Cecilie Bredrup

Publications (12)58.2 Total impact

• Source

  Available from: Kristoffer Haugarvoll

  Article: MRI characterisation of adult onset alpha-methylacyl-coA racemase deficiency diagnosed by exome sequencing.

  Kristoffer Haugarvoll, Stefan Johansson, Charalampos Tzoulis, Bjørn Ivar Haukanes, Cecilie Bredrup, Gesche Neckelmann, Helge Boman, Per Morten Knappskog, Laurence A Bindoff
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  ABSTRACT: BACKGROUND: Correct diagnosis is pivotal to understand and treat neurological disease. Herein, we report the diagnostic work-up utilizing exome sequencing and the characterization of clinical features and brain MRI in two siblings with a complex, adult-onset phenotype; including peripheral neuropathy, epilepsy, relapsing encephalopathy, bilateral thalamic lesions, type 2 diabetes mellitus, cataract, pigmentary retinopathy and tremor. METHODS: We applied clinical and genealogical investigations, homozygosity mapping and exome sequencing to establish the diagnosis and MRI to characterize the cerebral lesions. RESULTS: A recessive genetic defect was suspected in two siblings of healthy, but consanguineous parents. Homozygosity mapping revealed three shared homozygous regions and exome sequencing, revealed a novel homozygous c.367 G>A [p.Asp123Asn] mutation in the alpha-methylacyl-coA racemase (AMACR) gene in both patients. The genetic diagnosis of alpha-methylacyl-coA racemase deficiency was confirmed by demonstrating markedly increased pristanic acid levels in blood (169 mumol/L, normal <1.5 mumol/L). MRI studies showed characteristic degeneration of cerebellar afferents and efferents, including the dentatothalamic tract and thalamic lesions in both patients. CONCLUSIONS: Metabolic diseases presenting late are diagnostically challenging. We show that appropriately applied, homozygosity mapping and exome sequencing can be decisive for establishing diagnoses such as late onset alpha-methylacyl-coA racemase deficiency, an autosomal recessive peroxisomal disorder with accumulation of pristanic acid. Our study also highlights radiological features that may assist in diagnosis. Early diagnosis is important as patients with this disorder may benefit from restricted dietary phytanic and pristanic acid intake.
  Orphanet Journal of Rare Diseases 01/2013; 8(1):1. · 5.83 Impact Factor
• Article: Early panretinal photocoagulation for ERG-verified ischaemic central retinal vein occlusion.

  Ole Kjeka, Ragnhild W Jansson, Cecilie Bredrup, Jørgen Krohn
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  ABSTRACT: Purpose:  We have previously shown that photopic cone b-wave implicit time ≥35.0 ms in 30 Hz flicker electroretinography (ERG) predicts ocular neovascularization (NV) in central retinal vein occlusion (CRVO). Here, we evaluate the effects of early panretinal photocoagulation (PRP) in patients with ERG-verified ischaemic CRVO. Methods:  Patients with CRVO, admitted to our department between 2000 and 2008, were classified as having ischaemic or non-ischaemic CRVO based on the ERG-results. In a first group of 71 patients, 18 patients had ischaemic CRVO and were assigned to standard treatment that is regular examinations and PRP as soon as NV was found. In a consecutive group of 65 patients, 18 patients with ischaemic CRVO received early PRP. In this group, ERG was performed on average 6 weeks after the first symptoms of CRVO. The patients underwent PRP as soon as possible after the ERG-examination, and the treatment was completed within one to three sessions. Results:  Twelve patients in the standard treatment group developed neovascular glaucoma during a mean period of 5 months after the CRVO. In the early treatment group, one patient developed subtle iris rubeosis 7 months after PRP. Otherwise, none of the patients showed any signs of ocular NV, and the intraocular pressure remained within normal range, without the necessity of supplementary medication, during a mean follow-up of 41 months. Conclusions:  This study indicates that ocular NV in patients with CRVO can be predicted by photopic 30 Hz flicker ERG and that early PRP in ERG-verified ischaemic CRVO could be suggested as standard treatment.
  Acta ophthalmologica 12/2011; · 2.44 Impact Factor
• Article: Ciliopathies with skeletal anomalies and renal insufficiency due to mutations in the IFT-A gene WDR19.

  Cecilie Bredrup, Sophie Saunier, Machteld M Oud, Torunn Fiskerstrand, Alexander Hoischen, Damien Brackman, Sabine M Leh, Marit Midtbø, Emilie Filhol, Christine Bole-Feysot, [......], Marie Matignon, Rolph Pfundt, Cécile Jeanpierre, Helge Boman, Eyvind Rødahl, Joris A Veltman, Per M Knappskog, Nine V A M Knoers, Ronald Roepman, Heleen H Arts
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  ABSTRACT: A subset of ciliopathies, including Sensenbrenner, Jeune, and short-rib polydactyly syndromes are characterized by skeletal anomalies accompanied by multiorgan defects such as chronic renal failure and retinitis pigmentosa. Through exome sequencing we identified compound heterozygous mutations in WDR19 in a Norwegian family with Sensenbrenner syndrome. In a Dutch family with the clinically overlapping Jeune syndrome, a homozygous missense mutation in the same gene was found. Both families displayed a nephronophthisis-like nephropathy. Independently, we also identified compound heterozygous WDR19 mutations by exome sequencing in a Moroccan family with isolated nephronophthisis. WDR19 encodes IFT144, a member of the intraflagellar transport (IFT) complex A that drives retrograde ciliary transport. We show that IFT144 is absent from the cilia of fibroblasts from one of the Sensenbrenner patients and that ciliary abundance and morphology is perturbed, demonstrating the ciliary pathogenesis. Our results suggest that isolated nephronophthisis, Jeune, and Sensenbrenner syndromes are clinically overlapping disorders that can result from a similar molecular cause.
  The American Journal of Human Genetics 11/2011; 89(5):634-43. · 10.60 Impact Factor
• Article: Decorin accumulation contributes to the stromal opacities found in congenital stromal corneal dystrophy.

  Cecilie Bredrup, Espen Stang, Ove Bruland, Barbara P Palka, Robert D Young, Jan Haavik, Per M Knappskog, Eyvind Rødahl
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  ABSTRACT: Congenital stromal corneal dystrophy (CSCD) is characterized by stromal opacities that morphologically are seen as interlamellar layers of amorphous substance with small filaments, the nature of which has hitherto been unknown. CSCD is associated with truncating mutations in the decorin gene (DCN). To understand the molecular basis for the corneal opacities we analyzed the expression of decorin in this disease, both at the morphologic and the molecular level. Corneal specimens were examined after contrast enhancement with cuprolinic blue and by immunoelectron microscopy. Decorin protein from corneal tissue and keratocyte culture was studied by immunoblot analysis before and after O- and N-deglycosylation. The relative level of DCN mRNA expression was examined using Q-RT-PCR, and cDNA was sequenced. Recombinant wild-type and truncated decorin transiently expressed in HEK293 cells were analyzed by gel filtration and immunoblotting. The areas of interlamellar filaments were stained by cuprolinic blue. Immunoelectron microscopy using decorin antibodies revealed intense labeling of these areas. Both wild-type and truncated decorin protein was expressed in corneal tissue and keratocytes of affected persons. When decorin expressed in HEK293 cells was examined by gel filtration, the truncated decorin eluted as high molecular weight aggregates. Accumulation of decorin was found in the interlamellar areas of amorphous substance. The truncated decorin is present in CSCD corneas, and there is evidence it may aggregate in vitro. Thus, decorin accumulation appears to contribute to the stromal opacities that are characteristic of CSCD.
  Investigative ophthalmology & visual science 11/2010; 51(11):5578-82. · 3.43 Impact Factor
• Source

  Available from: Stefan Johansson

  Article: Mutations in ABHD12 cause the neurodegenerative disease PHARC: An inborn error of endocannabinoid metabolism.

  Torunn Fiskerstrand, Dorra H'mida-Ben Brahim, Stefan Johansson, Abderrahim M'zahem, Bjørn Ivar Haukanes, Nathalie Drouot, Julian Zimmermann, Andrew J Cole, Christian Vedeler, Cecilie Bredrup, Mirna Assoum, Meriem Tazir, Thomas Klockgether, Abdelmadjid Hamri, Vidar M Steen, Helge Boman, Laurence A Bindoff, Michel Koenig, Per M Knappskog
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  ABSTRACT: Polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, and cataract (PHARC) is a neurodegenerative disease marked by early-onset cataract and hearing loss, retinitis pigmentosa, and involvement of both the central and peripheral nervous systems, including demyelinating sensorimotor polyneuropathy and cerebellar ataxia. Previously, we mapped this Refsum-like disorder to a 16 Mb region on chromosome 20. Here we report that mutations in the ABHD12 gene cause PHARC disease and we describe the clinical manifestations in a total of 19 patients from four different countries. The ABHD12 enzyme was recently shown to hydrolyze 2-arachidonoyl glycerol (2-AG), the main endocannabinoid lipid transmitter that acts on cannabinoid receptors CB1 and CB2. Our data therefore represent an example of an inherited disorder related to endocannabinoid metabolism. The endocannabinoid system is involved in a wide range of physiological processes including neurotransmission, mood, appetite, pain appreciation, addiction behavior, and inflammation, and several potential drugs targeting these pathways are in development for clinical applications. Our findings show that ABHD12 performs essential functions in both the central and peripheral nervous systems and the eye. Any future drug-mediated interference with this enzyme should consider the potential risk of long-term adverse effects.
  The American Journal of Human Genetics 09/2010; 87(3):410-7. · 10.60 Impact Factor
• Source

  Available from: Mikhail Kagan

  Article: Ophthalmological aspects of Pierson syndrome.

  Cecilie Bredrup, Verena Matejas, Margaret Barrow, Kvĕta Bláhová, Detlef Bockenhauer, Darren J Fowler, Richard M Gregson, Iwona Maruniak-Chudek, Ana Medeira, Erica Laima Mendonça, [......], Michael Schittkowski, Janusz Swietliński, Dorothy Thompson, Rene G VanDeVoorde, Dienke Wittebol-Post, Geoffrey Woodruff, Aleksandra Zurowska, Raoul C Hennekam, Martin Zenker, Isabelle Russell-Eggitt
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  ABSTRACT: To study the ocular phenotype of Pierson syndrome and to increase awareness among ophthalmologists of the diagnostic features of this condition. Retrospective, observational case series. A multicenter study of 17 patients with molecularly confirmed Pierson syndrome. The eye findings were reviewed and compared to pertinent findings from the literature. The most characteristic ocular anomaly was microcoria. A wide range of additional abnormalities were found, including posterior embryotoxon, megalocornea, iris hypoplasia, cataract, abnormal lens shape, posterior lenticonus, persistent fetal vasculature, retinal detachment, variable axial lengths, and glaucoma. There was high interocular and intrafamilial variability. Loss-of-function mutations in laminin beta2 (LAMB2) cause a broad range of ocular pathology, emphasizing the importance of laminin beta2 in eye development. Patients with Pierson syndrome can initially present with ocular signs alone. In newborns with marked bilateral microcoria, Pierson syndrome should be considered and renal function investigated.
  American journal of ophthalmology 08/2008; 146(4):602-611. · 3.83 Impact Factor
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  Available from: Arnold Berstad

  Article: Neurological features and enzyme therapy in patients with endocrine and exocrine pancreas dysfunction due to CEL mutations.

  Mette Vesterhus, Helge Raeder, Harald Aurlien, Clara G Gjesdal, Cecilie Bredrup, Pål I Holm, Anders Molven, Laurence Bindoff, Arnold Berstad, Pål R Njølstad
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  ABSTRACT: To further define clinical features associated with the syndrome of diabetes and pancreatic exocrine dysfunction due to mutations in the carboxyl-ester lipase (CEL) gene and to assess the effects of pancreatic enzyme substitution therapy. Nine patients with CEL gene mutation, exocrine deficiency, and diabetes were treated and followed for 30 months. Treatment improved symptoms in seven of nine patients. Exocrine and endocrine function assessed by fecal elastase and A1C were not affected, although fecal lipid excretion was reduced. Vitamin E was low in all patients but increased with treatment (P < 0.001 at 30 months) and improved in five subjects. A predominantly demyelinating neuropathy was seen in a majority of patients, and carpal tunnel syndrome was common. Pancreatic enzyme substitution alleviated symptoms and malabsorption and normalized vitamin E levels. Glycemic control was not significantly affected. The CEL syndrome seems associated with a demyelinating neuropathology.
  Diabetes care 06/2008; 31(9):1738-40. · 8.09 Impact Factor
• Article: Clinical manifestation of a novel PAX6 mutation Arg128Pro.

  Cecilie Bredrup, Per M Knappskog, Eyvind Rødahl, Helge Boman
  Archives of Ophthalmology 04/2008; 126(3):428-30. · 3.71 Impact Factor
• Article: Photopic 30 Hz flicker electroretinography predicts ocular neovascularization in central retinal vein occlusion.

  Ole Kjeka, Cecilie Bredrup, Jørgen Krohn
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  ABSTRACT: To confirm the predictive value of photopic cone b-wave implicit time in 30 Hz flicker electroretinography (ERG) for ocular neovascularization (NV) in central retinal vein occlusion (CRVO), and to compare the ERG results to the presumed healthy fellow eye. A retrospective analysis of 71 consecutive patients with CRVO. After ERG examination, all patients were followed for at least 12 months, or until NV was found. Three patients died during the study period; none of the other patients were lost to follow-up. Twenty-four patients (33.8%) developed NV during follow-up. The mean cone b-wave implicit time of all patients was 32.6 ms [standard deviation (SD) 5.21]. All 18 patients with an implicit time of 35.0 ms or higher (> 0.5 SD from mean) developed NV. In patients who developed NV, the average implicit time was 38.5 ms (range 29.7-43.9 ms); in patients without NV (n = 47), the average implicit time was 29.6 ms (range 24.7-34.9 ms) (P < 0.0001). The average implicit time in the presumed healthy fellow eye was 28.7 ms (range 24.4-33.9 ms) in patients with NV, and 26.5 ms (range 23.7-33.2 ms) in patients without NV (P = 0.002). The mean interocular difference in implicit time was 9.9 ms (range 4.1-15.7 ms) in patients with NV and 2.9 ms (range -1.0 to 10.0 ms) in patients without NV (P < 0.0001). Patients with CRVO should be examined routinely with photopic 30 Hz flicker ERG, which is a simple and objective clinical test that can identify patients at risk of ocular NV. On the assumption that the presented ERG settings are used, implicit times of 35.0 ms or higher (> 0.5 SD from mean) are clearly associated with the development of ocular NV. To compare the ERG result of the affected eye to the presumed healthy fellow eye is probably of less value.
  Acta Ophthalmologica Scandinavica 09/2007; 85(6):640-3. · 1.85 Impact Factor
• Article: A second decorin frame shift mutation in a family with congenital stromal corneal dystrophy.

  Eyvind Rødahl, Rita Van Ginderdeuren, Per M Knappskog, Cecilie Bredrup, Helge Boman
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  ABSTRACT: To identify the genetic defect in a Belgian family with congenital stromal corneal dystrophy. Case report and result of deoxyribonucleic acid (DNA) analyses. DNA sequencing of polymerase chain reaction (PCR) products generated from amplification of exons and adjacent introns of the decorin gene. The family consisted of a mother and her son, both suffering from congenital stromal corneal dystrophy. In both individuals, a single base pair deletion (c.941delC) in the coding sequence of the decorin gene was demonstrated, predicting a C-terminal truncation of the decorin protein (p.Pro314fsX14). This is the second family with congenital stromal corneal dystrophy of the cornea in which a frame shift mutation in the decorin gene has been detected. Both in this family and in a previously reported Norwegian family, a decorin protein missing the 33 C-terminal amino acids is predicted. This observation strongly supports a role for decorin in the pathogenesis of this disorder.
  American Journal of Ophthalmology 10/2006; 142(3):520-1. · 4.22 Impact Factor
• Source

  Available from: mcgill.ca

  Article: Congenital stromal dystrophy of the cornea caused by a mutation in the decorin gene.

  Cecilie Bredrup, Per M Knappskog, Jacek Majewski, Eyvind Rødahl, Helge Boman
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  ABSTRACT: To describe the clinical and pathologic characteristics of a family with a congenital stromal dystrophy of the cornea and to identify the genetic basis for this disorder. All family members in three generations underwent ophthalmic examination. Stored corneal buttons were examined by transmission electron microscopy. Molecular genetic studies, including a genome-wide scan with microsatellite markers, linkage analysis, and DNA sequencing, were performed. The dystrophy was inherited in an autosomal dominant pattern and was seen as clouded corneas shortly after birth. No associated systemic abnormalities or congenital diseases were present. After penetrating keratoplasty (PK), the grafts remained completely clear in 56% of the eyes with a mean (range) observation period of 19.5 years (3-36). Transmission electron microscopy of corneal buttons revealed lamellae with normal arrangement of collagen fibrils separated by abnormal fibrillar layers. Genome-wide screening revealed linkage to chromosome 12q22, with a maximum LOD score of 4.68 at D12S351. Subsequent sequencing of candidate genes revealed a frameshift mutation in the DCN gene (c.967delT) that encodes for decorin, predicting a C-terminal truncation of the decorin protein (p.S323fsX5). The authors hypothesize that truncated decorin binds to collagen in a suboptimal way, disturbing the regularity of corneal collagen fibril formation and thereby causing corneal opacities. To the best of the authors' knowledge, this is the first description of a disorder associated with an inherited alteration in the decorin gene in humans.
  Investigative Ophthalmology &amp Visual Science 03/2005; 46(2):420-6. · 3.60 Impact Factor
• Chapter: Congenital Stromal Corneal Dystrophy

  Eyvind Rødahl, Per M Knappskog, Cecilie Bredrup, Helge Boman
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  ABSTRACT: Congenital stromal corneal dystrophy is characterized by the presence of bilateral corneal opacities that can be seen at or shortly after birth. The surface of the cornea is normal or slightly irregular; small opacities seen throughout the stroma of the entire cornea give the cornea a cloudy appearance. Strabismus is common. Nystagmus is uncommon. Most individuals undergo penetrating keratoplasty in late adolescence or early adulthood with good results. DCN, encoding decorin, is the only gene in which mutations are known to cause congenital stromal corneal dystrophy. Molecular genetic testing is available. Treatment of manifestations: Spectacles or contact lenses for correction of refractive errors; patching and/or surgical correction of strabismus; penetrating keratoplasty. Congenital stromal corneal dystrophy is inherited in an autosomal dominant manner. Most individuals diagnosed with congenital stromal corneal dystrophy have an affected parent. Each child of an affected individual has a 50% chance of inheriting the mutation. No laboratories listed in the GeneTests™ Laboratory Directory offer molecular genetic testing for prenatal diagnosis of congenital stromal corneal dystrophy. However, prenatal testing may be available through laboratories offering custom prenatal testing for families in which the disease-causing mutation has been identified.