scholarly journals Detailed clinical characterisation, unique features and natural history of autosomal recessive RDH12-associated retinal degeneration

2019 ◽  
pp. bjophthalmol-2018-313580 ◽  
Author(s):  
Abigail T Fahim ◽  
Zaina Bouzia ◽  
Kari H Branham ◽  
Neruban Kumaran ◽  
Mauricio E Vargas ◽  
...  
Keyword(s):  
Natural History ◽  
Retinal Degeneration ◽  
Early Onset ◽  
Vision Loss ◽  
Age Of Onset ◽  
Retinal Dystrophy ◽  
Loss Of Function ◽  
Phenotypic Data ◽  
History Of ◽  
Clinical Records

BackgroundDefects in retinol dehydrogenase 12 (RDH12) account for 3.4%–10.5 % of Leber congenital amaurosis and early-onset severe retinal dystrophy (EOSRD) and are a potential target for gene therapy. Clinical trials in inherited retinal diseases have unique challenges, and natural history studies are critical to successful trial design. The purpose of this study was to characterise the natural history of RDH12-associated retinal degeneration.MethodsA retrospective chart review was performed in individuals with retinal degeneration and two likely disease-causing variants in RDH12.Results57 subjects were enrolled from nine countries. 33 subjects had clinical records available from childhood. The data revealed an EOSRD, with average age of onset of 4.1 years. Macular atrophy was a universal clinical finding in all subjects, as young as 2 years of age. Scotopic and photopic electroretinography (ERG) responses were markedly reduced in all subjects, and a non-recordable ERG was documented as young as 1 year of age. Assessment of visual acuity, visual field and optical coherence tomography revealed severe loss of function and structure in the majority of subjects after the age of 10 years. Widefield imaging in 23 subjects revealed a unique, variegated watercolour-like pattern of atrophy in 13 subjects and sparing of the peripapillary area in 18 subjects.ConclusionsThis study includes the largest collection of phenotypic data from children with RDH12-associated EOSRD and provides a comprehensive description of the timeline of vision loss in this severe, early-onset condition. These findings will help identify patients with RDH12-associated retinal degeneration and will inform future design of therapeutic trials.

scholarly journals Pathogenic STX3 variants affecting the retinal and intestinal transcripts cause an early-onset severe retinal dystrophy in microvillus inclusion disease subjects

2021 ◽  
Author(s):  
Andreas R. Janecke ◽  
Xiaoqin Liu ◽  
Rüdiger Adam ◽  
Sumanth Punuru ◽  
Arne Viestenz ◽  
...  
Keyword(s):  
Early Onset ◽  
Single Nucleotide Polymorphism Array ◽  
Outer Nuclear Layer ◽  
Retinal Dystrophy ◽  
Geographic Origin ◽  
Retinal Disease ◽  
Homozygosity Mapping ◽  
Rod Photoreceptor ◽  
Loss Of Function ◽  
Knockout Mouse Model

AbstractBiallelic STX3 variants were previously reported in five individuals with the severe congenital enteropathy, microvillus inclusion disease (MVID). Here, we provide a significant extension of the phenotypic spectrum caused by STX3 variants. We report ten individuals of diverse geographic origin with biallelic STX3 loss-of-function variants, identified through exome sequencing, single-nucleotide polymorphism array-based homozygosity mapping, and international collaboration. The evaluated individuals all presented with MVID. Eight individuals also displayed early-onset severe retinal dystrophy, i.e., syndromic—intestinal and retinal—disease. These individuals harbored STX3 variants that affected both the retinal and intestinal STX3 transcripts, whereas STX3 variants affected only the intestinal transcript in individuals with solitary MVID. That STX3 is essential for retinal photoreceptor survival was confirmed by the creation of a rod photoreceptor-specific STX3 knockout mouse model which revealed a time-dependent reduction in the number of rod photoreceptors, thinning of the outer nuclear layer, and the eventual loss of both rod and cone photoreceptors. Together, our results provide a link between STX3 loss-of-function variants and a human retinal dystrophy. Depending on the genomic site of a human loss-of-function STX3 variant, it can cause MVID, the novel intestinal-retinal syndrome reported here or, hypothetically, an isolated retinal dystrophy.

The natural history of intracranial venous angiomas

1991 ◽  
Vol 75 (5) ◽  
pp. 715-722 ◽  
Author(s):  
Timothy B. Garner ◽  
O. Del Curling ◽  
David L. Kelly ◽  
D. Wayne Laster
Keyword(s):  
Natural History ◽  
Imaging Techniques ◽  
Venous Drainage ◽  
Vascular Lesion ◽  
Neurological Dysfunction ◽  
Content Type ◽  
History Of ◽  
Clinical Records ◽  
Venous Angiomas ◽  
Fine Print

✓ Cerebral venous angiomas are congenital anomalies of the intracranial venous drainage. Many believe that they are associated with a high risk of hemorrhage and neurological dysfunction, but newer neurodiagnostic imaging techniques are showing not only that they are more common than previously known but also that many have no associated symptoms. In this retrospective study, the natural history of venous angiomas was examined in 100 patients (48 males and 52 females) with radiographically identifiable lesions treated over a 14-year period. Information on the natural history of the lesion was obtained from clinical records and follow-up data. Imaging studies included angiography, computerized tomography, and magnetic resonance imaging. Angioma locations were classified as frontal (42 cases), parietal (24 cases), occipital (4 cases), temporal (2 cases), basal or ventricular (11 cases), cerebellar (14 cases), or brain stem (3 cases); 47 lesions were on the left side. Headache as a presenting symptom was common (36 patients) and often led to other radiographic studies, but this appeared to be related to the vascular lesion in only four patients. Other possibly related complications were hemorrhage in one patient, seizures in five, and transient focal deficits in eight. Fifteen patients had no neurological signs or symptoms. The mean patient age at last contact was 45.3 years (range 3 to 94 years). All patients have been managed without surgery. It is concluded that significant complications secondary to venous angiomas are infrequent and that surgical resection of these lesions and of surrounding brain is rarely indicated.

scholarly journals The Natural History of Inherited Retinal Dystrophy Due to Biallelic Mutations in the RPE65 Gene

2019 ◽  
Vol 199 ◽  
pp. 58-70 ◽  
Author(s):  
Daniel C. Chung ◽  
Mette Bertelsen ◽  
Birgit Lorenz ◽  
Mark E. Pennesi ◽  
Bart P. Leroy ◽  
...  
Keyword(s):  
Natural History ◽  
Retinal Dystrophy ◽  
Inherited Retinal Dystrophy ◽  
History Of ◽  
Biallelic Mutations

A Family with Multiple Instances of Definite, Probable and Possible Early-Onset Alzheimer's Disease

1991 ◽  
Vol 159 (4) ◽  
pp. 524-530 ◽  
Author(s):  
H. Karlinsky ◽  
E. Madrick ◽  
J. Ridgley ◽  
J. M. Berg ◽  
R. Becker ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Early Onset ◽  
Age Of Onset ◽  
Diagnostic Difficulties ◽  
History Of ◽  
Early Onset Alzheimer’S Disease ◽  
The Mean ◽  
Age Of Death

A family with a multigenerational history of proven or suspected early-onset Alzheimer's disease (AD) consistent with autosomal-dominant inheritance is described. To date, the pedigree comprises five generations in which there are 13 known affected individuals. The mean age of onset of cognitive deficits in those for whom data are available (n = 11) is 47.6 (s.d. 3.0) years and the mean age of death (n = 10) is 58.8 (s.d. 4.0) years. The variability in the extent and quality of available data illustrates the diagnostic difficulties encountered in ascertaining such an extended pedigree, and the need for caution in interpreting the evidence.

Early Onset Obsessive-Compulsive Disorder With and Without Tics

CNS Spectrums ◽  
2009 ◽  
Vol 14 (7) ◽  
pp. 362-370 ◽  
Author(s):  
Maria Alice de Mathis ◽  
Juliana B. Diniz ◽  
Roseli G. Shavitt ◽  
Albina R. Torres ◽  
Ygor A. Ferrão ◽  
...  
Keyword(s):  
Obsessive Compulsive Disorder ◽  
Early Onset ◽  
Age Of Onset ◽  
Age At Onset ◽  
Clinical Manifestations ◽  
Tic Disorders ◽  
Obsessive Compulsive ◽  
Compulsive Disorder ◽  
Diagnostic And Statistical Manual ◽  
History Of

ABSTRACTIntroduction: Research suggests that obsessive-compulsive disorder (OCD) is not a unitary entity, but rather a highly heterogeneous condition, with complex and variable clinical manifestations.Objective: The aims of this study were to compare clinical and demographic characteristics of OCD patients with early and late age of onset of obsessive-compulsive symptoms (OCS); and to compare the same features in early onset OCD with and without tics. The independent impact of age at onset and presence of tics on comorbidity patterns was investigated.Methods: Three hundred and thirty consecutive outpatients meeting Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria for OCD were evaluated: 160 patients belonged to the “early onset” group (EOG): before 11 years of age, 75 patients hadResults: The EOG had a predominance of males, higher frequency of family history of OCS, higher mean scores on the “aggression/violence” and “miscellaneous” dimensions, and higher mean global DY-BOCS scores. Patients with EOG without tic disorders presented higher mean global DY-BOCS scores and higher mean scores in the “contamination/cleaning” dimension.Conclusion: The current results disentangle some of the clinical overlap between early onset OCD with and without tics.

scholarly journals COG5 variants lead to complex early onset retinal degeneration, upregulation of PERK and DNA damage

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Sami Tabbarah ◽  
Erika Tavares ◽  
Jason Charish ◽  
Ajoy Vincent ◽  
Andrew Paterson ◽  
...  
Keyword(s):  
Dna Damage ◽  
Retinal Degeneration ◽  
Skeletal Dysplasia ◽  
Early Onset ◽  
Protein Misfolding ◽  
Cultured Cells ◽  
Retinal Dystrophy ◽  
Compound Heterozygous ◽  
Cog Complex ◽  
Compound Heterozygous Variants

AbstractLeber congenital amaurosis (LCA), a form of autosomal recessive severe early-onset retinal degeneration, is an important cause of childhood blindness. This may be associated with systemic features or not. Here we identified COG5 compound-heterozygous variants in patients affected with a complex LCA phenotype associated with microcephaly and skeletal dysplasia. COG5 is a component of the COG complex, which facilitates retrograde Golgi trafficking; if disrupted this can result in protein misfolding. To date, variants in COG5 have been associated with a distinct congenital disorder of glycosylation (type IIi) and with a variant of Friedreich’s ataxia. We show that COG5 variants can also result in fragmentation of the Golgi apparatus and upregulation of the UPR modulator, PKR-like endoplasmic reticulum kinase (PERK). In addition, upregulation of PERK induces DNA damage in cultured cells and in murine retina. This study identifies a novel role for COG5 in maintaining ER protein homeostasis and that disruption of that role results in activation of PERK and early-onset retinal degeneration, microcephaly and skeletal dysplasia. These results also highlight the importance of the UPR pathway in early-onset retinal dystrophy and as potential therapeutic targets for patients.

A mutation in CRX causing pigmented paravenous retinochoroidal atrophy

2020 ◽  
pp. 112067212095759
Author(s):  
Jin Kyun Oh ◽  
Yan Nuzbrokh ◽  
Winston Lee ◽  
Jose Ronaldo Lima de Carvalho ◽  
Nan Kai Wong ◽  
...  
Keyword(s):  
Vision Loss ◽  
Retinal Dystrophy ◽  
Cone Dystrophy ◽  
Full Field ◽  
Inherited Retinal Dystrophy ◽  
History Of ◽  
Pigmented Paravenous Retinochoroidal Atrophy ◽  
Retinal Thinning ◽  
Bull's Eye ◽  
Sd Oct

Introduction: Mutations in the cone-rod homeobox ( CRX) gene, a known cause of inherited retinal dystrophy, are characterized by extensive phenotypic heterogeneity. We describe a novel presentation of rod-cone dystrophy (RCD) phenocopying pigmented paravenous retinochoroidal atrophy associated with a mutation in CRX. Case description: A 53-year-old man and his 48-year-old brother presented with a history of progressive vision loss and nyctalopia. Fundus examination revealed a bull’s eye lesion with chorioretinal atrophy and intraretinal pigment migration, while spectral-domain optical coherence tomography (SD-OCT) demonstrated retinal thinning with outer retinal atrophy. On short-wavelength autofluorescence (SW-AF) imaging, an atypical paravenous pattern of atrophy with a surrounding hyperautofluorescent border was observed. Full-field electroretinogram (ffERG) revealed a rod-cone pattern of dysfunction. A heterozygous pathogenic variant, c.119G>A:p.(Arg40Gln), in the CRX gene was identified in both brothers and segregated in their family. Conclusion: This case report broadens the currently known phenotypic presentations of CRX-associated retinopathy and suggests that mutations in CRX may be associated with pigmented paravenous retinochoroidal atrophy.

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