Cecilie Bredrup

Ciliopathies with Skeletal Anomalies and Renal Insufficiency due to Mutations in the IFT-A Gene WDR19

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.

Mutations in ABHD12 Cause the Neurodegenerative Disease PHARC: An Inborn Error of Endocannabinoid Metabolism

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.

Ic3d Classification of Corneal Dystrophies—edition 2

Purpose: To update the 2008 International Classification of Corneal Dystrophies (IC3D) incorporating new clinical, histopathologic, and genetic information. Methods: The IC3D reviewed worldwide peer-reviewed articles for new information on corneal dystrophies published between 2008 and 2014. Using this information, corneal dystrophy templates and anatomic classification were updated. New clinical, histopathologic, and confocal photographs were added. Results: On the basis of revisiting the cellular origin of corneal dystrophy, a modified anatomic classification is proposed consisting of (1) epithelial and subepithelial dystrophies, (2) epithelial–stromal TGFBI dystrophies, (3) stromal dystrophies, and (4) endothelial dystrophies. Most of the dystrophy templates are updated. The entity “Epithelial recurrent erosion dystrophies” actually includes a number of potentially distinct epithelial dystrophies (Franceschetti corneal dystrophy, Dystrophia Smolandiensis, and Dystrophia Helsinglandica) but must be differentiated from dystrophies such as TGFBI-induced dystrophies, which are also often associated with recurrent epithelial erosions. The chromosome locus of Thiel-Behnke corneal dystrophy is only located on 5q31. The entity previously designated as a variant of Thiel-Behnke corneal dystrophy on chromosome 10q24 may represent a novel corneal dystrophy. Congenital hereditary endothelial dystrophy (CHED, formerly CHED2) is most likely only an autosomal recessive disorder. The so-called autosomal dominant inherited CHED (formerly CHED1) is insufficiently distinct to continue to be considered a unique corneal dystrophy. On review of almost all of the published cases, the description appeared most similar to a type of posterior polymorphous corneal dystrophy linked to the same chromosome 20 locus (PPCD1). Confocal microscopy also has emerged as a helpful tool to reveal in vivo features of several corneal dystrophies that previously required histopathologic examination to definitively diagnose. Conclusions: This revision of the IC3D classification includes an updated anatomic classification of corneal dystrophies more accurately classifying TGFBI dystrophies that affect multiple layers rather than are confined to one corneal layer. Typical histopathologic and confocal images have been added to the corneal dystrophy templates.

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

BackgroundCorrect 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.MethodsWe applied clinical and genealogical investigations, homozygosity mapping and exome sequencing to establish the diagnosis and MRI to characterize the cerebral lesions.ResultsA 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 α-methylacyl-coA racemase (AMACR) gene in both patients. The genetic diagnosis of α-methylacyl-coA racemase deficiency was confirmed by demonstrating markedly increased pristanic acid levels in blood (169 μmol/L, normal <1.5 μmol/L). MRI studies showed characteristic degeneration of cerebellar afferents and efferents, including the dentatothalamic tract and thalamic lesions in both patients.ConclusionsMetabolic 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 α-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.

The IC3D Classification of the Corneal Dystrophies

BACKGROUND The recent availability of genetic analyses has demonstrated the shortcomings of the current phenotypic method of corneal dystrophy classification. Abnormalities in different genes can cause a single phenotype, whereas different defects in a single gene can cause different phenotypes. Some disorders termed corneal dystrophies do not appear to have a genetic basis. PURPOSE The purpose of this study was to develop a new classification system for corneal dystrophies, integrating up-to-date information on phenotypic description, pathologic examination, and genetic analysis. METHODS The International Committee for Classification of Corneal Dystrophies (IC3D) was created to devise a current and accurate nomenclature. RESULTS This anatomic classification continues to organize dystrophies according to the level chiefly affected. Each dystrophy has a template summarizing genetic, clinical, and pathologic information. A category number from 1 through 4 is assigned, reflecting the level of evidence supporting the existence of a given dystrophy. The most defined dystrophies belong to category 1 (a well-defined corneal dystrophy in which a gene has been mapped and identified and specific mutations are known) and the least defined belong to category 4 (a suspected dystrophy where the clinical and genetic evidence is not yet convincing). The nomenclature may be updated over time as new information regarding the dystrophies becomes available. CONCLUSIONS The IC3D Classification of Corneal Dystrophies is a new classification system that incorporates many aspects of the traditional definitions of corneal dystrophies with new genetic, clinical, and pathologic information. Standardized templates provide key information that includes a level of evidence for there being a corneal dystrophy. The system is user-friendly and upgradeable and can be retrieved on the website www.corneasociety.org/ic3d .

Ophthalmological Aspects of Pierson Syndrome

PURPOSE To study the ocular phenotype of Pierson syndrome and to increase awareness among ophthalmologists of the diagnostic features of this condition. DESIGN Retrospective, observational case series. METHODS A multicenter study of 17 patients with molecularly confirmed Pierson syndrome. The eye findings were reviewed and compared to pertinent findings from the literature. RESULTS 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. CONCLUSIONS 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.

Decorin accumulation contributes to the stromal opacities found in congenital stromal corneal dystrophy.

PURPOSE 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. METHODS 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. RESULTS 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. CONCLUSIONS 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.

Neurological Features and Enzyme Therapy in Patients With Endocrine and Exocrine Pancreas Dysfunction Due to CEL Mutations

OBJECTIVE—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. RESEARCH DESIGN AND METHODS—Nine patients with CEL gene mutation, exocrine deficiency, and diabetes were treated and followed for 30 months. RESULTS—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. CONCLUSIONS—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.

Early panretinal photocoagulation for ERG‐verified ischaemic central retinal vein occlusion

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.

The intronic ABCA4 c.5461-10T>C variant, frequently seen in patients with Stargardt disease, causes splice defects and reduced ABCA4 protein level

Despite being the third most common ABCA4 variant observed in patients with Stargardt disease, the functional effect of the intronic ABCA4 variant c.5461‐10T>C is unknown. The purpose of this study was to investigate the molecular effect of this variant.