of pathogenic TMEM126A variants are from affected individuals of Maghrebian origin, who all carry an identical nonsense variant. Here we report two novel variants in the TMEM126A gene from non-Maghreb individuals, both found in affected individuals with an arOA phenotype. Case presentation We report three affected individuals from two families. The proband of family A, a 24-year-old Turkish woman, was diagnosed with visual loss in early childhood but a diagnosis of optic atrophy was only made at 14 years. A diagnostic gene panel revealed a splice donor variant (c.86 + 2 T > C) in homozygous state in the TMEM126A gene. Analysis of this variant based on RNA from whole blood revealed a single aberrant transcript lacking exon 2, presumably representing a functional null allele. Two siblings from family B, a 16-year old Iraqi girl and her 14-year old brother, were diagnosed with optic atrophy in early childhood. A missense variant p.(S36 L) in the TMEM126A gene was identified in homozygous state in a gene panel-based diagnostic setting in both siblings. This missense variant is ultra rare in the general population, affects a highly evolutionarily conserved amino acid and segregates with the disease within the family. The three probands reported in this study had a relatively mild clinical course without any evidence of a syndromic (e.g. neurological) comorbidity, which is in line with previous studies. Conclusions We provide additional evidence for the implication of biallelic pathogenic TMEM126A variants in arOA. Our findings extend both the mutational spectrum and geographic presence of TMEM126A in arOA. Screening of the entire gene should be considered in affected individuals presenting with features resembling arOA and also from non-Maghrebian descent.
Published: 2019
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2. Mutation spectrum of the OPA1 gene in a large cohort of patients with suspected dominant optic atrophy: Identification and classification of 48 novel variants.

Author: Nicole Weisschuh, Simone Schimpf-Linzenbold, Pascale Mazzola, Sinja Kieninger, Ting Xiao, Ulrich Kellner, Teresa Neuhann, Carina Kelbsch, Felix Tonagel, Helmut Wilhelm, Susanne Kohl, and Bernd Wissinger
Subjects: Medicine, Science
Abstract: Autosomal dominant optic atrophy is one of the most common inherited optic neuropathies. This disease is genetically heterogeneous, but most cases are due to pathogenic variants in the OPA1 gene: depending on the population studied, 32-90% of cases harbor pathogenic variants in this gene. The aim of this study was to provide a comprehensive overview of the entire spectrum of likely pathogenic variants in the OPA1 gene in a large cohort of patients. Over a period of 20 years, 755 unrelated probands with a diagnosis of bilateral optic atrophy were referred to our laboratory for molecular genetic investigation. Genetic testing of the OPA1 gene was initially performed by a combined analysis using either single-strand conformation polymorphism or denaturing high performance liquid chromatography followed by Sanger sequencing to validate aberrant bands or melting profiles. The presence of copy number variations was assessed using multiplex ligation-dependent probe amplification. Since 2012, genetic testing was based on next-generation sequencing platforms. Genetic screening of the OPA1 gene revealed putatively pathogenic variants in 278 unrelated probands which represent 36.8% of the entire cohort. A total of 156 unique variants were identified, 78% of which can be considered null alleles. Variant c.2708_2711del/p.(V903Gfs*3) was found to constitute 14% of all disease-causing alleles. Special emphasis was placed on the validation of splice variants either by analyzing cDNA derived from patients´ blood samples or by heterologous splice assays using minigenes. Splicing analysis revealed different aberrant splicing events, including exon skipping, activation of exonic or intronic cryptic splice sites, and the inclusion of pseudoexons. Forty-eight variants that we identified were novel. Nine of them were classified as pathogenic, 34 as likely pathogenic and five as variant of uncertain significance. Our study adds a significant number of novel variants to the mutation spectrum of the OPA1 gene and will thereby facilitate genetic diagnostics of patients with suspected dominant optic atrophy.
Published: 2021
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3. The first reported case of a deletion of the entire RPGR gene in a family with X-linked retinitis pigmentosa

Author: Nataša Mihailovic, Simone Schimpf-Linzenbold, Inga Sattler, Nicole Eter, and Peter Heiduschka
Subjects: Ophthalmology, Phenotype, Mutation, Pediatrics, Perinatology and Child Health, Humans, Genetic Diseases, X-Linked, Eye Proteins, Retina, Retinitis Pigmentosa, Genetics (clinical), Pedigree
Abstract: Clinical phenotypes of a patient with a deletion of the entire
Published: 2022
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4. Dominant

Author: Majida, Charif, Naïg, Gueguen, Marc, Ferré, Zouhair, Elkarhat, Salim, Khiati, Morgane, LeMao, Arnaud, Chevrollier, Valerie, Desquiret-Dumas, David, Goudenège, Céline, Bris, Selma, Kane, Jennifer, Alban, Stéphanie, Chupin, Céline, Wetterwald, Leonardo, Caporali, Francesca, Tagliavini, Chiara, LaMorgia, Michele, Carbonelli, Neringa, Jurkute, Abdelhamid, Barakat, Philippe, Gohier, Christophe, Verny, Magalie, Barth, Vincent, Procaccio, Dominique, Bonneau, Xavier, Zanlonghi, Isabelle, Meunier, Nicole, Weisschuh, Simone, Schimpf-Linzenbold, Felix, Tonagel, Ulrich, Kellner, Patrick, Yu-Wai-Man, Valerio, Carelli, Bernd, Wissinger, Patrizia, Amati-Bonneau, Pascal, Reynier, and Guy, Lenaers
Subjects: mitochondria, AcademicSubjects/SCI01870, Original Article, AcademicSubjects/MED00310, Krebs cycle, eye diseases, ACO2, aconitase 2, optic neuropathy
Abstract: Biallelic mutations in ACO2, encoding the mitochondrial aconitase 2, have been identified in individuals with neurodegenerative syndromes, including infantile cerebellar retinal degeneration and recessive optic neuropathies (locus OPA9). By screening European cohorts of individuals with genetically unsolved inherited optic neuropathies, we identified 61 cases harbouring variants in ACO2, among whom 50 carried dominant mutations, emphasizing for the first time the important contribution of ACO2 monoallelic pathogenic variants to dominant optic atrophy. Analysis of the ophthalmological and clinical data revealed that recessive cases are affected more severely than dominant cases, while not significantly earlier. In addition, 27% of the recessive cases and 11% of the dominant cases manifested with extraocular features in addition to optic atrophy. In silico analyses of ACO2 variants predicted their deleterious impacts on ACO2 biophysical properties. Skin derived fibroblasts from patients harbouring dominant and recessive ACO2 mutations revealed a reduction of ACO2 abundance and enzymatic activity, and the impairment of the mitochondrial respiration using citrate and pyruvate as substrates, while the addition of other Krebs cycle intermediates restored a normal respiration, suggesting a possible short-cut adaptation of the tricarboxylic citric acid cycle. Analysis of the mitochondrial genome abundance disclosed a significant reduction of the mitochondrial DNA amount in all ACO2 fibroblasts. Overall, our data position ACO2 as the third most frequently mutated gene in autosomal inherited optic neuropathies, after OPA1 and WFS1, and emphasize the crucial involvement of the first steps of the Krebs cycle in the maintenance and survival of retinal ganglion cells., Graphical Abstract Graphical Abstract, By screening European cohorts of individuals with genetically unsolved inherited optic neuropathies, Charif et al. report 61 new cases harbouring variants in ACO2, among whom 50 with dominant mutations, emphasizing for the first time the important contribution of ACO2 monoallelic pathogenic variants to dominant optic atrophy.
Published: 2021

5. Disease expression caused by different variants in the BEST1 gene: genotype and phenotype findings in bestrophinopathies

Author: Robert Rejdak, Agnieszka Brzozowska, Fadi Nasser, Saskia Biskup, Eberhart Zrenner, Simone Schimpf-Linzenbold, Katarzyna Nowomiejska, Katarina Stingl, and Susanne Kohl
Subjects: medicine.medical_specialty, Visual acuity, Genotype, genetic structures, Fundus (eye), symbols.namesake, Genotype-phenotype distinction, Retinal Diseases, Ophthalmology, Humans, Medicine, Bestrophins, Retrospective Studies, Sanger sequencing, business.industry, General Medicine, Phenotype, eye diseases, Pedigree, Vitelliform Macular Dystrophy, Visual field, Mutation, symbols, sense organs, medicine.symptom, business, Tomography, Optical Coherence, Autosomal recessive bestrophinopathy
Abstract: Purpose To analyse the spectrum of clinical features and molecular genetic data in a series of patients carrying likely disease-associated variants in the BEST1 gene. Methods Retrospective observational analysis of clinical data extracted from the medical records of visual function, multimodal imaging and electrophysiology of 62 eyes of 31 patients. Molecular genetic analysis was performed by means of panel-based NGS or Sanger sequencing. Results The spectrum of variants in the BEST1 gene comprised 19 different variants and three of which are novel. Fundus photographs and OCT images allowed categorization of 52 eyes as Best vitelliform macular dystrophy (BVMD) with stages 1 to 5 and 10 eyes with autosomal recessive bestrophinopathy (ARB), with more severe phenotype. One patient was shown to be heterozygous for a variant, which has so far been described only in ARB, but this patient had the BVMD phenotype. There was no significant progression of the visual acuity during the follow-up period of 5 years both in BVMD and ARB. The most prevalent pattern of fundus autofluorescence (FAF) in BVMD was 'patchy'. There were diverse visual field defects in static automated perimetry (SAP) depending on the stage. The Arden ratio was significantly lower in ARB patients and in eyes with stage 5 of BVMD. Conclusions The genotype does not always predict the phenotype in patients with BVMD and ARB; however, having two mutations in the BEST1 gene causes a more severe phenotype. FAF helped to distinguish ARB from BVMD. Most of the observed eyes did not progress functionally during the follow-up. ARB and the atrophic stage of BVMD as the disease end-stage had the worst visual functions and EOG results.
Published: 2021
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6. Dominant ACO2 mutations are a frequent cause of isolated optic atrophy

Author: Chiara LaMorgia, Pascal Reynier, Céline Wetterwald, Vincent Procaccio, Simone Schimpf-Linzenbold, Bernd Wissinger, Valérie Desquiret-Dumas, Stéphanie Chupin, Felix Tonagel, Leonardo Caporali, Selma Kane, Valerio Carelli, Magalie Barth, Naïg Gueguen, Xavier Zanlonghi, Majida Charif, Patrick Yu-Wai-Man, Neringa Jurkute, Morgane LeMao, Francesca Tagliavini, David Goudenège, Zouhair Elkarhat, Céline Bris, Marc Ferré, Jennifer Alban, Isabelle Meunier, Guy Lenaers, Arnaud Chevrollier, Abdelhamid Barakat, Ulrich Kellner, Patrizia Amati-Bonneau, Christophe Verny, Salim Khiati, Nicole Weisschuh, Philippe Gohier, Michele Carbonelli, Dominique Bonneau, Charif, Majida, Gueguen, Naïg, Ferré, Marc, Elkarhat, Zouhair, Khiati, Salim, LeMao, Morgane, Chevrollier, Arnaud, Desquiret-Dumas, Valerie, Goudenège, David, Bris, Céline, Kane, Selma, Alban, Jennifer, Chupin, Stéphanie, Wetterwald, Céline, Caporali, Leonardo, Tagliavini, Francesca, LaMorgia, Chiara, Carbonelli, Michele, Jurkute, Neringa, Barakat, Abdelhamid, Gohier, Philippe, Verny, Christophe, Barth, Magalie, Procaccio, Vincent, Bonneau, Dominique, Zanlonghi, Xavier, Meunier, Isabelle, Weisschuh, Nicole, Schimpf-Linzenbold, Simone, Tonagel, Felix, Kellner, Ulrich, Yu-Wai-Man, Patrick, Carelli, Valerio, Wissinger, Bernd, Amati-Bonneau, Patrizia, Reynier, Pascal, Lenaers, Guy, Université Mohamed 1 Oujda MAROC, MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), SFR UA 4208 Interactions Cellulaires et Applications Thérapeutiques (ICAT), Université d'Angers (UA), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Institut Pasteur du Maroc, Réseau International des Instituts Pasteur (RIIP), University of Bologna/Università di Bologna, Maggiore-Bellaria Hospital [Bologna], University College of London [London] (UCL), Moorfields Eye Hospital [London], Cambridge University Hospitals - NHS (CUH), University of Cambridge [UK] (CAM), Clinique Jules-Vernes [Nantes], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), University of Tübingen, Molecular Genetics Laboratory [Tuebingen, Germany] (Centre for Ophthalmology), Institute for Ophthalmic Research [Tuebingen, Germany]-University Clinics Tuebingen [Germany], Rare Retinal Disease Center [Siegburg, Germany], AugenZentrum Siegburg-MVZ ADTC Siegburg GmbH [Germany], and LENAERS, Guy
Subjects: 0301 basic medicine, Retinal degeneration, Mitochondrial DNA, [SDV]Life Sciences [q-bio], Biology, Mitochondrion, medicine.disease_cause, Retinal ganglion, Optic neuropathy, 03 medical and health sciences, 0302 clinical medicine, Atrophy, medicine, ACO2, Genetics, Mutation, General Engineering, medicine.disease, eye diseases, aconitase 2, optic neuropathy, [SDV] Life Sciences [q-bio], mitochondria, 030104 developmental biology, sense organs, Krebs cycle, 030217 neurology & neurosurgery, Optic nerve disorder
Abstract: Biallelic mutations in ACO2, encoding the mitochondrial aconitase 2, have been identified in individuals with neurodegenerative syndromes, including infantile cerebellar retinal degeneration and recessive optic neuropathies (locus OPA9). By screening European cohorts of individuals with genetically unsolved inherited optic neuropathies, we identified 61 cases harbouring variants in ACO2, among whom 50 carried dominant mutations, emphasizing for the first time the important contribution of ACO2 monoallelic pathogenic variants to dominant optic atrophy. Analysis of the ophthalmological and clinical data revealed that recessive cases are affected more severely than dominant cases, while not significantly earlier. In addition, 27% of the recessive cases and 11% of the dominant cases manifested with extraocular features in addition to optic atrophy. In silico analyses of ACO2 variants predicted their deleterious impacts on ACO2 biophysical properties. Skin derived fibroblasts from patients harbouring dominant and recessive ACO2 mutations revealed a reduction of ACO2 abundance and enzymatic activity, and the impairment of the mitochondrial respiration using citrate and pyruvate as substrates, while the addition of other Krebs cycle intermediates restored a normal respiration, suggesting a possible short-cut adaptation of the tricarboxylic citric acid cycle. Analysis of the mitochondrial genome abundance disclosed a significant reduction of the mitochondrial DNA amount in all ACO2 fibroblasts. Overall, our data position ACO2 as the third most frequently mutated gene in autosomal inherited optic neuropathies, after OPA1 and WFS1, and emphasize the crucial involvement of the first steps of the Krebs cycle in the maintenance and survival of retinal ganglion cells.
Published: 2021
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7. Haploinsufficiency due to a novel ACO2 deletion causes mitochondrial dysfunction in fibroblasts from a patient with dominant optic nerve atrophy

Author: Dana Dayan, Dajana Grossmann, Jill Bohler, Simone Schimpf-Linzenbold, Sylvie Delcambre, Bernd Wissinger, Rejko Krüger, François Massart, Anne Grünewald, Amit Kessel, Katarina Stingl, Jenny Ghelfi, Ludger Schöls, Reut Ben-Menachem, Abdussalam Azem, Tim M. Strom, Ophry Pines, and Marie Anne-Catherine Neumann
Subjects: 0301 basic medicine, Male, pathology [Optic Atrophy], lcsh:Medicine, Haploinsufficiency, Biochemistry, biophysics & molecular biology [F05] [Life sciences], medicine.disease_cause, pathology [Mitochondria], genetics [Optic Atrophy], 0302 clinical medicine, metabolism [Aconitate Hydratase], Exome, Biochimie, biophysique & biologie moléculaire [F05] [Sciences du vivant], lcsh:Science, Sequence Deletion, Aconitate Hydratase, Multidisciplinary, ACO2, Hypotonia, Mitochondria, Neurology, Cerebellar atrophy, Female, medicine.symptom, pathology [Fibroblasts], metabolism [Fibroblasts], Mitochondrial DNA, Programmed cell death, genetics [Aconitate Hydratase], Biology, DNA, Mitochondrial, Article, 03 medical and health sciences, Atrophy, Genetics, medicine, Humans, lcsh:R, Optic Nerve, Fibroblasts, medicine.disease, metabolism [Mitochondria], Molecular biology, Optic Atrophy, 030104 developmental biology, metabolism [Optic Atrophy], lcsh:Q, genetics [Mitochondria], pathology [Optic Nerve], ddc:600, 030217 neurology & neurosurgery, Oxidative stress, Neuroscience, metabolism [Optic Nerve]
Abstract: ACO2 is a mitochondrial protein, which is critically involved in the function of the tricarboxylic acid cycle (TCA), the maintenance of iron homeostasis, oxidative stress defense and the integrity of mitochondrial DNA (mtDNA). Mutations in the ACO2 gene were identified in patients suffering from a broad range of symptoms, including optic nerve atrophy, cortical atrophy, cerebellar atrophy, hypotonia, seizures and intellectual disabilities. In the present study, we identified a heterozygous 51 bp deletion (c.1699_1749del51) in ACO2 in a family with autosomal dominant inherited isolated optic atrophy. A complementation assay using aco1-deficient yeast revealed a growth defect for the mutant ACO2 variant substantiating a pathogenic effect of the deletion. We used patient-derived fibroblasts to characterize cellular phenotypes and found a decrease of ACO2 protein levels, while ACO2 enzyme activity was not affected compared to two age- and gender-matched control lines. Several parameters of mitochondrial function, including mitochondrial morphology, mitochondrial membrane potential or mitochondrial superoxide production, were not changed under baseline conditions. However, basal respiration, maximal respiration, and spare respiratory capacity were reduced in mutant cells. Furthermore, we observed a reduction of mtDNA copy number and reduced mtDNA transcription levels in ACO2-mutant fibroblasts. Inducing oxidative stress led to an increased susceptibility for cell death in ACO2-mutant fibroblasts compared to controls. Our study reveals that a monoallelic mutation in ACO2 is sufficient to promote mitochondrial dysfunction and increased vulnerability to oxidative stress as main drivers of cell death related to optic nerve atrophy.
Published: 2020
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8. Allelic Expression Imbalance in the Human Retinal Transcriptome and Potential Impact on Inherited Retinal Diseases

Author: Jan Vetter, Pablo Llavona, Simone Schimpf-Linzenbold, Efdal Yoeruek, Bernd Wissinger, Susanne Kohl, Margherita Mutarelli, Sebastian Thaler, Veer Singh Marwah, Michele Pinelli, and Institute of Biotechnology
Subjects: 0301 basic medicine, retina, lcsh:QH426-470, Single-nucleotide polymorphism, Context (language use), Biology, PHENOTYPE, expressivity, Transcriptome, 03 medical and health sciences, 0302 clinical medicine, Inherited retinal diseases, Genetics, 3125 Otorhinolaryngology, ophthalmology, Expressivity (genetics), Allele, penetrance, MUTATION, Genetics (clinical), Massive parallel sequencing, Communication, 1184 Genetics, developmental biology, physiology, DYSTROPHY, Penetrance, lcsh:Genetics, 030104 developmental biology, Expression quantitative trait loci, 030221 ophthalmology & optometry, allelic expression imbalance
Abstract: Inherited retinal diseases (IRDs) are often associated with variable clinical expressivity (VE) and incomplete penetrance (IP). Underlying mechanisms may include environmental, epigenetic, and genetic factors. Cis-acting expression quantitative trait loci (cis-eQTLs) can be implicated in the regulation of genes by favoring or hampering the expression of one allele over the other. Thus, the presence of such loci elicits allelic expression imbalance (AEI) that can be traced by massive parallel sequencing techniques. In this study, we performed an AEI analysis on RNA-sequencing (RNA-seq) data, from 52 healthy retina donors, that identified 194 imbalanced single nucleotide polymorphisms(SNPs) in 67 IRD genes. Focusing on SNPs displaying AEI at a frequency higher than 10%, we found evidence of AEI in several IRD genes regularly associated with IP and VE (BEST1, RP1, PROM1, and PRPH2). Based on these SNPs commonly undergoing AEI, we performed pyrosequencing in an independent sample set of 17 healthy retina donors in order to confirm our findings. Indeed, we were able to validate CDHR1, BEST1, and PROM1 to be subjected to cis-acting regulation. With this work, we aim to shed light on differentially expressed alleles in the human retina transcriptome that, in the context of autosomal dominant IRD cases, could help to explain IP or VE.
Published: 2017

9. Comprehensive cDNA study and quantitative transcript analysis of mutantOPA1transcripts containing premature termination codons

Author: Bernd Wissinger, Simone Schimpf, Nico Fuhrmann, and Simone Schaich
Subjects: endocrine system, DNA, Complementary, DNA Mutational Analysis, Nonsense-mediated decay, Mutant, Biology, medicine.disease_cause, GTP Phosphohydrolases, Exon, Complementary DNA, Optic Atrophy, Autosomal Dominant, Genetics, medicine, Humans, Gene, Alleles, Genetics (clinical), Mutation, Genetic Variation, Molecular biology, eye diseases, Codon, Nonsense, Allelic heterogeneity, Haploinsufficiency
Abstract: Autosomal dominant optic atrophy (adOA) is most commonly caused by mutations in the OPA1 gene. There is a considerable allelic heterogeneity among adOA-associated OPA1 mutations, however these mutations have mostly been identified and studied only at the genomic DNA level. Here we report the identification of 22 novel OPA1 mutations and their analysis at the cDNA level along with 15 already known OPA1 mutations. We found that 18 of these mutations cause splice defects that involve either skipping of the adjacent exon or the activation of a cryptic splice site. We also observed a reduced level of the mutant transcript in several adOA subjects. Allele-specific quantification of the transcript steady-state level was performed for 13 different OPA1 mutations applying pyrosequencing to a RT-PCR amplified cSNP (c.2109C>T) in OPA1. Using this new assay we could demonstrate that the majority of OPA1 mutations that lead to a premature termination codon (PTC) undergo nonsense-mediated mRNA decay (NMD). Mutant transcript levels were reduced between 1.25- and 2.5-fold and varied between PTC containing mutations, and between subjects. Our results emphasize the value of cDNA analysis in the characterization of OPA1 mutations and further strengthen the model of haploinsufficiency as a major pathomechanism in OPA1-associated adOA.
Published: 2008
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10. OPA1 mutations associated with dominant optic atrophy impair oxidative phosphorylation and mitochondrial fusion

Author: Bernd Wissinger, Claudia Zanna, Richard J. Youle, Anna Maria Porcelli, Marcello Pinti, Simone Schimpf, Sara Vidoni, Michela Rugolo, Mariusz Karbowski, Anna Ghelli, Andrea Cossarizza, Maria Lucia Valentino, Valerio Carelli, Zanna C., Ghelli A., Porcelli A.M., Karbowski M., Youle R.J., Schimpf S., Wissinger B., Pinti M., Cossarizza A., Vidoni S., Valentino M.L., Rugolo M., and Carelli V.
Subjects: medicine.medical_specialty, Mutation, ATP synthase, biology, Oxidative phosphorylation, Mitochondrion, AIF, DOA, Mitochondrial fusion, OPA1, medicine.disease_cause, medicine.disease, eye diseases, Cell biology, Endocrinology, medicine.anatomical_structure, mitochondrial fusion, Retinal ganglion cell, Internal medicine, medicine, biology.protein, Apoptosis-inducing factor, Neurology (clinical), Mitochondrial optic neuropathies
Abstract: Dominant optic atrophy (DOA) is characterized by retinal ganglion cell degeneration leading to optic neuropathy. A subset of DOA is caused by mutations in the OPA1 gene, encoding for a dynamin-related GTPase required for mitochondrial fusion. The functional consequences of OPA1 mutations in DOA patients are still poorly understood. This study investigated the effect of five different OPA1 pathogenic mutations on the energetic efficiency and mitochondrial network dynamics of skin fibroblasts from patients. Although DOA fibroblasts maintained their ATP levels and grew in galactose medium, i.e. under forced oxidative metabolism, a significant impairment in mitochondrial ATP synthesis driven by complex I substrates was found. Furthermore, balloon-like structures in the mitochondrial reticulum were observed in galactose medium and mitochondrial fusion was completely inhibited in about 50% of DOA fibroblasts, but not in control cells. Respiratory complex assembly and the expression level of complex I subunits were similar in control and DOA fibroblasts. Co-immunoprecipitation experiments revealed that OPA1 directly interacts with subunits of complexes I, II and III, but not IV and with apoptosis inducing factor. The results disclose a novel link between OPA1, apoptosis inducing factor and the respiratory complexes that may shed some light on the pathogenic mechanism of DOA.
Published: 2007
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11. A splice site mutation in the murine Opa1 gene features pathology of autosomal dominant optic atrophy

Author: Lukas Rüttiger, Hans F. Wehrl, Thomas Peters, Marlies Knipper, Bernd Wissinger, Susanne C. Beck, Frank Schuettauf, Felix Tonagel, Simone Schimpf, Juergen Laufs, Marcel V. Alavi, Ulrich Schraermeyer, Bernd J. Pichler, and Stefanie Bette
Subjects: Retinal Ganglion Cells, Pathology, medicine.medical_specialty, Transcription, Genetic, Mutant, Biology, DNA, Mitochondrial, Retinal ganglion, Retina, GTP Phosphohydrolases, Mice, Hearing, Microscopy, Electron, Transmission, Mutant protein, Optic Atrophy, Autosomal Dominant, Electroretinography, medicine, Animals, Amino Acids, Cells, Cultured, Mice, Inbred C3H, Splice site mutation, Optic Nerve, Exons, medicine.disease, Magnetic Resonance Imaging, eye diseases, Mitochondria, Ganglion, Disease Models, Animal, medicine.anatomical_structure, Sensory Thresholds, Mutation, Optic nerve, RNA Splice Sites, Neurology (clinical), DNA, Circular, Mitochondrial optic neuropathies, Haploinsufficiency
Abstract: Autosomal dominant optic atrophy (adOA) is a juvenile onset, progressive ocular disorder characterized by bilateral loss of vision, central visual field defects, colour vision disturbances, and optic disc pallor. adOA is most frequently associated with mutations in OPA1 encoding a dynamin-related large GTPase that localizes to mitochondria. Histopathological studies in adOA patients have shown a degeneration of retinal ganglion cells (RGCs) and a loss of axons in the optic nerve. However little is known about the molecular mechanism and pathophysiology of adOA due to the lack of appropriate in vivo models. Here we report a first mouse model carrying a splice site mutation (c.1065 + 5G --> A) in the Opa1 gene. The mutation induces a skipping of exon 10 during transcript processing and leads to an in-frame deletion of 27 amino acid residues in the GTPase domain. Western blot analysis showed no evidence of a shortened mutant protein but a approximately 50% reduced OPA1 protein level supporting haploinsufficiency as a major disease mechanism in adOA. Homozygous mutant mice die in utero during embryogenesis with first notable developmental delay at E8.5 as detected by magnetic resonance imaging (MRI). Heterozygous mutants are viable and of normal habitus but exhibit an age-dependent loss of RGCs that eventually progresses to a severe degeneration of the ganglion cell and nerve fibre layer. In addition optic nerves of mutant mice showed a reduced number of axons, and a swelling and abnormal shape of the remaining axons. Mitochondria in these axons showed disorganized cristae structures. All these defects recapitulate crucial features of adOA in humans and therefore document the validity and importance of this model for future research.
Published: 2006
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12. Structural model of the OPA1 GTPase domain may explain the molecular consequences of a novel mutation in a family with autosomal dominant optic atrophy

Author: Masoud Garshasbi, Seyed Razi Dadgar, Sharareh Dadgar, Simone Schimpf, Bernd Wissinger, Ehsan Nobakht Haghighi, and Olivier Hagens
Subjects: Models, Molecular, Genetics, Mitochondrial DNA, Adolescent, Mutation, Missense, Sequence Homology, Autosomal dominant trait, Locus (genetics), GTPase, Biology, medicine.disease, eye diseases, Sensory Systems, GTP Phosphohydrolases, Protein Structure, Tertiary, Optic neuropathy, Cellular and Molecular Neuroscience, Ophthalmology, Genetic linkage, Optic Atrophy, Autosomal Dominant, medicine, Animals, Humans, Missense mutation, Dynamin
Abstract: Autosomal dominant optic atrophy (ADOA) is the most frequent hereditary optic neuropathy. Three loci have been reported for ADOA: a major locus, harboring all identified mutations to date, maps to 3q28 (OPA1), a second locus is linked to 18q12.2–q12.3 (OPA4) and a third locus on 22q12.1–q13.1 (OPA5) has been reported recently. We describe a six-generation Iranian family in which optic atrophy runs as an autosomal dominant trait with an age of onset at 14–15 years. We performed linkage analysis with markers mapping to 3q28 and 18q12.2–q12.3 and found linkage to 3q28. Subsequent sequencing of OPA1 identified a novel heterozygous missense mutation (c.1313A>G) replacing aspartic acid by glycine (p.D438G) in the GTPase domain of OPA1. Interestingly, another missense mutation at the same position (c.1313A>T, D438V) has been reported before in two unrelated German families, indicating a possible mutation hot spot. Further evidence supporting the importance of D438 is its conservation from human to acoelomata. OPA1 is believed to be the human orthologue of yeast MGM1, a dynamin-related protein required for the integrity of mitochondrial DNA. Homology modeling of the OPA1 GTPase domain revealed extensive structural similarity to the Dictyostelium dynamin A GTPase domain and showed that D438 may interact with residues of the G1 and the G4 motifs, which are crucial in coordinating GTP. Based on this analysis, we propose a mechanism which explains the gradual decline of vision in ADOA patients with OPA1 mutations at position 438.
Published: 2006
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13. A novel heterozygous OPA3 mutation located in the mitochondrial target sequence results in altered steady-state levels and fragmented mitochondrial network

Author: Tanja Grau, Simone Schimpf-Linzenbold, Cécile Delettre, Konrad Oexle, Rejko Krüger, Benjamin Delprat, Doron Rapaport, Gertraud Engl, Beate Leo-Kottler, Tony Roscioli, Bernd Wissinger, Lena F. Burbulla, Molecular Genetics Laboratory [Tuebingen, Germany] (Centre for Ophthalmology), University Clinics Tuebingen [Germany]-Institute for Ophthalmic Research [Tuebingen, Germany], Werner Reichardt Centre for Integrative Neuroscience [Tuebingen, Germany], Tuebingen University [Germany] -Institute for Ophthalmology [Tuebingen, Germany], Laboratory of Functional Neurogenomics [Tuebingen, Germany], Center of Neurology and Hertie-Institute for Clinical Brain Research [Tuebingen, Germany]-University of Tuebingen, German Research Center for Neurodegenerative Diseases - Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Interfaculty Institute of Biochemistry [Tuebingen, Germany], University of Tuebingen, Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Université Montpellier 1 (UM1), Université Montpellier 2 - Sciences et Techniques (UM2), Institute of Human Genetics [Munich, Germany], Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), Department of Ophthalmology [Tuebingen, Germany], University Eye Hospital Tuebingen-University Clinics Tuebingen, School of Women's and Children's Health [Sydney, Australia], University of New South Wales [Sydney] (UNSW)-Sydney Children's hospital, This work was supported by grants from the Federal Ministry for Education and Research ((BMBF), E-RARE/ERMION: 01GM1006 to BW, NGFNplus, 01GS08134 to RK, MitoNET to DR) and by grants from the Fritz Thyssen Foundation (Az. 10.11.2.153 to RK), the German Research Council (DFG, KR2119/8-1 to RK), the United Mitochondrial Disease Foundation (to DR) and by a doctoral scholarship from the charitable Hertie Foundation (to LFB)., Delprat, Benjamin, Institute for Ophthalmic Research [Tuebingen, Germany]-University Clinics Tuebingen [Germany], University of Tuebingen-Center of Neurology and Hertie-Institute for Clinical Brain Research [Tuebingen, Germany], and Institut des Neurosciences de Montpellier (INM)
Subjects: Male, [SDV]Life Sciences [q-bio], Mutant, DNA Mutational Analysis, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Mitochondrion, OPA3, medicine.disease_cause, pathology [Mitochondria], Costeff syndrome, Cohort Studies, 0302 clinical medicine, Mutant protein, cytology [Fibroblasts], Genetics (clinical), Cells, Cultured, Genetics, Aged, 80 and over, 0303 health sciences, Mutation, Middle Aged, Phenotype, Pedigree, Mitochondria, [SDV] Life Sciences [q-bio], Female, Adult, Adolescent, genetics [Optic Atrophy, Autosomal Dominant], genetics [Mutation], [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, 03 medical and health sciences, Atrophy, Optic Atrophy, Autosomal Dominant, Optic Atrophy, [SDV.BC.BC] Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], medicine, Humans, ddc:610, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, 030304 developmental biology, Aged, OPA3 protein, human, Proteins, Fibroblasts, metabolism [Mitochondria], medicine.disease, genetics [Proteins], Molecular biology, Mutation testing, genetics [Mitochondria], 030217 neurology & neurosurgery
Abstract: International audience; Background: Mutations in OPA3 have been reported in patients with autosomal dominant optic atrophy plus cataract and Costeff syndrome. Here, we report the results of a comprehensive study on OPA3 mutations, including the mutation spectrum and its prevalence in a large cohort of OPA1-negative autosomal dominant optic atrophy (ADOA) patients, the associated clinical phenotype and the functional characterisation of a newly identified OPA3 mutant.Methods: Mutation analysis was carried out in a patient cohort of 121 independent ADOA patients. To characterise a novel OPA3 mutation, we analysed the mitochondrial import, steady-state levels and the mitochondrial localisation of the mutated protein in patients' fibroblasts. Furthermore, the morphology of mitochondria harbouring the mutated OPA3 was monitored.Results: We identified four independent cases (representing families with multiple affected members) with OPA3 mutations. Besides the known p.Q105E mutation, we observed a novel insertion, c.10_11insCGCCCG/p.V3_G4insAP which is located in the mitochondrial presequence. Detailed functional analysis of mitochondria harbouring this novel mutation demonstrates a fragmented mitochondrial network with a decreased mitochondrial mass in patient fibroblasts. In addition, quantification of the OPA3 protein reveals decreased steady-state levels of the mutant protein compared with the native one. Comparison of the clinical phenotypes suggests that OPA3 mutations can additionally evoke hearing loss and by that extend the clinical manifestation of OPA3-associated optic atrophy. This finding is supported by expression analysis of OPA3 in murine cochlear tissue.Conclusions: In summary, our study provides new insights into the clinical spectrum and the pathogenesis of dominant optic atrophy caused by mutations in the OPA3 gene.
Published: 2013
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14. A clinically complex form of dominant optic atrophy (OPA8) maps on chromosome 16

Author: Pasquale Montagna, Britta Baumann, Rosanna Carroccia, Nico Fuhrmann, Michela Rugolo, Giovanna Cenacchi, Simone Schaich, Anna Ghelli, Monika Papke, Raffaele Lodi, Rocco Liguori, Bernd Wissinger, Valerio Carelli, Marcel V. Alavi, Piero Barboni, Richard J. Youle, Maria Pia Giannoccaro, Laura Bucchi, Simone Schimpf, Lora Longanesi, Claudia Zanna, Caterina Tonon, Maria Lucia Valentino, Sabine Tippmann, Luisa Iommarini, Carelli V., Schimpf S., Fuhrmann N., Valentino M.L., Zanna C., Iommarini L., Papke M., Schaich S., Tippmann S., Baumann B., Barboni P., Longanesi L., Rugolo M., Ghelli A., Alavi M.V., Youle R.J., Bucchi L., Carroccia R., Giannoccaro M.P., Tonon C., Lodi R., Cenacchi G., Montagna P., Liguori R., and Wissinger B.
Subjects: Adult, Male, Mitochondrial DNA, Candidate gene, Adolescent, DNA Copy Number Variations, Locus (genetics), Mitochondrion, Biology, DNA, Mitochondrial, Young Adult, Chromosome 16, Gene mapping, Optic Atrophy, Autosomal Dominant, Genetics, Humans, optic atrophy, Child, Muscle, Skeletal, Molecular Biology, Genetics (clinical), Comparative Genomic Hybridization, Polymorphism, Genetic, Retinal Vessels, General Medicine, Middle Aged, Mitochondria, Pedigree, Mitochondrial biogenesis, Haplotypes, Female, Optic nerve disorder, Chromosomes, Human, Pair 16, Genome-Wide Association Study, Microsatellite Repeats
Abstract: Dominant optic atrophy (DOA) is genetically heterogeneous and pathogenic mutations have been identified in the OPA1 and OPA3 genes, both encoding for mitochondrial proteins. We characterized clinical and laboratory features in a large OPA1-negative family with complicated DOA. Search for mitochondrial dysfunction was performed by studying muscle biopsies, fibroblasts, platelets and magnetic resonance (MR) spectroscopy. Genetic investigations included mitochondrial DNA (mtDNA) analysis, linkage analysis, copy number variation (CNV) analysis and candidate gene screening. Optic neuropathy was undistinguishable from that in OPA1-DOA and frequently associated with late-onset sensorineural hearing loss, increases of central conduction times at somato-sensory evoked potentials and various cardiac abnormalities. Serum lactic acid after exercise, platelet respiratory complex activities, adenosine triphosphate (ATP) content in fibroblasts and muscle phosphorus MR spectroscopy all failed to reveal a mitochondrial dysfunction. However, muscle biopsies and their mtDNA analysis showed increased mitochondrial biogenesis. Furthermore, patient's fibroblasts grown in the galactose medium were unable to increase ATP content compared with controls, and exhibited abnormally high rate of fusion activity. Genome-wide linkage revealed a locus on chromosome 16q21-q22 with a maximum two-point LOD score of 8.84 for the marker D16S752 and a non-recombinant interval of ∼ 6.96 cM. Genomic screening of 45 genes in this interval including several likely candidate genes (CALB2, CYB5B, TK2, DHODH, PLEKHG4) revealed no mutation. Moreover, we excluded the presence of CNVs using array-based comparative genome hybridization. The identification of a new OPA locus (OPA8) in this pedigree demonstrates further genetic heterogeneity in DOA, and our results indicate that the pathogenesis may still involve mitochondria.
Published: 2011

15. Defective Mitochondrial Adenosine Triphosphate Production in Skeletal Muscle From Patients With Dominant Optic Atrophy Due to OPA1 Mutations

Author: Raffaele Lodi, Bernd Wissinger, Valerio Carelli, Chiara La Morgia, Caterina Tonon, Agostino Baruzzi, Massimo Zeviani, Emil Malucelli, David Neil Manners, Maria Lucia Valentino, Rocco Liguori, Simone Schimpf, Bruno Barbiroli, Piero Barboni, Claudia Testa, Michele Carbonelli, Lodi R., Tonon C., Valentino M.L., Manners D., Testa C., Malucelli E., La Morgia C., Barboni P., Carbonelli M., Schimpf S., Wissinger B., Zeviani M., Baruzzi A., Liguori R., Barbiroli B., and Carelli V.
Subjects: Adult, Male, Mitochondrial DNA, medicine.medical_specialty, DOMINANT OPTIC ATROPHY, Mutation, Missense, Mitochondrion, Biology, medicine.disease_cause, DNA, Mitochondrial, Oxidative Phosphorylation, GTP Phosphohydrolases, Young Adult, chemistry.chemical_compound, Adenosine Triphosphate, Atrophy, Arts and Humanities (miscellaneous), MITOCHONDRIA, Internal medicine, Optic Atrophy, Autosomal Dominant, medicine, Humans, Missense mutation, Muscle, Skeletal, Aged, Mutation, Muscle biopsy, medicine.diagnostic_test, Female, Middle Aged, Skeletal muscle, DNA, Skeletal, Energy metabolism, medicine.disease, eye diseases, Mitochondrial, Optic Atrophy, Endocrinology, medicine.anatomical_structure, chemistry, 31P MRS, Autosomal Dominant, Muscle, Neurology (clinical), Missense, Adenosine triphosphate
Abstract: OBJECTIVE: To assess whether impaired energy metabolism in skeletal muscle is a hallmark feature of patients with dominant optic atrophy due to several different mutations in the OPA1 gene. DESIGN: We used phosphorus 31 magnetic resonance spectroscopy to assess calf muscle oxidative metabolism in subjects with molecularly defined dominant optic atrophy carrying different mutations in the OPA1 gene. In a subset of patients, we also evaluated serum lactate levels after exercise and muscle biopsy results for histology and mitochondrial DNA analysis. SETTING: University neuromuscular and neurogenetics and magnetic resonance imaging units. PATIENTS: Eighteen patients with dominant optic atrophy were enrolled from 8 unrelated families, 7 of which carried an OPA1 mutation predicted to induce haploinsufficiency and 1 with a missense mutation in exon 27. Fifteen patients had documented optic atrophy. MAIN OUTCOME MEASURES: Presence of skeletal muscle mitochondrial oxidative phosphorylation dysfunction as assessed by phosphorus 31 magnetic resonance spectroscopy, serum lactate levels, and histological and mitochondrial DNA analysis. RESULTS: Phosphorus 31 magnetic resonance spectroscopy showed reduced phosphorylation potential in the calf muscle at rest in patients with an OPA1 mutation (-24% from normal mean; P = .003) as well as a reduced maximum rate of mitochondrial adenosine triphosphate synthesis (-36%; P < .001; ranging from -28% to -49% in association with different mutations). In 4 of 10 patients (40%), the serum lactate level after exercise was elevated. Only 2 of 5 muscle biopsies, from the 2 patients with a missense mutation, showed slight myopathic changes. Low levels of mitochondrial DNA multiple deletions were found in all muscle biopsies. CONCLUSIONS: Defective oxidative phosphorylation in skeletal muscle is a subclinical feature of patients with OPA1-related dominant optic atrophy, indicating a systemic expression of the OPA1 defect, similar to that previously reported for Leber hereditary optic neuropathy due to complex I dysfunction. This defect of oxidative phosphorylation does not appear to depend on the low amounts of mitochondrial DNA multiple deletions detected in muscle biopsies.
Published: 2011

16. OPA1 mutations associated with dominant optic atrophy influence optic nerve head size

Author: Piero Barboni, Maria Lucia Valentino, Bernd Wissinger, B. Foscarini, Michele Carbonelli, Annamaria De Negri, Arturo Carta, Vincenzo Parisi, Valerio Carelli, Simone Schimpf, Alfredo A. Sadun, Federico Sadun, Massimo Zeviani, Giacomo Savini, Barboni P., Carbonelli M., Savini G., Foscarini B., Parisi V., Valentino M.L., Carta A., De Negri A., Sadun F., Zeviani M., Sadun A.A., Schimpf S., Wissinger B., and Carelli V.
Subjects: Adult, Male, medicine.medical_specialty, genetic structures, Adolescent, Population, Optic Disk, Gene mutation, medicine.disease_cause, Polymerase Chain Reaction, GTP Phosphohydrolases, Young Adult, Atrophy, Ophthalmology, Optic Atrophy, Autosomal Dominant, Medicine, Missense mutation, Humans, education, Aged, Child, Cross-Sectional Studies, Female, Middle Aged, Pedigree, Tomography, Optical Coherence, Mutation, Tomography, education.field_of_study, business.industry, Anatomy, medicine.disease, eye diseases, Optic Atrophy, medicine.anatomical_structure, Autosomal Dominant, Optical Coherence, Eye development, Optic nerve, sense organs, business, Optic disc
Abstract: Purpose To analyze the influence of OPA1 gene mutations on the optic nerve head (ONH) morphology in patients with dominant optic atrophy (DOA). Design Cross-sectional study. Participants Twenty-eight patients with DOA from 11 pedigrees, which were positive for the presence of OPA1 gene mutations, and 56 age-matched control subjects, were enrolled. Methods The ONH of DOA patients was studied by optical coherence tomography and compared with an age-matched control group of 56 individuals. Main Outcome Measures ONH area, and vertical and horizontal diameters. Results The ONH analysis of DOA patients showed a significantly smaller optic disc area ( P P = 0.018), and horizontal ( P OPA1 mutation revealed normal ONH area with 2 mutations, whereas the only missense mutation linked to a "DOA plus" phenotype had the smallest ONH measurements. Conclusions The DOA patients carrying OPA1 gene mutations present, as a group, a significantly smaller ONH compared with the range of size observed in a control population; this feature may be mutation specific. This observation suggests that OPA1 is involved in shaping the anatomic conformation of the ONH in patients with DOA. The relevance of OPA1 in regulating apoptosis and modeling the eye development has been recently shown by others. Thus, mutations in the OPA1 gene may determine the previously unrecognized feature of a smaller optic disc size and this in turn may have relevance for DOA pathogenesis. Furthermore, OPA1 gene polymorphic variants may contribute to the normal variability of ONH size in the general population. Financial Disclosure(s) The authors have no proprietary or commercial interest in any of the materials discussed in this article.
Published: 2010

17. Osteopoikilosis

Author: Marc Slawik, Felix Beuschlein, Katrina Light, Roger Mulder, Gordon Dent, Mark G. Buckley, Stephen T. Holgate, Rosalia Misseri, Kirstan K. Meldrum, Massimiliano Mirabella, Gabriella Silvestri, Thomas Frieling, Alexander K. C. Leung, Andrew L. Wong, Marcus Schmitt, Jürgen Kohlhase, Sevan Hopyan, William Lane M. Robson, Maria Judit Molnar, Andrew J. Saxon, Simone Schimpf, Stefan R. Bornstein, Regina Ensenauer, Arno Fuchshuber, Carlo Nunes, Michael Escudier, Jo Spencer, Miranda Lomer, Stephen Challacombe, Jeremy Sanderson, Manish Suneja, Christie P. Thomas, Donatella Granchi, Nicola Baldini, George E. Ehrlich, Matthew B. Dobbs, Yasuaki Nakagawa, James Hyland, Roland Staud, Rajiv Kumar, Mary H. Hohenhaus, Nananda F. Col, Miep Helfrich, Anna Villa, Jan Hellemans, Geert Mortier, Minrong Ai, Matthew L. Warman, Markus Pfister, Hans-Peter Zenner, and Stefan K. Plontke
Published: 2009
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18. Overproduction of Eosinophils

Author: Marc Slawik, Felix Beuschlein, Katrina Light, Roger Mulder, Gordon Dent, Mark G. Buckley, Stephen T. Holgate, Rosalia Misseri, Kirstan K. Meldrum, Massimiliano Mirabella, Gabriella Silvestri, Thomas Frieling, Alexander K. C. Leung, Andrew L. Wong, Marcus Schmitt, Jürgen Kohlhase, Sevan Hopyan, William Lane M. Robson, Maria Judit Molnar, Andrew J. Saxon, Simone Schimpf, Stefan R. Bornstein, Regina Ensenauer, Arno Fuchshuber, Carlo Nunes, Michael Escudier, Jo Spencer, Miranda Lomer, Stephen Challacombe, Jeremy Sanderson, Manish Suneja, Christie P. Thomas, Donatella Granchi, Nicola Baldini, George E. Ehrlich, Matthew B. Dobbs, Yasuaki Nakagawa, James Hyland, Roland Staud, Rajiv Kumar, Mary H. Hohenhaus, Nananda F. Col, Miep Helfrich, Anna Villa, Jan Hellemans, Geert Mortier, Minrong Ai, Matthew L. Warman, Markus Pfister, Hans-Peter Zenner, and Stefan K. Plontke
Published: 2009
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19. Oral Crohn’s Disease

Author: Marc Slawik, Felix Beuschlein, Katrina Light, Roger Mulder, Gordon Dent, Mark G. Buckley, Stephen T. Holgate, Rosalia Misseri, Kirstan K. Meldrum, Massimiliano Mirabella, Gabriella Silvestri, Thomas Frieling, Alexander K. C. Leung, Andrew L. Wong, Marcus Schmitt, Jürgen Kohlhase, Sevan Hopyan, William Lane M. Robson, Maria Judit Molnar, Andrew J. Saxon, Simone Schimpf, Stefan R. Bornstein, Regina Ensenauer, Arno Fuchshuber, Carlo Nunes, Michael Escudier, Jo Spencer, Miranda Lomer, Stephen Challacombe, Jeremy Sanderson, Manish Suneja, Christie P. Thomas, Donatella Granchi, Nicola Baldini, George E. Ehrlich, Matthew B. Dobbs, Yasuaki Nakagawa, James Hyland, Roland Staud, Rajiv Kumar, Mary H. Hohenhaus, Nananda F. Col, Miep Helfrich, Anna Villa, Jan Hellemans, Geert Mortier, Minrong Ai, Matthew L. Warman, Markus Pfister, Hans-Peter Zenner, and Stefan K. Plontke
Published: 2009
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20. Overriding Aorta

Author: Marc Slawik, Felix Beuschlein, Katrina Light, Roger Mulder, Gordon Dent, Mark G. Buckley, Stephen T. Holgate, Rosalia Misseri, Kirstan K. Meldrum, Massimiliano Mirabella, Gabriella Silvestri, Thomas Frieling, Alexander K. C. Leung, Andrew L. Wong, Marcus Schmitt, Jürgen Kohlhase, Sevan Hopyan, William Lane M. Robson, Maria Judit Molnar, Andrew J. Saxon, Simone Schimpf, Stefan R. Bornstein, Regina Ensenauer, Arno Fuchshuber, Carlo Nunes, Michael Escudier, Jo Spencer, Miranda Lomer, Stephen Challacombe, Jeremy Sanderson, Manish Suneja, Christie P. Thomas, Donatella Granchi, Nicola Baldini, George E. Ehrlich, Matthew B. Dobbs, Yasuaki Nakagawa, James Hyland, Roland Staud, Rajiv Kumar, Mary H. Hohenhaus, Nananda F. Col, Miep Helfrich, Anna Villa, Jan Hellemans, Geert Mortier, Minrong Ai, Matthew L. Warman, Markus Pfister, Hans-Peter Zenner, and Stefan K. Plontke
Published: 2009
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21. Over-Breathing

Author: Marc Slawik, Felix Beuschlein, Katrina Light, Roger Mulder, Gordon Dent, Mark G. Buckley, Stephen T. Holgate, Rosalia Misseri, Kirstan K. Meldrum, Massimiliano Mirabella, Gabriella Silvestri, Thomas Frieling, Alexander K. C. Leung, Andrew L. Wong, Marcus Schmitt, Jürgen Kohlhase, Sevan Hopyan, William Lane M. Robson, Maria Judit Molnar, Andrew J. Saxon, Simone Schimpf, Stefan R. Bornstein, Regina Ensenauer, Arno Fuchshuber, Carlo Nunes, Michael Escudier, Jo Spencer, Miranda Lomer, Stephen Challacombe, Jeremy Sanderson, Manish Suneja, Christie P. Thomas, Donatella Granchi, Nicola Baldini, George E. Ehrlich, Matthew B. Dobbs, Yasuaki Nakagawa, James Hyland, Roland Staud, Rajiv Kumar, Mary H. Hohenhaus, Nananda F. Col, Miep Helfrich, Anna Villa, Jan Hellemans, Geert Mortier, Minrong Ai, Matthew L. Warman, Markus Pfister, Hans-Peter Zenner, and Stefan K. Plontke
Published: 2009
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22. Otitis Media, Acute

Author: Marc Slawik, Felix Beuschlein, Katrina Light, Roger Mulder, Gordon Dent, Mark G. Buckley, Stephen T. Holgate, Rosalia Misseri, Kirstan K. Meldrum, Massimiliano Mirabella, Gabriella Silvestri, Thomas Frieling, Alexander K. C. Leung, Andrew L. Wong, Marcus Schmitt, Jürgen Kohlhase, Sevan Hopyan, William Lane M. Robson, Maria Judit Molnar, Andrew J. Saxon, Simone Schimpf, Stefan R. Bornstein, Regina Ensenauer, Arno Fuchshuber, Carlo Nunes, Michael Escudier, Jo Spencer, Miranda Lomer, Stephen Challacombe, Jeremy Sanderson, Manish Suneja, Christie P. Thomas, Donatella Granchi, Nicola Baldini, George E. Ehrlich, Matthew B. Dobbs, Yasuaki Nakagawa, James Hyland, Roland Staud, Rajiv Kumar, Mary H. Hohenhaus, Nananda F. Col, Miep Helfrich, Anna Villa, Jan Hellemans, Geert Mortier, Minrong Ai, Matthew L. Warman, Markus Pfister, Hans-Peter Zenner, and Stefan K. Plontke
Published: 2009
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23. Opioid Dependence

Author: Marc Slawik, Felix Beuschlein, Katrina Light, Roger Mulder, Gordon Dent, Mark G. Buckley, Stephen T. Holgate, Rosalia Misseri, Kirstan K. Meldrum, Massimiliano Mirabella, Gabriella Silvestri, Thomas Frieling, Alexander K. C. Leung, Andrew L. Wong, Marcus Schmitt, Jürgen Kohlhase, Sevan Hopyan, William Lane M. Robson, Maria Judit Molnar, Andrew J. Saxon, Simone Schimpf, Stefan R. Bornstein, Regina Ensenauer, Arno Fuchshuber, Carlo Nunes, Michael Escudier, Jo Spencer, Miranda Lomer, Stephen Challacombe, Jeremy Sanderson, Manish Suneja, Christie P. Thomas, Donatella Granchi, Nicola Baldini, George E. Ehrlich, Matthew B. Dobbs, Yasuaki Nakagawa, James Hyland, Roland Staud, Rajiv Kumar, Mary H. Hohenhaus, Nananda F. Col, Miep Helfrich, Anna Villa, Jan Hellemans, Geert Mortier, Minrong Ai, Matthew L. Warman, Markus Pfister, Hans-Peter Zenner, and Stefan K. Plontke
Published: 2009
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24. Orthodeoxia-Platypnea Syndrome

Author: Marc Slawik, Felix Beuschlein, Katrina Light, Roger Mulder, Gordon Dent, Mark G. Buckley, Stephen T. Holgate, Rosalia Misseri, Kirstan K. Meldrum, Massimiliano Mirabella, Gabriella Silvestri, Thomas Frieling, Alexander K. C. Leung, Andrew L. Wong, Marcus Schmitt, Jürgen Kohlhase, Sevan Hopyan, William Lane M. Robson, Maria Judit Molnar, Andrew J. Saxon, Simone Schimpf, Stefan R. Bornstein, Regina Ensenauer, Arno Fuchshuber, Carlo Nunes, Michael Escudier, Jo Spencer, Miranda Lomer, Stephen Challacombe, Jeremy Sanderson, Manish Suneja, Christie P. Thomas, Donatella Granchi, Nicola Baldini, George E. Ehrlich, Matthew B. Dobbs, Yasuaki Nakagawa, James Hyland, Roland Staud, Rajiv Kumar, Mary H. Hohenhaus, Nananda F. Col, Miep Helfrich, Anna Villa, Jan Hellemans, Geert Mortier, Minrong Ai, Matthew L. Warman, Markus Pfister, Hans-Peter Zenner, and Stefan K. Plontke
Published: 2009
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25. Ornithine Transcarbamylase

Author: Marc Slawik, Felix Beuschlein, Katrina Light, Roger Mulder, Gordon Dent, Mark G. Buckley, Stephen T. Holgate, Rosalia Misseri, Kirstan K. Meldrum, Massimiliano Mirabella, Gabriella Silvestri, Thomas Frieling, Alexander K. C. Leung, Andrew L. Wong, Marcus Schmitt, Jürgen Kohlhase, Sevan Hopyan, William Lane M. Robson, Maria Judit Molnar, Andrew J. Saxon, Simone Schimpf, Stefan R. Bornstein, Regina Ensenauer, Arno Fuchshuber, Carlo Nunes, Michael Escudier, Jo Spencer, Miranda Lomer, Stephen Challacombe, Jeremy Sanderson, Manish Suneja, Christie P. Thomas, Donatella Granchi, Nicola Baldini, George E. Ehrlich, Matthew B. Dobbs, Yasuaki Nakagawa, James Hyland, Roland Staud, Rajiv Kumar, Mary H. Hohenhaus, Nananda F. Col, Miep Helfrich, Anna Villa, Jan Hellemans, Geert Mortier, Minrong Ai, Matthew L. Warman, Markus Pfister, Hans-Peter Zenner, and Stefan K. Plontke
Published: 2009
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26. Outer Membrane Carnitine Palmitoyl Transferase

Author: Marc Slawik, Felix Beuschlein, Katrina Light, Roger Mulder, Gordon Dent, Mark G. Buckley, Stephen T. Holgate, Rosalia Misseri, Kirstan K. Meldrum, Massimiliano Mirabella, Gabriella Silvestri, Thomas Frieling, Alexander K. C. Leung, Andrew L. Wong, Marcus Schmitt, Jürgen Kohlhase, Sevan Hopyan, William Lane M. Robson, Maria Judit Molnar, Andrew J. Saxon, Simone Schimpf, Stefan R. Bornstein, Regina Ensenauer, Arno Fuchshuber, Carlo Nunes, Michael Escudier, Jo Spencer, Miranda Lomer, Stephen Challacombe, Jeremy Sanderson, Manish Suneja, Christie P. Thomas, Donatella Granchi, Nicola Baldini, George E. Ehrlich, Matthew B. Dobbs, Yasuaki Nakagawa, James Hyland, Roland Staud, Rajiv Kumar, Mary H. Hohenhaus, Nananda F. Col, Miep Helfrich, Anna Villa, Jan Hellemans, Geert Mortier, Minrong Ai, Matthew L. Warman, Markus Pfister, Hans-Peter Zenner, and Stefan K. Plontke
Published: 2009
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27. Orthostatic Hypotensive Disorder, Familial, Streeten Type

Author: Marc Slawik, Felix Beuschlein, Katrina Light, Roger Mulder, Gordon Dent, Mark G. Buckley, Stephen T. Holgate, Rosalia Misseri, Kirstan K. Meldrum, Massimiliano Mirabella, Gabriella Silvestri, Thomas Frieling, Alexander K. C. Leung, Andrew L. Wong, Marcus Schmitt, Jürgen Kohlhase, Sevan Hopyan, William Lane M. Robson, Maria Judit Molnar, Andrew J. Saxon, Simone Schimpf, Stefan R. Bornstein, Regina Ensenauer, Arno Fuchshuber, Carlo Nunes, Michael Escudier, Jo Spencer, Miranda Lomer, Stephen Challacombe, Jeremy Sanderson, Manish Suneja, Christie P. Thomas, Donatella Granchi, Nicola Baldini, George E. Ehrlich, Matthew B. Dobbs, Yasuaki Nakagawa, James Hyland, Roland Staud, Rajiv Kumar, Mary H. Hohenhaus, Nananda F. Col, Miep Helfrich, Anna Villa, Jan Hellemans, Geert Mortier, Minrong Ai, Matthew L. Warman, Markus Pfister, Hans-Peter Zenner, and Stefan K. Plontke
Published: 2009
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28. Ocular Coloboma-Imperforate Anus Syndrome

Author: Marc Slawik, Felix Beuschlein, Katrina Light, Roger Mulder, Gordon Dent, Mark G. Buckley, Stephen T. Holgate, Rosalia Misseri, Kirstan K. Meldrum, Massimiliano Mirabella, Gabriella Silvestri, Thomas Frieling, Alexander K. C. Leung, Andrew L. Wong, Marcus Schmitt, Jürgen Kohlhase, Sevan Hopyan, William Lane M. Robson, Maria Judit Molnar, Andrew J. Saxon, Simone Schimpf, Stefan R. Bornstein, Regina Ensenauer, Arno Fuchshuber, Carlo Nunes, Michael Escudier, Jo Spencer, Miranda Lomer, Stephen Challacombe, Jeremy Sanderson, Manish Suneja, Christie P. Thomas, Donatella Granchi, Nicola Baldini, George E. Ehrlich, Matthew B. Dobbs, Yasuaki Nakagawa, James Hyland, Roland Staud, Rajiv Kumar, Mary H. Hohenhaus, Nananda F. Col, Miep Helfrich, Anna Villa, Jan Hellemans, Geert Mortier, Minrong Ai, Matthew L. Warman, Markus Pfister, Hans-Peter Zenner, and Stefan K. Plontke
Published: 2009
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29. Ophthalmoplegia, Chronic Progressive External and Kearns Sayre Syndrome

Author: Marc Slawik, Felix Beuschlein, Katrina Light, Roger Mulder, Gordon Dent, Mark G. Buckley, Stephen T. Holgate, Rosalia Misseri, Kirstan K. Meldrum, Massimiliano Mirabella, Gabriella Silvestri, Thomas Frieling, Alexander K. C. Leung, Andrew L. Wong, Marcus Schmitt, Jürgen Kohlhase, Sevan Hopyan, William Lane M. Robson, Maria Judit Molnar, Andrew J. Saxon, Simone Schimpf, Stefan R. Bornstein, Regina Ensenauer, Arno Fuchshuber, Carlo Nunes, Michael Escudier, Jo Spencer, Miranda Lomer, Stephen Challacombe, Jeremy Sanderson, Manish Suneja, Christie P. Thomas, Donatella Granchi, Nicola Baldini, George E. Ehrlich, Matthew B. Dobbs, Yasuaki Nakagawa, James Hyland, Roland Staud, Rajiv Kumar, Mary H. Hohenhaus, Nananda F. Col, Miep Helfrich, Anna Villa, Jan Hellemans, Geert Mortier, Minrong Ai, Matthew L. Warman, Markus Pfister, Hans-Peter Zenner, and Stefan K. Plontke
Published: 2009
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30. OCTN2 Transporter Deficiency

Author: Marc Slawik, Felix Beuschlein, Katrina Light, Roger Mulder, Gordon Dent, Mark G. Buckley, Stephen T. Holgate, Rosalia Misseri, Kirstan K. Meldrum, Massimiliano Mirabella, Gabriella Silvestri, Thomas Frieling, Alexander K. C. Leung, Andrew L. Wong, Marcus Schmitt, Jürgen Kohlhase, Sevan Hopyan, William Lane M. Robson, Maria Judit Molnar, Andrew J. Saxon, Simone Schimpf, Stefan R. Bornstein, Regina Ensenauer, Arno Fuchshuber, Carlo Nunes, Michael Escudier, Jo Spencer, Miranda Lomer, Stephen Challacombe, Jeremy Sanderson, Manish Suneja, Christie P. Thomas, Donatella Granchi, Nicola Baldini, George E. Ehrlich, Matthew B. Dobbs, Yasuaki Nakagawa, James Hyland, Roland Staud, Rajiv Kumar, Mary H. Hohenhaus, Nananda F. Col, Miep Helfrich, Anna Villa, Jan Hellemans, Geert Mortier, Minrong Ai, Matthew L. Warman, Markus Pfister, Hans-Peter Zenner, and Stefan K. Plontke
Published: 2009
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31. Ogilvie's Syndrome

Author: Marc Slawik, Felix Beuschlein, Katrina Light, Roger Mulder, Gordon Dent, Mark G. Buckley, Stephen T. Holgate, Rosalia Misseri, Kirstan K. Meldrum, Massimiliano Mirabella, Gabriella Silvestri, Thomas Frieling, Alexander K. C. Leung, Andrew L. Wong, Marcus Schmitt, Jürgen Kohlhase, Sevan Hopyan, William Lane M. Robson, Maria Judit Molnar, Andrew J. Saxon, Simone Schimpf, Stefan R. Bornstein, Regina Ensenauer, Arno Fuchshuber, Carlo Nunes, Michael Escudier, Jo Spencer, Miranda Lomer, Stephen Challacombe, Jeremy Sanderson, Manish Suneja, Christie P. Thomas, Donatella Granchi, Nicola Baldini, George E. Ehrlich, Matthew B. Dobbs, Yasuaki Nakagawa, James Hyland, Roland Staud, Rajiv Kumar, Mary H. Hohenhaus, Nananda F. Col, Miep Helfrich, Anna Villa, Jan Hellemans, Geert Mortier, Minrong Ai, Matthew L. Warman, Markus Pfister, Hans-Peter Zenner, and Stefan K. Plontke
Published: 2009
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32. Outlet Obstruction

Author: Marc Slawik, Felix Beuschlein, Katrina Light, Roger Mulder, Gordon Dent, Mark G. Buckley, Stephen T. Holgate, Rosalia Misseri, Kirstan K. Meldrum, Massimiliano Mirabella, Gabriella Silvestri, Thomas Frieling, Alexander K. C. Leung, Andrew L. Wong, Marcus Schmitt, Jürgen Kohlhase, Sevan Hopyan, William Lane M. Robson, Maria Judit Molnar, Andrew J. Saxon, Simone Schimpf, Stefan R. Bornstein, Regina Ensenauer, Arno Fuchshuber, Carlo Nunes, Michael Escudier, Jo Spencer, Miranda Lomer, Stephen Challacombe, Jeremy Sanderson, Manish Suneja, Christie P. Thomas, Donatella Granchi, Nicola Baldini, George E. Ehrlich, Matthew B. Dobbs, Yasuaki Nakagawa, James Hyland, Roland Staud, Rajiv Kumar, Mary H. Hohenhaus, Nananda F. Col, Miep Helfrich, Anna Villa, Jan Hellemans, Geert Mortier, Minrong Ai, Matthew L. Warman, Markus Pfister, Hans-Peter Zenner, and Stefan K. Plontke
Published: 2009
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33. Osteoarthritis: Developmental Dysplasia of the Hip

Author: Marc Slawik, Felix Beuschlein, Katrina Light, Roger Mulder, Gordon Dent, Mark G. Buckley, Stephen T. Holgate, Rosalia Misseri, Kirstan K. Meldrum, Massimiliano Mirabella, Gabriella Silvestri, Thomas Frieling, Alexander K. C. Leung, Andrew L. Wong, Marcus Schmitt, Jürgen Kohlhase, Sevan Hopyan, William Lane M. Robson, Maria Judit Molnar, Andrew J. Saxon, Simone Schimpf, Stefan R. Bornstein, Regina Ensenauer, Arno Fuchshuber, Carlo Nunes, Michael Escudier, Jo Spencer, Miranda Lomer, Stephen Challacombe, Jeremy Sanderson, Manish Suneja, Christie P. Thomas, Donatella Granchi, Nicola Baldini, George E. Ehrlich, Matthew B. Dobbs, Yasuaki Nakagawa, James Hyland, Roland Staud, Rajiv Kumar, Mary H. Hohenhaus, Nananda F. Col, Miep Helfrich, Anna Villa, Jan Hellemans, Geert Mortier, Minrong Ai, Matthew L. Warman, Markus Pfister, Hans-Peter Zenner, and Stefan K. Plontke
Published: 2009
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34. Osteogenesis Imperfecta

Author: Marc Slawik, Felix Beuschlein, Katrina Light, Roger Mulder, Gordon Dent, Mark G. Buckley, Stephen T. Holgate, Rosalia Misseri, Kirstan K. Meldrum, Massimiliano Mirabella, Gabriella Silvestri, Thomas Frieling, Alexander K. C. Leung, Andrew L. Wong, Marcus Schmitt, Jürgen Kohlhase, Sevan Hopyan, William Lane M. Robson, Maria Judit Molnar, Andrew J. Saxon, Simone Schimpf, Stefan R. Bornstein, Regina Ensenauer, Arno Fuchshuber, Carlo Nunes, Michael Escudier, Jo Spencer, Miranda Lomer, Stephen Challacombe, Jeremy Sanderson, Manish Suneja, Christie P. Thomas, Donatella Granchi, Nicola Baldini, George E. Ehrlich, Matthew B. Dobbs, Yasuaki Nakagawa, James Hyland, Roland Staud, Rajiv Kumar, Mary H. Hohenhaus, Nananda F. Col, Miep Helfrich, Anna Villa, Jan Hellemans, Geert Mortier, Minrong Ai, Matthew L. Warman, Markus Pfister, Hans-Peter Zenner, and Stefan K. Plontke
Published: 2009
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35. OL-EDA-ID

Author: Marc Slawik, Felix Beuschlein, Katrina Light, Roger Mulder, Gordon Dent, Mark G. Buckley, Stephen T. Holgate, Rosalia Misseri, Kirstan K. Meldrum, Massimiliano Mirabella, Gabriella Silvestri, Thomas Frieling, Alexander K. C. Leung, Andrew L. Wong, Marcus Schmitt, Jürgen Kohlhase, Sevan Hopyan, William Lane M. Robson, Maria Judit Molnar, Andrew J. Saxon, Simone Schimpf, Stefan R. Bornstein, Regina Ensenauer, Arno Fuchshuber, Carlo Nunes, Michael Escudier, Jo Spencer, Miranda Lomer, Stephen Challacombe, Jeremy Sanderson, Manish Suneja, Christie P. Thomas, Donatella Granchi, Nicola Baldini, George E. Ehrlich, Matthew B. Dobbs, Yasuaki Nakagawa, James Hyland, Roland Staud, Rajiv Kumar, Mary H. Hohenhaus, Nananda F. Col, Miep Helfrich, Anna Villa, Jan Hellemans, Geert Mortier, Minrong Ai, Matthew L. Warman, Markus Pfister, Hans-Peter Zenner, and Stefan K. Plontke
Published: 2009
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36. Oro-facio-digital Syndrome Type I

Author: Marc Slawik, Felix Beuschlein, Katrina Light, Roger Mulder, Gordon Dent, Mark G. Buckley, Stephen T. Holgate, Rosalia Misseri, Kirstan K. Meldrum, Massimiliano Mirabella, Gabriella Silvestri, Thomas Frieling, Alexander K. C. Leung, Andrew L. Wong, Marcus Schmitt, Jürgen Kohlhase, Sevan Hopyan, William Lane M. Robson, Maria Judit Molnar, Andrew J. Saxon, Simone Schimpf, Stefan R. Bornstein, Regina Ensenauer, Arno Fuchshuber, Carlo Nunes, Michael Escudier, Jo Spencer, Miranda Lomer, Stephen Challacombe, Jeremy Sanderson, Manish Suneja, Christie P. Thomas, Donatella Granchi, Nicola Baldini, George E. Ehrlich, Matthew B. Dobbs, Yasuaki Nakagawa, James Hyland, Roland Staud, Rajiv Kumar, Mary H. Hohenhaus, Nananda F. Col, Miep Helfrich, Anna Villa, Jan Hellemans, Geert Mortier, Minrong Ai, Matthew L. Warman, Markus Pfister, Hans-Peter Zenner, and Stefan K. Plontke
Published: 2009
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37. Occipital Horn Syndrome

Author: Marc Slawik, Felix Beuschlein, Katrina Light, Roger Mulder, Gordon Dent, Mark G. Buckley, Stephen T. Holgate, Rosalia Misseri, Kirstan K. Meldrum, Massimiliano Mirabella, Gabriella Silvestri, Thomas Frieling, Alexander K. C. Leung, Andrew L. Wong, Marcus Schmitt, Jürgen Kohlhase, Sevan Hopyan, William Lane M. Robson, Maria Judit Molnar, Andrew J. Saxon, Simone Schimpf, Stefan R. Bornstein, Regina Ensenauer, Arno Fuchshuber, Carlo Nunes, Michael Escudier, Jo Spencer, Miranda Lomer, Stephen Challacombe, Jeremy Sanderson, Manish Suneja, Christie P. Thomas, Donatella Granchi, Nicola Baldini, George E. Ehrlich, Matthew B. Dobbs, Yasuaki Nakagawa, James Hyland, Roland Staud, Rajiv Kumar, Mary H. Hohenhaus, Nananda F. Col, Miep Helfrich, Anna Villa, Jan Hellemans, Geert Mortier, Minrong Ai, Matthew L. Warman, Markus Pfister, Hans-Peter Zenner, and Stefan K. Plontke
Published: 2009
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38. Obstructive Uropathies

Author: Marc Slawik, Felix Beuschlein, Katrina Light, Roger Mulder, Gordon Dent, Mark G. Buckley, Stephen T. Holgate, Rosalia Misseri, Kirstan K. Meldrum, Massimiliano Mirabella, Gabriella Silvestri, Thomas Frieling, Alexander K. C. Leung, Andrew L. Wong, Marcus Schmitt, Jürgen Kohlhase, Sevan Hopyan, William Lane M. Robson, Maria Judit Molnar, Andrew J. Saxon, Simone Schimpf, Stefan R. Bornstein, Regina Ensenauer, Arno Fuchshuber, Carlo Nunes, Michael Escudier, Jo Spencer, Miranda Lomer, Stephen Challacombe, Jeremy Sanderson, Manish Suneja, Christie P. Thomas, Donatella Granchi, Nicola Baldini, George E. Ehrlich, Matthew B. Dobbs, Yasuaki Nakagawa, James Hyland, Roland Staud, Rajiv Kumar, Mary H. Hohenhaus, Nananda F. Col, Miep Helfrich, Anna Villa, Jan Hellemans, Geert Mortier, Minrong Ai, Matthew L. Warman, Markus Pfister, Hans-Peter Zenner, and Stefan K. Plontke
Published: 2009
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39. Osteomalacia (Hypophosphathemic Rickets)

Author: Marc Slawik, Felix Beuschlein, Katrina Light, Roger Mulder, Gordon Dent, Mark G. Buckley, Stephen T. Holgate, Rosalia Misseri, Kirstan K. Meldrum, Massimiliano Mirabella, Gabriella Silvestri, Thomas Frieling, Alexander K. C. Leung, Andrew L. Wong, Marcus Schmitt, Jürgen Kohlhase, Sevan Hopyan, William Lane M. Robson, Maria Judit Molnar, Andrew J. Saxon, Simone Schimpf, Stefan R. Bornstein, Regina Ensenauer, Arno Fuchshuber, Carlo Nunes, Michael Escudier, Jo Spencer, Miranda Lomer, Stephen Challacombe, Jeremy Sanderson, Manish Suneja, Christie P. Thomas, Donatella Granchi, Nicola Baldini, George E. Ehrlich, Matthew B. Dobbs, Yasuaki Nakagawa, James Hyland, Roland Staud, Rajiv Kumar, Mary H. Hohenhaus, Nananda F. Col, Miep Helfrich, Anna Villa, Jan Hellemans, Geert Mortier, Minrong Ai, Matthew L. Warman, Markus Pfister, Hans-Peter Zenner, and Stefan K. Plontke
Published: 2009
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40. Ocular Melanosis

Author: Marc Slawik, Felix Beuschlein, Katrina Light, Roger Mulder, Gordon Dent, Mark G. Buckley, Stephen T. Holgate, Rosalia Misseri, Kirstan K. Meldrum, Massimiliano Mirabella, Gabriella Silvestri, Thomas Frieling, Alexander K. C. Leung, Andrew L. Wong, Marcus Schmitt, Jürgen Kohlhase, Sevan Hopyan, William Lane M. Robson, Maria Judit Molnar, Andrew J. Saxon, Simone Schimpf, Stefan R. Bornstein, Regina Ensenauer, Arno Fuchshuber, Carlo Nunes, Michael Escudier, Jo Spencer, Miranda Lomer, Stephen Challacombe, Jeremy Sanderson, Manish Suneja, Christie P. Thomas, Donatella Granchi, Nicola Baldini, George E. Ehrlich, Matthew B. Dobbs, Yasuaki Nakagawa, James Hyland, Roland Staud, Rajiv Kumar, Mary H. Hohenhaus, Nananda F. Col, Miep Helfrich, Anna Villa, Jan Hellemans, Geert Mortier, Minrong Ai, Matthew L. Warman, Markus Pfister, Hans-Peter Zenner, and Stefan K. Plontke
Published: 2009
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41. Osebold-Remondini Syndrome

Author: Marc Slawik, Felix Beuschlein, Katrina Light, Roger Mulder, Gordon Dent, Mark G. Buckley, Stephen T. Holgate, Rosalia Misseri, Kirstan K. Meldrum, Massimiliano Mirabella, Gabriella Silvestri, Thomas Frieling, Alexander K. C. Leung, Andrew L. Wong, Marcus Schmitt, Jürgen Kohlhase, Sevan Hopyan, William Lane M. Robson, Maria Judit Molnar, Andrew J. Saxon, Simone Schimpf, Stefan R. Bornstein, Regina Ensenauer, Arno Fuchshuber, Carlo Nunes, Michael Escudier, Jo Spencer, Miranda Lomer, Stephen Challacombe, Jeremy Sanderson, Manish Suneja, Christie P. Thomas, Donatella Granchi, Nicola Baldini, George E. Ehrlich, Matthew B. Dobbs, Yasuaki Nakagawa, James Hyland, Roland Staud, Rajiv Kumar, Mary H. Hohenhaus, Nananda F. Col, Miep Helfrich, Anna Villa, Jan Hellemans, Geert Mortier, Minrong Ai, Matthew L. Warman, Markus Pfister, Hans-Peter Zenner, and Stefan K. Plontke
Published: 2009
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42. Oculopharyngeal Muscular Dystrophy

Author: Marc Slawik, Felix Beuschlein, Katrina Light, Roger Mulder, Gordon Dent, Mark G. Buckley, Stephen T. Holgate, Rosalia Misseri, Kirstan K. Meldrum, Massimiliano Mirabella, Gabriella Silvestri, Thomas Frieling, Alexander K. C. Leung, Andrew L. Wong, Marcus Schmitt, Jürgen Kohlhase, Sevan Hopyan, William Lane M. Robson, Maria Judit Molnar, Andrew J. Saxon, Simone Schimpf, Stefan R. Bornstein, Regina Ensenauer, Arno Fuchshuber, Carlo Nunes, Michael Escudier, Jo Spencer, Miranda Lomer, Stephen Challacombe, Jeremy Sanderson, Manish Suneja, Christie P. Thomas, Donatella Granchi, Nicola Baldini, George E. Ehrlich, Matthew B. Dobbs, Yasuaki Nakagawa, James Hyland, Roland Staud, Rajiv Kumar, Mary H. Hohenhaus, Nananda F. Col, Miep Helfrich, Anna Villa, Jan Hellemans, Geert Mortier, Minrong Ai, Matthew L. Warman, Markus Pfister, Hans-Peter Zenner, and Stefan K. Plontke
Published: 2009
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43. Obsessive-compulsive Personality Disorder

Author: Marc Slawik, Felix Beuschlein, Katrina Light, Roger Mulder, Gordon Dent, Mark G. Buckley, Stephen T. Holgate, Rosalia Misseri, Kirstan K. Meldrum, Massimiliano Mirabella, Gabriella Silvestri, Thomas Frieling, Alexander K. C. Leung, Andrew L. Wong, Marcus Schmitt, Jürgen Kohlhase, Sevan Hopyan, William Lane M. Robson, Maria Judit Molnar, Andrew J. Saxon, Simone Schimpf, Stefan R. Bornstein, Regina Ensenauer, Arno Fuchshuber, Carlo Nunes, Michael Escudier, Jo Spencer, Miranda Lomer, Stephen Challacombe, Jeremy Sanderson, Manish Suneja, Christie P. Thomas, Donatella Granchi, Nicola Baldini, George E. Ehrlich, Matthew B. Dobbs, Yasuaki Nakagawa, James Hyland, Roland Staud, Rajiv Kumar, Mary H. Hohenhaus, Nananda F. Col, Miep Helfrich, Anna Villa, Jan Hellemans, Geert Mortier, Minrong Ai, Matthew L. Warman, Markus Pfister, Hans-Peter Zenner, and Stefan K. Plontke
Published: 2009
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44. Osteogenesis Imperfecta Ocular Form

Author: Marc Slawik, Felix Beuschlein, Katrina Light, Roger Mulder, Gordon Dent, Mark G. Buckley, Stephen T. Holgate, Rosalia Misseri, Kirstan K. Meldrum, Massimiliano Mirabella, Gabriella Silvestri, Thomas Frieling, Alexander K. C. Leung, Andrew L. Wong, Marcus Schmitt, Jürgen Kohlhase, Sevan Hopyan, William Lane M. Robson, Maria Judit Molnar, Andrew J. Saxon, Simone Schimpf, Stefan R. Bornstein, Regina Ensenauer, Arno Fuchshuber, Carlo Nunes, Michael Escudier, Jo Spencer, Miranda Lomer, Stephen Challacombe, Jeremy Sanderson, Manish Suneja, Christie P. Thomas, Donatella Granchi, Nicola Baldini, George E. Ehrlich, Matthew B. Dobbs, Yasuaki Nakagawa, James Hyland, Roland Staud, Rajiv Kumar, Mary H. Hohenhaus, Nananda F. Col, Miep Helfrich, Anna Villa, Jan Hellemans, Geert Mortier, Minrong Ai, Matthew L. Warman, Markus Pfister, Hans-Peter Zenner, and Stefan K. Plontke
Published: 2009
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45. Osteomalacia, Tumor-induced

Author: Marc Slawik, Felix Beuschlein, Katrina Light, Roger Mulder, Gordon Dent, Mark G. Buckley, Stephen T. Holgate, Rosalia Misseri, Kirstan K. Meldrum, Massimiliano Mirabella, Gabriella Silvestri, Thomas Frieling, Alexander K. C. Leung, Andrew L. Wong, Marcus Schmitt, Jürgen Kohlhase, Sevan Hopyan, William Lane M. Robson, Maria Judit Molnar, Andrew J. Saxon, Simone Schimpf, Stefan R. Bornstein, Regina Ensenauer, Arno Fuchshuber, Carlo Nunes, Michael Escudier, Jo Spencer, Miranda Lomer, Stephen Challacombe, Jeremy Sanderson, Manish Suneja, Christie P. Thomas, Donatella Granchi, Nicola Baldini, George E. Ehrlich, Matthew B. Dobbs, Yasuaki Nakagawa, James Hyland, Roland Staud, Rajiv Kumar, Mary H. Hohenhaus, Nananda F. Col, Miep Helfrich, Anna Villa, Jan Hellemans, Geert Mortier, Minrong Ai, Matthew L. Warman, Markus Pfister, Hans-Peter Zenner, and Stefan K. Plontke
Published: 2009
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46. Orbicular Eczema

Author: Marc Slawik, Felix Beuschlein, Katrina Light, Roger Mulder, Gordon Dent, Mark G. Buckley, Stephen T. Holgate, Rosalia Misseri, Kirstan K. Meldrum, Massimiliano Mirabella, Gabriella Silvestri, Thomas Frieling, Alexander K. C. Leung, Andrew L. Wong, Marcus Schmitt, Jürgen Kohlhase, Sevan Hopyan, William Lane M. Robson, Maria Judit Molnar, Andrew J. Saxon, Simone Schimpf, Stefan R. Bornstein, Regina Ensenauer, Arno Fuchshuber, Carlo Nunes, Michael Escudier, Jo Spencer, Miranda Lomer, Stephen Challacombe, Jeremy Sanderson, Manish Suneja, Christie P. Thomas, Donatella Granchi, Nicola Baldini, George E. Ehrlich, Matthew B. Dobbs, Yasuaki Nakagawa, James Hyland, Roland Staud, Rajiv Kumar, Mary H. Hohenhaus, Nananda F. Col, Miep Helfrich, Anna Villa, Jan Hellemans, Geert Mortier, Minrong Ai, Matthew L. Warman, Markus Pfister, Hans-Peter Zenner, and Stefan K. Plontke
Published: 2009
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47. Obstructive Sleep Apnea

Author: Marc Slawik, Felix Beuschlein, Katrina Light, Roger Mulder, Gordon Dent, Mark G. Buckley, Stephen T. Holgate, Rosalia Misseri, Kirstan K. Meldrum, Massimiliano Mirabella, Gabriella Silvestri, Thomas Frieling, Alexander K. C. Leung, Andrew L. Wong, Marcus Schmitt, Jürgen Kohlhase, Sevan Hopyan, William Lane M. Robson, Maria Judit Molnar, Andrew J. Saxon, Simone Schimpf, Stefan R. Bornstein, Regina Ensenauer, Arno Fuchshuber, Carlo Nunes, Michael Escudier, Jo Spencer, Miranda Lomer, Stephen Challacombe, Jeremy Sanderson, Manish Suneja, Christie P. Thomas, Donatella Granchi, Nicola Baldini, George E. Ehrlich, Matthew B. Dobbs, Yasuaki Nakagawa, James Hyland, Roland Staud, Rajiv Kumar, Mary H. Hohenhaus, Nananda F. Col, Miep Helfrich, Anna Villa, Jan Hellemans, Geert Mortier, Minrong Ai, Matthew L. Warman, Markus Pfister, Hans-Peter Zenner, and Stefan K. Plontke
Published: 2009
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48. Ophthalmoplegia and Rimmed Vacuoles

Author: Marc Slawik, Felix Beuschlein, Katrina Light, Roger Mulder, Gordon Dent, Mark G. Buckley, Stephen T. Holgate, Rosalia Misseri, Kirstan K. Meldrum, Massimiliano Mirabella, Gabriella Silvestri, Thomas Frieling, Alexander K. C. Leung, Andrew L. Wong, Marcus Schmitt, Jürgen Kohlhase, Sevan Hopyan, William Lane M. Robson, Maria Judit Molnar, Andrew J. Saxon, Simone Schimpf, Stefan R. Bornstein, Regina Ensenauer, Arno Fuchshuber, Carlo Nunes, Michael Escudier, Jo Spencer, Miranda Lomer, Stephen Challacombe, Jeremy Sanderson, Manish Suneja, Christie P. Thomas, Donatella Granchi, Nicola Baldini, George E. Ehrlich, Matthew B. Dobbs, Yasuaki Nakagawa, James Hyland, Roland Staud, Rajiv Kumar, Mary H. Hohenhaus, Nananda F. Col, Miep Helfrich, Anna Villa, Jan Hellemans, Geert Mortier, Minrong Ai, Matthew L. Warman, Markus Pfister, Hans-Peter Zenner, and Stefan K. Plontke
Published: 2009
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49. Obstructive Cholestasis

Author: Marc Slawik, Felix Beuschlein, Katrina Light, Roger Mulder, Gordon Dent, Mark G. Buckley, Stephen T. Holgate, Rosalia Misseri, Kirstan K. Meldrum, Massimiliano Mirabella, Gabriella Silvestri, Thomas Frieling, Alexander K. C. Leung, Andrew L. Wong, Marcus Schmitt, Jürgen Kohlhase, Sevan Hopyan, William Lane M. Robson, Maria Judit Molnar, Andrew J. Saxon, Simone Schimpf, Stefan R. Bornstein, Regina Ensenauer, Arno Fuchshuber, Carlo Nunes, Michael Escudier, Jo Spencer, Miranda Lomer, Stephen Challacombe, Jeremy Sanderson, Manish Suneja, Christie P. Thomas, Donatella Granchi, Nicola Baldini, George E. Ehrlich, Matthew B. Dobbs, Yasuaki Nakagawa, James Hyland, Roland Staud, Rajiv Kumar, Mary H. Hohenhaus, Nananda F. Col, Miep Helfrich, Anna Villa, Jan Hellemans, Geert Mortier, Minrong Ai, Matthew L. Warman, Markus Pfister, Hans-Peter Zenner, and Stefan K. Plontke
Published: 2009
Full Text: View/download PDF

50. Orofacial Granulomatosis

Author: Marc Slawik, Felix Beuschlein, Katrina Light, Roger Mulder, Gordon Dent, Mark G. Buckley, Stephen T. Holgate, Rosalia Misseri, Kirstan K. Meldrum, Massimiliano Mirabella, Gabriella Silvestri, Thomas Frieling, Alexander K. C. Leung, Andrew L. Wong, Marcus Schmitt, Jürgen Kohlhase, Sevan Hopyan, William Lane M. Robson, Maria Judit Molnar, Andrew J. Saxon, Simone Schimpf, Stefan R. Bornstein, Regina Ensenauer, Arno Fuchshuber, Carlo Nunes, Michael Escudier, Jo Spencer, Miranda Lomer, Stephen Challacombe, Jeremy Sanderson, Manish Suneja, Christie P. Thomas, Donatella Granchi, Nicola Baldini, George E. Ehrlich, Matthew B. Dobbs, Yasuaki Nakagawa, James Hyland, Roland Staud, Rajiv Kumar, Mary H. Hohenhaus, Nananda F. Col, Miep Helfrich, Anna Villa, Jan Hellemans, Geert Mortier, Minrong Ai, Matthew L. Warman, Markus Pfister, Hans-Peter Zenner, and Stefan K. Plontke
Published: 2009
Full Text: View/download PDF

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