ABSTRACT
BACKGROUND: Studies of patients with retinitis pigmentosa (RP) have reported an increased prevalence of optic disc drusen (ODD) compared with the ODD prevalence in the general population. The diagnostic gold standard method for identifying ODD is enhanced depth imaging optical coherence tomography (EDI-OCT), but this modality has not previously been used systematically for identifying ODD in patients with RP. This study aimed to estimate the prevalence of ODD in patients with RP using EDI-OCT. METHODS: In this cross-sectional study, 40 patients with clinically diagnosed RP aged 18 years or older were included. All patients underwent an ophthalmic examination, including kinetic perimetry, EDI-OCT of the optic nerve head, and fundus photography. Genetic testing with a next-generation sequencing panel of retinal dystrophy genes was performed on the RP patients without a prior genetic diagnosis. RESULTS: Twelve patients (30.0%) had at least one ODD. Six patients had bilateral ODD. No significant differences between patients with and without ODD were found according to age, refraction, best-corrected visual acuity, Bruch membrane opening, or visual field. The genetic variation causing RP was found in 11 of 12 cases in the ODD group and in 17 of 28 cases in the group without ODD. CONCLUSIONS: We found the prevalence of ODD in patients with RP to be 30.0%. This is 15 times higher than in the general population and much higher than previously estimated in most studies, potentially indicating that the 2 conditions might be pathogenically related.
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BACKGROUND: Transcorneal electrical stimulation (TES) has been suggested as a possible treatment for retinitis pigmentosa (RP). OBJECTIVE: To expand the safety assessment of repeated applications of an electrical current from a DTL-like electrode in patients with RP. METHODS: This single-arm open label interventional safety trial included a total of 105 RP patients from 11 European centers, who received weekly TES for 6 months on 1 eye followed by observation for another 6 months without stimulation. The primary outcome measure was safety, indicated by the frequency and severity of adverse events. Secondary measures included intraocular pressure and central retinal thickness. Visual field and visual acuity were examined using the methods available at each site. RESULTS: Dry eye sensation was the most common adverse event recorded (37.5%). Serious adverse events secondary to TES were not observed. Most adverse events were mild and all resolved without sequelae. The secondary outcome measures revealed no significant or clinically relevant changes. CONCLUSION: The present results confirm the excellent safety profile of TES. Transient dry eye symptoms were the most common adverse event.
Subject(s)
Electric Stimulation Therapy/instrumentation , Retinitis Pigmentosa/therapy , Visual Acuity , Adolescent , Adult , Aged , Aged, 80 and over , Electroretinography , Equipment Design , Female , Follow-Up Studies , Humans , Intraocular Pressure/physiology , Male , Middle Aged , Prospective Studies , Retinitis Pigmentosa/diagnosis , Treatment Outcome , Young AdultABSTRACT
Autosomal recessive Stargardt disease (STGD1, MIM 248200) is caused by mutations in the ABCA4 gene. Complete sequencing of ABCA4 in STGD patients identifies compound heterozygous or homozygous disease-associated alleles in 65-70% of patients and only one mutation in 15-20% of patients. This study was designed to find the missing disease-causing ABCA4 variation by a combination of next-generation sequencing (NGS), array-Comparative Genome Hybridization (aCGH) screening, familial segregation and in silico analyses. The entire 140 kb ABCA4 genomic locus was sequenced in 114 STGD patients with one known ABCA4 exonic mutation revealing, on average, 200 intronic variants per sample. Filtering of these data resulted in 141 candidates for new mutations. Two variants were detected in four samples, two in three samples, and 20 variants in two samples, the remaining 117 new variants were detected only once. Multimodal analysis suggested 12 new likely pathogenic intronic ABCA4 variants, some of which were specific to (isolated) ethnic groups. No copy number variation (large deletions and insertions) was detected in any patient suggesting that it is a very rare event in the ABCA4 locus. Many variants were excluded since they were not conserved in non-human primates, were frequent in African populations and, therefore, represented ancestral, and not disease-associated, variants. The sequence variability in the ABCA4 locus is extensive and the non-coding sequences do not harbor frequent mutations in STGD patients of European-American descent. Defining disease-associated alleles in the ABCA4 locus requires exceptionally well characterized large cohorts and extensive analyses by a combination of various approaches.
Subject(s)
ATP-Binding Cassette Transporters/genetics , Genetic Loci , Genetic Variation , Macular Degeneration/congenital , Mutation , Alleles , Black People , Case-Control Studies , Comparative Genomic Hybridization , Exons , Female , Gene Expression , Genes, Recessive , Heterozygote , High-Throughput Nucleotide Sequencing , Homozygote , Humans , Introns , Macular Degeneration/ethnology , Macular Degeneration/genetics , Macular Degeneration/pathology , Male , Pedigree , Stargardt Disease , White PeopleABSTRACT
OBJECTIVE: In the years following military deployment, soldiers may experience problems integrating into the community. However, little is known about the nature and prevalence of these problems and if they relate to posttraumatic symptomatology. METHODS: In a prospective, longitudinal study of Danish soldiers deployed to Afghanistan in 2009 (N = 743), we assessed community reintegration difficulties 2.5 years after home coming (study sample: N = 454). Furthermore, symptoms of posttraumatic stress disorder (PTSD) were assessed before, during, and after deployment. Trajectories of PTSD symptoms from a previously published latent growth mixture modeling analysis were used to address whether community reintegration difficulties differ as a result of course and level of PTSD symptoms. RESULTS: Between 3.6 and 18.0% reported to have some, a lot, or extreme difficulties in reintegration domains such as interpersonal functioning, productivity, community involvement, and self-care. Mean level of reintegration difficulties differed significantly across six PTSD symptom trajectories (range 6.35-36.00); with more symptomatic trajectories experiencing greater community reintegration difficulties. CONCLUSIONS: Reintegration difficulties after deployment are present in less than 20% of Danish soldiers who return from Afghanistan. Difficulties are greater in individuals who follow symptomatic PTSD trajectories in the first years following deployment than in those who follow a low-stable trajectory with no or few symptoms.
Subject(s)
Community Integration , Military Personnel/psychology , Self Care , Social Adjustment , Stress Disorders, Post-Traumatic/pathology , Adult , Afghan Campaign 2001- , Denmark , Female , Humans , Longitudinal Studies , Male , Young AdultABSTRACT
OBJECTIVE: The purpose of the present study was to examine theoretically motivated predictors for the development of positive changes following potentially traumatic experiences (i.e., posttraumatic growth). Specifically, we wanted to examine the prediction that memories of highly negative and positive deployment events predict subsequent posttraumatic growth. METHOD: A total of 251 Danish soldiers (7% female, mean age 26.4) deployed to forward operating bases in Afghanistan filled out questionnaires before, during, and after deployment. This allowed us to perform prospective as well as cross-sectional analyses of the data. RESULTS: The main findings were that the centrality of highly emotional memories from deployment predicted growth alongside openness to experience, combat exposure, and social support. Importantly, the centrality of both positive and negative memories predicted growth equally well. CONCLUSION: The perceived importance of both negative and positive events may play an important part in the development of posttraumatic growth.
Subject(s)
Combat Disorders/psychology , Memory , Stress Disorders, Post-Traumatic/psychology , Veterans/psychology , Adolescent , Adult , Afghan Campaign 2001- , Denmark , Extraversion, Psychological , Female , Humans , Linear Models , Longitudinal Studies , Male , Middle Aged , Military Personnel , Social Support , Surveys and Questionnaires , Young AdultABSTRACT
PURPOSE: The gene encoding nicotinamide nucleotide adenylyltransferase 1 (NMNAT1) was recently found to be mutated in a subset of patients with Leber congenital amaurosis (LCA) with macular atrophy. The aim of this study was to determine the occurrence and frequency of NMNAT1 mutations and associated phenotypes in different types of inherited retinal dystrophies. METHODS: DNA samples of 161 patients with LCA without genetic diagnosis were analyzed for variants in NMNAT1 using Sanger sequencing. Variants in exon 5 of NMNAT1, which harbors the majority of the previously identified mutations, were screened in 532 additional patients with retinal dystrophies. This cohort encompassed 108 persons with isolated or autosomal recessive cone-rod dystrophy (CRD), 271 with isolated or autosomal recessive retinitis pigmentosa (RP), and 49 with autosomal dominant RP, as well as 104 persons with LCA in whom the causative mutation was previously identified. RESULTS: Compound heterozygous alterations were found in six patients with LCA and in one person with early-onset RP. All except one carried the common p.E257K variant on one allele. Macular atrophy was absent in one patient, who carried this variant in combination with a truncating mutation on the other allele. The p.E257K alteration was also found in a heterozygous state in five individuals with LCA and one with RP while no mutation was detected on the other allele. Two individuals with LCA carried other NMNAT1 variants in a heterozygous state, whereas no NMNAT1 variants in exon 5 were identified in individuals with CRD. The p.E257K variant was found to be enriched in a heterozygous state in individuals with LCA (0.94%) compared to Caucasian controls (0.18%), although the difference was statistically insignificant (p=0.12). CONCLUSIONS: Although macular atrophy can occur in LCA and CRD, no NMNAT1 mutations were found in the latter cohort. NMNAT1 variants were also not found in a large group of patients with sporadic or autosomal recessive RP. The enrichment of p.E257K in a heterozygous state in patients with LCA versus controls suggests that this allele could act as a modifier in other genetic subtypes of LCA.
Subject(s)
Genetic Association Studies , Genetic Predisposition to Disease , Heterozygote , Leber Congenital Amaurosis/enzymology , Leber Congenital Amaurosis/genetics , Nicotinamide-Nucleotide Adenylyltransferase/genetics , Adolescent , Adult , Aged , Child , Child, Preschool , Female , Humans , Male , Middle Aged , Mutation/genetics , Young AdultABSTRACT
PURPOSE: To assess mortality in patients with central retinal vein occlusion (CRVO). DESIGN: Registry-based cohort study. PARTICIPANTS AND CONTROLS: Four hundred thirty-nine photographically verified CRVO patients and a control cohort of 2195 unexposed subjects matched by age and gender and alive on the date CRVO was diagnosed in the corresponding case. METHODS: Data from nationwide registries were used to compare mortality rates in CRVO patients with a control cohort over a mean follow-up of 5.1 years for cases and of 5.7 years for controls. MAIN OUTCOME MEASURES: Hazard ratios (HRs) obtained by Cox regression and standardized mortality ratios (SMRs) stratified by age and gender served as measures of relative mortality risk. RESULTS: Mortality was higher in patients with CRVO (HR, 1.45; 95% confidence interval [CI], 1.19-1.76) than in the control cohort, adjusted for age, gender, and time of diagnosis. Mortality was comparable between the 2 groups (HR, 1.19; 95% CI, 0.96-1.46) when adjusting for overall occurrence of cardiovascular disease and diabetes. Subgroup analysis found that the age-stratified mortality rate was increased significantly in the total group of men (SMR, 1.27; 95% CI, 1.03-1.56) and in women 60 to 69 years of age (SMR, 1.94; 95% CI, 1.22-3.08). CONCLUSIONS: Central retinal vein occlusion was associated with an overall increase in mortality compared with controls that was attributed statistically to cardiovascular disorders and diabetes. We recommend treatment of hypertension and diabetes, if present, and referral of patients found to have CRVO who are not already being treated by a primary care physician.
Subject(s)
Retinal Vein Occlusion/mortality , Age Distribution , Aged , Aged, 80 and over , Cohort Studies , Denmark/epidemiology , Female , Fluorescein Angiography , Humans , Male , Middle Aged , Photography , Proportional Hazards Models , Registries , Retinal Vein Occlusion/diagnosis , Risk Factors , Sex DistributionABSTRACT
PURPOSE: To describe the phenotype of Danish patients with genetically verified achromatopsia (ACHM) with special focus on signs of progression on structural or functional parameters, and possible genotype-phenotype correlations. METHODS: Forty-eight patients were identified, with disease-causing variants in five different genes: CNGA3, CNGB3, GNAT2, PDE6C and PDE6H. Longitudinal evaluation was possible for 11 patients and 27 patients participated in a renewed in-depth phenotyping consisting of visual acuity assessment, optical coherence tomography (OCT), fundus autofluorescence, colour vision evaluation, contrast sensitivity, mesopic microperimetry and full-field electroretinography. Foveal morphology was evaluated based on OCT images for all 48 patients using a grading system based on the integrity of the hyperreflective photoreceptor band, the inner segment ellipsoid zone (ISe). Signs of progression were evaluated based on longitudinal data and correlation with age. RESULTS: We found a statistically significant positive correlation between OCT grade and age (Spearman ρ = 0.62, p < 0.0001) and we observed changes in the foveal morphology in 2 of 11 patients with ≥5 years of follow-up. We did not find any convincing correlation between age and functional parameters (visual acuity, retinal sensitivity and contrast sensitivity) nor did we find correlation between structural and functional parameters, or any clear genotype-phenotype correlation. CONCLUSIONS: Some patients with ACHM demonstrate signs of progressive foveal changes in OCT characteristics with increasing age. This is relevant in terms of possible new treatments. However, functional characteristics, such as visual acuity, remained stable despite changing foveal structure. Thus, seen from a patient perspective, ACHM can still be considered a non-progressive condition.
Subject(s)
Color Vision Defects , Cyclic Nucleotide-Gated Cation Channels , Electroretinography , Phenotype , Tomography, Optical Coherence , Visual Acuity , Humans , Color Vision Defects/genetics , Color Vision Defects/physiopathology , Color Vision Defects/diagnosis , Male , Tomography, Optical Coherence/methods , Female , Visual Acuity/physiology , Adult , Denmark , Adolescent , Young Adult , Child , Middle Aged , Cyclic Nucleotide-Gated Cation Channels/genetics , Cyclic Nucleotide Phosphodiesterases, Type 6/genetics , Mutation , Visual Field Tests , Contrast Sensitivity/physiology , Follow-Up Studies , Fluorescein Angiography/methods , Eye Proteins/genetics , Guanylate Cyclase/genetics , Visual Fields/physiology , Genetic Association Studies , DNA Mutational Analysis , DNA/genetics , Color Vision/physiologyABSTRACT
BACKGROUND: Information about the cost-effectiveness of early intervention programmes for first-episode psychosis is limited. AIMS: To evaluate the cost-effectiveness of an intensive early-intervention programme (called OPUS) (trial registration NCT00157313) consisting of enriched assertive community treatment, psychoeducational family treatment and social skills training for individuals with first-episode psychosis compared with standard treatment. METHOD: An incremental cost-effectiveness analysis of a randomised controlled trial, adopting a public sector perspective was undertaken. RESULTS: The mean total costs of OPUS over 5 years (123,683, s.e. = 8970) were not significantly different from that of standard treatment (148,751, s.e. = 13073). At 2-year follow-up the mean Global Assessment of Functioning (GAF) score in the OPUS group (55.16, s.d. = 15.15) was significantly higher than in standard treatment group (51.13, s.d. = 15.92). However, the mean GAF did not differ significantly between the groups at 5-year follow-up (55.35 (s.d. = 18.28) and 54.16 (s.d. = 18.41), respectively). Cost-effectiveness planes based on non-parametric bootstrapping showed that OPUS was less costly and more effective in 70% of the replications. For a willingness-to-pay up to 50,000 the probability that OPUS was cost-effective was more than 80%. CONCLUSIONS: The incremental cost-effectiveness analysis showed that there was a high probability of OPUS being cost-effective compared with standard treatment.
Subject(s)
Community Mental Health Services/economics , Early Medical Intervention/economics , Health Care Costs/statistics & numerical data , Health Services/statistics & numerical data , Outcome and Process Assessment, Health Care , Psychotic Disorders/economics , Adolescent , Adult , Antipsychotic Agents/therapeutic use , Community Mental Health Services/organization & administration , Cost-Benefit Analysis , Denmark , Diagnosis-Related Groups/economics , Family Therapy/economics , Humans , Intention to Treat Analysis , Middle Aged , Patient Care Team/economics , Patient Education as Topic/economics , Psychotic Disorders/therapy , Schizophrenia/economics , Schizophrenia/therapy , Single-Blind Method , Socialization , Young AdultABSTRACT
BACKGROUND/AIM: To describe the clinical phenotype of retinitis pigmentosa (RP) caused by PRPF31-variants and clinical characterization of asymptomatic PRPF31 carriers. MATERIALS AND METHODS: We conducted a descriptive cross-sectional deep phenotyping study. We included subjects with PRPF31 variants predicted to be disease-causing, both individuals with RP and asymptomatic carriers. Participants underwent a comprehensive clinical examination of standard visual function parameters (visual acuity, contrast sensitivity, Goldmann visual field), full-field stimulus threshold (FST), full-field electroretinogram (ff-ERG), and a structural investigation with slit lamp and multimodal imaging. We used Spearman correlation analyses to evaluate associations between quantitative outcomes. RESULTS: We included 21 individuals with disease-causing PRPF31-variants: 16 symptomatic and 5 asymptomatic subjects. The symptomatic subjects demonstrated a typical RP phenotype with constricted visual fields, extinguished ff-ERG, and disrupted outer retinal anatomy. FST was impaired and correlated significantly with other outcome measures in RP subjects. Structure-function correlations with Spearman correlation analysis showed moderate correlation coefficients due to a few outliers in each analysis. The asymptomatic individuals had normal best-corrected visual acuity and visual fields, but showed reduced ff-ERG amplitudes, borderline FST sensitivity, and structural abnormalities on OCT and fundoscopy. CONCLUSIONS: RP11 has a typical RP phenotype but varies in terms of severity. FST measurements correlated well with other functional and structural metrics and may be a reliable outcome measure in future trials as it is sensitive to a broad range of disease severities. Asymptomatic carriers showed sub-clinical disease manifestations, and our findings underline that reported non-penetrance in PRPF31-related RP is not an all-or-none phenomenon.
Subject(s)
Retinitis Pigmentosa , Humans , Cross-Sectional Studies , Retinitis Pigmentosa/diagnosis , Retinitis Pigmentosa/genetics , Retina , Electroretinography , Heterozygote , Eye Proteins/geneticsABSTRACT
(1) Background/aims: To examine potential genetic modifiers of disease penetrance in PRPF31-associated retinitis pigmentosa 11 (RP11). (2) Methods: Blood samples from individuals (n = 37) with PRPF31 variants believed to be disease-causing were used for molecular genetic testing and, in some cases (n = 23), also for mRNA expression analyses. Medical charts were used to establish if individuals were symptomatic (RP) or asymptomatic non-penetrant carriers (NPC). RNA expression levels of PRPF31 and CNOT3 were measured on peripheral whole blood using quantitative real-time PCR normalized to GAPDH. Copy number variation of minisatellite repeat element 1 (MSR1) was performed with DNA fragment analysis. (3) Results: mRNA expression analyses on 22 individuals (17 with RP and 5 non-penetrant carriers) revealed no statistically significant differences in PRPF31 or CNOT3 mRNA expression levels between individuals with RP and non-penetrant carriers. Among 37 individuals, we found that all three carriers of a 4-copy MSR1 sequence on their wild-type (WT) allele were non-penetrant carriers. However, copy number variation of MSR1 is not the sole determinant factor of non-penetrance, as not all non-penetrant carriers carried a 4-copy WT allele. A 4-copy MSR1 mutant allele was not associated with non-penetrance. (4) Conclusions: In this Danish cohort, a 4-copy MSR1 WT allele was associated with non-penetrance of retinitis pigmentosa caused by PRPF31 variants. The level of PRPF31 mRNA expression in peripheral whole blood was not a useful indicator of disease status.
Subject(s)
DNA Copy Number Variations , Retinitis Pigmentosa , Humans , Transcription Factors/genetics , Retinitis Pigmentosa/genetics , RNA, Messenger , Denmark , RNA , Eye Proteins/geneticsABSTRACT
Achromatopsia is a rare congenital condition with cone photoreceptor dysfunction causing color blindness, reduced vision, nystagmus and photophobia. New treatments are being developed, but the current evidence is still conflicting regarding possible progression over time, and there is no clear genotype-phenotype correlation. This natural history study aimed to further explore the course of disease and potential clinical differences between various genotypes. The retrospective design allowed for the study of a large cohort with a long follow-up. Patients were identified from the Danish national registries. If not already available, genetic analysis was offered to the patient. Clinical data from 1945-2022 were retrieved from medical records and included best-corrected visual acuity (BCVA), color vision, refractive error, nystagmus, visual fields and fundoscopic findings. We identified variants believed to be disease causing in five of the known achromatopsia genes: CNGA3; CNGB3; GNAT2; PDE6C and PDE6H; and novel variants were identified in CNGB3 and PDE6C. Progressive deterioration of BCVA only attributable to achromatopsia was found in three of 58 patients. Progressive phenotype was seen with variants in CNGB3 and PDE6C. The results indicate that myopia could be more frequently occurring with variants in GNAT2, PDE6C and PDE6H and support the evidence that achromatopsia is a predominantly stationary condition with respect to BCVA. Although a clear genotype-phenotype correlation can still not be concluded, there may be differences in phenotypical characteristics with variants in different genes.
Subject(s)
Color Vision Defects , Humans , Color Vision Defects/genetics , Retrospective Studies , Cyclic Nucleotide-Gated Cation Channels/genetics , DenmarkABSTRACT
BACKGROUND/AIMS: To investigate the natural history of PRPF31-related retinitis pigmentosa (RP11). MATERIALS AND METHODS: We identified individuals with RP11 and collected retrospective data from disease onset to present date including genetics, demographic data, Goldmann visual field areas, and visual acuity measurements. Visual fields were evaluated as summed squared degrees and best-corrected visual acuity was converted to logMAR. We performed linear mixed model regression analysis to evaluate annual disease progression, and survival analysis to evaluate the age of legal blindness. RESULTS: We included 46 subjects with RP11. Median age of disease onset was 10 years (range 5-65). Follow-up spanned from 0 to 36 years with a median of 8 years. Median Goldmann visual field areas decreased by 10.0% per year (95% CI 7.5%-12.4%) with target IV4e, 7.9% (95% CI 4.5% - 11.2%) with target III4e, and 9.3% (95% CI: 7.0% -11.5%) when combining target sizes. Individuals with RP11 maintained good visual acuity until late stage of disease. Legal blindness was reached at a median age of 57 years (95% CI 50-75 years). CONCLUSIONS: PRPF31 variants cause autosomal dominant retinitis pigmentosa that most commonly manifests in childhood with a variable disease progression. Visual field area deteriorates faster than visual acuity and was the major cause of legal blindness in our study population. This study characterizes disease progression in retinitis pigmentosa caused by PRPF31-variants and demonstrates the importance of differentiation between specific genotypes when counselling patients and conducting natural history studies of RP.
Subject(s)
Eye Proteins , Retinitis Pigmentosa , Humans , Child, Preschool , Child , Adolescent , Young Adult , Adult , Middle Aged , Aged , Retrospective Studies , Follow-Up Studies , Eye Proteins/genetics , Electroretinography , Mutation , Retinitis Pigmentosa/diagnosis , Retinitis Pigmentosa/genetics , Blindness , Disease ProgressionABSTRACT
Genetic conditions are often familial, but not all relatives receive counseling from the same institution. It is therefore necessary to ensure consistency in variant interpretation, counseling practices, and clinical follow up across health care providers. Furthermore, as new possibilities for gene-specific treatments emerge and whole genome sequencing becomes more widely available, efficient data handling and knowledge sharing between clinical laboratory geneticists and medical specialists in clinical genetics are increasingly important. In Denmark, these needs have been addressed through the establishment of collaborative national networks called Genetic Expert Networks or "GENets". These networks have enhanced patient and family care significantly by bringing together groups of experts in national collaborations. This promotes coordinated clinical care, the dissemination of best clinical practices, and facilitates the exchange of new knowledge.
Subject(s)
Gene Regulatory Networks , Viverridae , Humans , Animals , Health Personnel , Denmark , Genetic CounselingABSTRACT
In the study reported here, we examined posttraumatic stress disorder (PTSD) symptoms in 746 Danish soldiers measured on five occasions before, during, and after deployment to Afghanistan. Using latent class growth analysis, we identified six trajectories of change in PTSD symptoms. Two resilient trajectories had low levels across all five times, and a new-onset trajectory started low and showed a marked increase of PTSD symptoms. Three temporary-benefit trajectories, not previously described in the literature, showed decreases in PTSD symptoms during (or immediately after) deployment, followed by increases after return from deployment. Predeployment emotional problems and predeployment traumas, especially childhood adversities, were predictors for inclusion in the nonresilient trajectories, whereas deployment-related stress was not. These findings challenge standard views of PTSD in two ways. First, they show that factors other than immediately preceding stressors are critical for PTSD development, with childhood adversities being central. Second, they demonstrate that the development of PTSD symptoms shows heterogeneity, which indicates the need for multiple measurements to understand PTSD and identify people in need of treatment.
Subject(s)
Military Personnel/psychology , Resilience, Psychological , Stress Disorders, Post-Traumatic/psychology , Adult , Afghan Campaign 2001- , Combat Disorders/etiology , Combat Disorders/psychology , Denmark , Humans , Male , Severity of Illness Index , Stress Disorders, Post-Traumatic/etiology , Time Factors , WarfareABSTRACT
PURPOSE: Retinol binding protein (RBP4) is important for transport of vitamin A from liver to end organs. Variants in the RBP4 gene have been associated with a broad range of ocular phenotypes but only in a small number of patients. METHODS: We describe the phenotypes in a multi-generation family with RPB4 variants. RESULTS: A sibling pair was found to be homozygous for a novel pathogenic variant (c.112-2A>G) in RBP4. Both had presented with early-onset atypical retinitis pigmentosa and they had rheumatoid arthritis and acne. The female sibling became the mother of a child, heterozygote for the variant. The child was born with ocular malformations including corneal opacities, microcornea, posterior staphyloma including the optic nerves. The child did not demonstrate any signs of night blindness or progressive retinal dystrophy. In addition, two older family members were reported to be night blind and two distant relatives were born with spina bifida but were not available for genetic testing. DISCUSSION: Homozygous variants were associated with severe retinal dystrophy, rheumatoid disease, and acne whereas malformations were likely associated with reduced intra-uterine vitamin A levels. It seems advisable to monitor and treat vitamin A deficiency in all patients carrying one or more variants in the RBP4 gene especially during pregnancy.
Subject(s)
Night Blindness , Retinal Dystrophies , Retinitis Pigmentosa , Female , Humans , Vitamin A , Retinitis Pigmentosa/genetics , Retinol-Binding Proteins, Plasma/genetics , Denmark/epidemiologyABSTRACT
Inherited retinal disorders (IRD) are a common cause of severe visual impairment among children and young adults in Denmark. Gene therapy with voretigene neparvovec for a specific, and in Denmark common, cause of IRD (RPE65-related retinal dystrophy) was implemented as standard clinical practice in 2020 as the first of its kind. Twelve Danish patients have been treated with very positive outcomes. Genetically based therapies for other genetic causes of IRD are underway in clinical trials and are expected to change the outlooks for patients who would otherwise become blind early in life.
Subject(s)
Eye Diseases, Hereditary , Retinal Dystrophies , Child , Young Adult , Humans , Genetic Therapy , Retinal Dystrophies/genetics , Retinal Dystrophies/therapy , Eye Diseases, Hereditary/genetics , Eye Diseases, Hereditary/therapy , MutationABSTRACT
Many transcription factors regulating the production, survival, and function of photoreceptor cells have been identified, but little is known about transcriptional co-regulators in retinal health and disease. Here, we show that BCL6 co-repressor (BCOR), a Polycomb repressive complex 1 factor mutated in various cancers, is involved in photoreceptor degenerative diseases. Using proteomics and transcription assays, we report that BCOR interacts with the transcription factors CRX and OTX2 and reduces their ability to activate the promoters of photoreceptor-specific genes. CUT&RUN sequencing further shows that BCOR shares genome-wide binding profiles with CRX/OTX2, consistent with a general co-repression activity. We also identify missense mutations in human BCOR in five families that have no evidence of cancer but present severe early-onset X-linked retinal degeneration. Last, we show that the human BCOR mutants cause degeneration when expressed in the mouse retina and have enhanced repressive activity on OTX2. These results uncover a role for BCOR in photoreceptors in both health and disease.
ABSTRACT
PURPOSE: Von Hippel-Lindau (VHL) is a rare hereditary and potentially fatal cancer syndrome. Because of its unpredictable manifestations in various organ systems, surveillance is not linked to a single department and may therefore be incomplete. Denmark published national guidelines for the surveillance of patients with manifest and possible VHL in 2005 and was one of the first countries to do so. The present study is the first of its kind; patients with suspected and manifest VHL were followed at a single institution according to the national guidelines. The purpose was to evaluate (1) to what extent the guidelines were being followed and (2) what findings were disclosed. METHODS: The study included 27 individuals with diagnosed (14 patients) or suspected (13 patients) VHL, observing the Danish VHL guidelines at the Department of Neurosurgery, Rigshospitalet, Denmark, from October 2002 to April 2008. The data were collected by reviewing patient records. RESULTS: Manifestations that influenced the treatment were revealed in 48% of the patients, and 26% of the patients demonstrated asymptomatic manifestations. All investigations were conducted at a lower frequency than recommended. Individuals diagnosed with VHL were subjected to more clinical testing than individuals with suspected VHL. CONCLUSIONS: This study shows that the national clinical guidelines were not being fully complied with. The investigations revealing the most serious VHL manifestations were those carried out with a frequency closest to the recommendations. Many investigations led to clinical consequences. Therefore, we recommend that all patients with suspected or manifest VHL are monitored according to structured clinical guidelines.
Subject(s)
Guideline Adherence , Health Policy/trends , Population Surveillance/methods , Practice Guidelines as Topic/standards , von Hippel-Lindau Disease/surgery , Adolescent , Adult , Denmark/epidemiology , Female , Humans , Male , Middle Aged , Young Adult , von Hippel-Lindau Disease/diagnosis , von Hippel-Lindau Disease/epidemiologyABSTRACT
The Danish Draft Board has used the same test for assessing general cognitive ability, the Børge Prien's Prøve (BPP), for over 50 years during which time all men on reaching the age of 18 become liable for conscription. Data from the test has, over the decades, been used in numerous and wide-ranging research studies. Nonetheless, owing to the special circumstances of its administration, some psychometric properties, which are generally assessed for psychological tests, have not previously been investigated for the BPP. First, since the test is only used at the assessment phase, retesting with the BPP occurs only rarely and under exceptional circumstances. Therefore, its Test-Retest reliability has hitherto not been documented. Second, questions have often been raised as to whether the validity of the BPP is undermined by either a lack of motivation and under-performing among some of the men taking the test, being, as they are, compelled to do so, and/or by gradual obsolescence of the test over the decades of its use. We here present findings from three new studies to show that (a) the BPP has a satisfactory Test-Retest reliability, r=0.77, (b) BPP test scores are not positively associated with expressed attitude to being called upon to serve conscription and (c) the correlation between the BPP and a measure of educational level has remained stable (at about 0.5) through the last two decades. Taken together these three findings further support the continuing value of the BPP in research relating to cognitive ability.