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| 4. |
- Alef, S., et al.
(författare)
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The BGOOD experimental setup at ELSA
- 2020
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Ingår i: European Physical Journal A. - : Springer Science and Business Media LLC. - 1434-6001 .- 1434-601X. ; 56:4
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Tidskriftsartikel (refereegranskat)abstract
- The BGOOD experiment at the ELSA facility in Bonn has been commissioned within the framework of an international collaboration. The experiment pursues a systematic investigation of non-strange and strange meson photoproduction, in particular t-channel processes at low momentum transfer. The setup uniquely combines a central almost 4 π acceptance BGO crystal calorimeter with a large aperture forward magnetic spectrometer providing excellent detection of both neutral and charged particles, complementary to other setups such as Crystal Barrel, Crystal Ball, LEPS and CLAS.
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| 5. |
- Hunter, P, et al.
(författare)
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A vision and strategy for the virtual physiological human in 2010 and beyond
- 2010
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Ingår i: Philosophical transactions. Series A, Mathematical, physical, and engineering sciences. - : The Royal Society. - 1364-503X. ; 368:1920, s. 2595-2614
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Tidskriftsartikel (refereegranskat)abstract
- European funding under framework 7 (FP7) for the virtual physiological human (VPH) project has been in place now for nearly 2 years. The VPH network of excellence (NoE) is helping in the development of common standards, open-source software, freely accessible data and model repositories, and various training and dissemination activities for the project. It is also helping to coordinate the many clinically targeted projects that have been funded under the FP7 calls. An initial vision for the VPH was defined by framework 6 strategy for a European physiome (STEP) project in 2006. It is now time to assess the accomplishments of the last 2 years and update the STEP vision for the VPH. We consider the biomedical science, healthcare and information and communications technology challenges facing the project and we propose the VPH Institute as a means of sustaining the vision of VPH beyond the time frame of the NoE.
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| 6. |
- Varela, AR, et al.
(författare)
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Status and Trends of Physical Activity Surveillance, Policy, and Research in 164 Countries: Findings From the Global Observatory for Physical Activity-GoPA! 2015 and 2020 Surveys
- 2023
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Ingår i: Journal of physical activity & health. - : Human Kinetics. - 1543-5474 .- 1543-3080. ; 20:2, s. 112-128
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Tidskriftsartikel (refereegranskat)abstract
- Background: Physical activity (PA) surveillance, policy, and research efforts need to be periodically appraised to gain insight into national and global capacities for PA promotion. The aim of this paper was to assess the status and trends in PA surveillance, policy, and research in 164 countries. Methods: We used data from the Global Observatory for Physical Activity (GoPA!) 2015 and 2020 surveys. Comprehensive searches were performed for each country to determine the level of development of their PA surveillance, policy, and research, and the findings were verified by the GoPA! Country Contacts. Trends were analyzed based on the data available for both survey years. Results: The global 5-year progress in all 3 indicators was modest, with most countries either improving or staying at the same level. PA surveillance, policy, and research improved or remained at a high level in 48.1%, 40.6%, and 42.1% of the countries, respectively. PA surveillance, policy, and research scores decreased or remained at a low level in 8.3%, 15.8%, and 28.6% of the countries, respectively. The highest capacity for PA promotion was found in Europe, the lowest in Africa and low- and lower-middle-income countries. Although a large percentage of the world’s population benefit from at least some PA policy, surveillance, and research efforts in their countries, 49.6 million people are without PA surveillance, 629.4 million people are without PA policy, and 108.7 million live in countries without any PA research output. A total of 6.3 billion people or 88.2% of the world’s population live in countries where PA promotion capacity should be significantly improved. Conclusion: Despite PA is essential for health, there are large inequalities between countries and world regions in their capacity to promote PA. Coordinated efforts are needed to reduce the inequalities and improve the global capacity for PA promotion.
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| 7. |
- Kohl, S, et al.
(författare)
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CNGB3 mutations account for 50% of all cases with autosomal recessive achromatopsia
- 2005
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Ingår i: European Journal of Human Genetics. - : Springer Science and Business Media LLC. - 1476-5438 .- 1018-4813. ; 13:3, s. 302-308
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Tidskriftsartikel (refereegranskat)abstract
- Achromatopsia is a congenital, autosomal recessively inherited disorder characterized by a lack of color discrimination, low visual acuity (<0.2), photophobia, and nystagmus. Mutations in the genes for CNGA3, CNGB3, and GNAT2 have been associated with this disorder. Here, we analyzed the spectrum and prevalence of CNGB3 gene mutations in a cohort of 341 independent patients with achromatopsia. In 163 patients, CNGB3 mutations could be identified. A total of 105 achromats carried apparent homozygous mutations, 44 were compound (double) heterozygotes, and 14 patients had only a single mutant allele. The derived CNGB3 mutation spectrum comprises 28 different mutations including 12 nonsense mutations, eight insertions and/or deletions, five putative splice site mutations, and three missense mutations. Thus, the majority of mutations in the CNGB3 gene result in significantly altered and/or truncated polypeptides. Several mutations were found recurrently, in particular a 1 bp deletion, c.1148delC, which accounts for over 70% of all CNGB3 mutant alleles. In conclusion, mutations in the CNGB3 gene are responsible for approximately 50% of all patients with achromatopsia. This indicates that the CNGB3/ACHM3 locus on chromosome 8q21 is the major locus for achromatopsia in patients of European origin or descent.
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| 8. |
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| 9. |
- Coveney, PV, et al.
(författare)
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Integrative approaches to computational biomedicine
- 2013
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Ingår i: INTERFACE FOCUS. - : The Royal Society. - 2042-8898 .- 2042-8901. ; 3:2
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- The new discipline of computational biomedicine is concerned with the application of computer-based techniques and particularly modelling and simulation to human health. Since 2007, this discipline has been synonymous, in Europe, with the name given to the European Union's ambitious investment in integrating these techniques with the eventual aim of modelling the human body as a whole: the virtual physiological human. This programme and its successors are expected, over the next decades, to transform the study and practice of healthcare, moving it towards the priorities known as ‘4P's’: predictive, preventative, personalized and participatory medicine.
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| 10. |
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| 11. |
- Joerger, R, et al.
(författare)
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Optical properties of inhomogeneous media
- 1998
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Ingår i: SOLAR ENERGY MATERIALS AND SOLAR CELLS. - : ELSEVIER SCIENCE BV. - 0927-0248. ; 54:1-4, s. 351-361
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Tidskriftsartikel (refereegranskat)abstract
- Inhomogeneous media such as ceramic-metal composites are used in a wide range of applications as functional optical coatings e.g, in selective solar absorber coatings. Their optical properties can be calculated by the use of effective medium theories. The
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| 12. |
- Kotmayer, L, et al.
(författare)
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Landscape of BCL2 Resistance Mutations in a Real-World Cohort of Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia Treated with Venetoclax
- 2023
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Ingår i: International journal of molecular sciences. - : MDPI AG. - 1422-0067. ; 24:6
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Tidskriftsartikel (refereegranskat)abstract
- The oral, highly selective Bcl2 inhibitor venetoclax has substantially improved the therapeutic landscape of chronic lymphocytic leukemia (CLL). Despite the remarkable response rates in patients with relapsed/refractory (R/R) disease, acquired resistance is the leading cause of treatment failure, with somatic BCL2 mutations being the predominant genetic drivers underpinning venetoclax resistance. To assess the correlation between disease progression and the most common BCL2 mutations G101V and D103Y, sensitive (10−4) screening for the most common BCL2 mutations G101V and D103Y was performed in 67 R/R CLL patients during venetoclax single-agent or venetoclax–rituximab combination therapy. With a median follow-up time of 23 months, BCL2 G101V and D103Y were detected in 10.4% (7/67) and 11.9% (8/67) of the cases, respectively, with four patients harboring both resistance mutations. Ten out of eleven patients carrying BCL2 G101V and/or D103Y experienced relapse during the follow-up period, representing 43.5% of the cases (10/23) showing clinical signs of disease progression. All BCL2 G101V or D103Y variants were detected in patients receiving venetoclax as a continuous single-agent treatment while these mutations were not observed during or after fixed-duration venetoclax therapy. Targeted ultra-deep sequencing of BCL2 uncovered three additional variants in four patient samples obtained at relapse, suggesting convergent evolution and implying a cooperating role of BCL2 mutations in driving venetoclax resistance. This cohort is the largest R/R CLL patient population reported to date in which BCL2 resistance mutations were investigated. Our study demonstrates the feasibility and clinical value of sensitive screening for BCL2 resistance mutations in R/R CLL.
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| 17. |
- Sattler, MC, et al.
(författare)
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Physical activity self-reports: past or future?
- 2021
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Ingår i: British journal of sports medicine. - : BMJ. - 1473-0480 .- 0306-3674. ; 55:16, s. 889-
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
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| 18. |
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| 19. |
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| 20. |
- Buena-Atienza, E, et al.
(författare)
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De novo intrachromosomal gene conversion from OPN1MW to OPN1LW in the male germline results in Blue Cone Monochromacy
- 2016
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Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 6, s. 28253-
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Tidskriftsartikel (refereegranskat)abstract
- X-linked cone dysfunction disorders such as Blue Cone Monochromacy and X-linked Cone Dystrophy are characterized by complete loss (of) or reduced L- and M- cone function due to defects in the OPN1LW/OPN1MW gene cluster. Here we investigated 24 affected males from 16 families with either a structurally intact gene cluster or at least one intact single (hybrid) gene but harbouring rare combinations of common SNPs in exon 3 in single or multiple OPN1LW and OPN1MW gene copies. We assessed twelve different OPN1LW/MW exon 3 haplotypes by semi-quantitative minigene splicing assay. Nine haplotypes resulted in aberrant splicing of ≥20% of transcripts including the known pathogenic haplotypes (i.e. ‘LIAVA’, ‘LVAVA’) with absent or minute amounts of correctly spliced transcripts, respectively. De novo formation of the ‘LIAVA’ haplotype derived from an ancestral less deleterious ‘LIAVS’ haplotype was observed in one family with strikingly different phenotypes among affected family members. We could establish intrachromosomal gene conversion in the male germline as underlying mechanism. Gene conversion in the OPN1LW/OPN1MW genes has been postulated, however, we are first to demonstrate a de novo gene conversion within the lineage of a pedigree.
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| 21. |
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| 22. |
- Ezewudo, M, et al.
(författare)
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Integrating standardized whole genome sequence analysis with a global Mycobacterium tuberculosis antibiotic resistance knowledgebase
- 2018
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Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 8:1, s. 15382-
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Tidskriftsartikel (refereegranskat)abstract
- Drug-resistant tuberculosis poses a persistent public health threat. The ReSeqTB platform is a collaborative, curated knowledgebase, designed to standardize and aggregate global Mycobacterium tuberculosis complex (MTBC) variant data from whole genome sequencing (WGS) with phenotypic drug susceptibility testing (DST) and clinical data. We developed a unified analysis variant pipeline (UVP) (https://github.com/CPTR-ReSeqTB/UVP) to identify variants and assign lineage from MTBC sequence data. Stringent thresholds and quality control measures were incorporated in this open source tool. The pipeline was validated using a well-characterized dataset of 90 diverse MTBC isolates with conventional DST and DNA Sanger sequencing data. The UVP exhibited 98.9% agreement with the variants identified using Sanger sequencing and was 100% concordant with conventional methods of assigning lineage. We analyzed 4636 publicly available MTBC isolates in the ReSeqTB platform representing all seven major MTBC lineages. The variants detected have an above 94% accuracy of predicting drug based on the accompanying DST results in the platform. The aggregation of variants over time in the platform will establish confidence-graded mutations statistically associated with phenotypic drug resistance. These tools serve as critical reference standards for future molecular diagnostic assay developers, researchers, public health agencies and clinicians working towards the control of drug-resistant tuberculosis.
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| 23. |
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| 26. |
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| 27. |
- Jacobsson, Susanne, 1974-, et al.
(författare)
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WGS analysis and molecular resistance mechanisms of azithromycin-resistant (MIC >2 mg/L) Neisseria gonorrhoeae isolates in Europe from 2009 to 2014
- 2016
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Ingår i: Journal of Antimicrobial Chemotherapy. - Oxford, United Kingdom : Oxford University Press. - 0305-7453 .- 1460-2091. ; 71:11, s. 3109-3116
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: To elucidate the genome-based epidemiology and phylogenomics of azithromycin-resistant (MIC >2 mg/L) Neisseria gonorrhoeae strains collected in 2009-14 in Europe and clarify the azithromycin resistance mechanisms.Methods: Seventy-five azithromycin-resistant (MIC 4 to >256 mg/L) N. gonorrhoeae isolates collected in 17 European countries during 2009-14 were examined using antimicrobial susceptibility testing and WGS.Results: Thirty-six N. gonorrhoeae multi-antigen sequence typing STs and five phylogenomic clades, including 4-22 isolates from several countries per clade, were identified. The azithromycin target mutation A2059G (Escherichia coli numbering) was found in all four alleles of the 23S rRNA gene in all isolates with high-level azithromycin resistance (n = 4; MIC ≥256 mg/L). The C2611T mutation was identified in two to four alleles of the 23S rRNA gene in the remaining 71 isolates. Mutations in mtrR and its promoter were identified in 43 isolates, comprising isolates within the whole azithromycin MIC range. No mutations associated with azithromycin resistance were found in the rplD gene or the rplV gene and none of the macrolide resistance-associated genes [mef(A/E), ere(A), ere(B), erm(A), erm(B), erm(C) and erm(F)] were identified in any isolate.Conclusions: Clonal spread of relatively few N. gonorrhoeae strains accounts for the majority of the azithromycin resistance (MIC >2 mg/L) in Europe. The four isolates with high-level resistance to azithromycin (MIC ≥256 mg/L) were widely separated in the phylogenomic tree and did not belong to any of the main clades. The main azithromycin resistance mechanisms were the A2059G mutation (high-level resistance) and the C2611T mutation (low- and moderate-level resistance) in the 23S rRNA gene.
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| 28. |
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| 29. |
- Kuehlewein, Laura, et al.
(författare)
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Clinical phenotype and course of PDE6A-associated retinitis pigmentosa disease, characterized in preparation for a gene supplementation trial
- 2020
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Ingår i: JAMA Ophthalmology. - : American Medical Association (AMA). - 2168-6165. ; 138:12, s. 1241-1250
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Tidskriftsartikel (refereegranskat)abstract
- IMPORTANCE Treatment trials require sound knowledge on the natural course of disease. OBJECTIVE To assess clinical features, genetic findings, and genotype-phenotype correlations in patients with retinitis pigmentosa (RP) associated with biallelic sequence variations in the PDE6A gene in preparation for a gene supplementation trial. DESIGN, SETTING, AND PARTICIPANTS This prospective, longitudinal, observational cohort study was conducted from January 2001 to December 2019 in a single center (Centre for Ophthalmology of the University of Tübingen, Germany) with patients recruited multinationally from 12 collaborating European tertiary referral centers. Patients with retinitis pigmentosa, sequence variants in PDE6A, and the ability to provide informed consent were included. EXPOSURES Comprehensive ophthalmological examinations; validation of compound heterozygosity and biallelism by familial segregation analysis, allelic cloning, or assessment of next-generation sequencing-read data, where possible. MAIN OUTCOMES AND MEASURES Genetic findings and clinical features describing the entire cohort and comparing patients harboring the 2 most common disease-causing variants in a homozygous state (c.304C>A;p.(R102S) and c.998 + 1G>A;p.?). RESULTS Fifty-seven patients (32 female patients [56%]; mean [SD], 40 [14] years) from 44 families were included. All patients completed the study. Thirty patients were homozygous for disease-causing alleles. Twenty-seven patients were heterozygous for 2 different PDE6A variants each. The most frequently observed alleles were c.304C>A;p.(R102S), c.998 + 1G>A;p.?, and c.2053G>A;p.(V685M). The mean (SD) best-corrected visual acuity was 0.43 (0.48) logMAR (Snellen equivalent, 20/50). The median visual field area with object III4e was 660 square degrees (5th and 95th percentiles, 76 and 11 019 square degrees; 25th and 75th percentiles, 255 and 3923 square degrees). Dark-adapted and light-adapted full-field electroretinography showed no responses in 88 of 108 eyes (81.5%). Sixty-nine of 108 eyes (62.9%) showed additional findings on optical coherence tomography imaging (eg, cystoid macular edema or macular atrophy). The variant c.998 + 1G>A;p.? led to a more severe phenotype when compared with the variant c.304C>A;p.(R102S). CONCLUSIONS AND RELEVANCE Seventeen of the PDE6A variants found in these patients appeared to be novel. Regarding the clinical findings, disease was highly symmetrical between the right and left eyes and visual impairment was mild or moderate in 90% of patients, providing a window of opportunity for gene therapy.
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| 30. |
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| 31. |
- Köhn, Linda, et al.
(författare)
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PITPNM3 is an uncommon cause of cone and cone-rod dystrophies.
- 2010
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Ingår i: Ophthalmic Genetics. - : Informa Healthcare. - 1381-6810 .- 1744-5094. ; 31:3, s. 139-140
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Tidskriftsartikel (refereegranskat)abstract
- The first mutation in PITPNM3, a human homologue of the Drosophila retinal degeneration (rdgB not not) gene was reported in two large Swedish families with autosomal dominant cone dystrophy. To establish the global impact that PITPNM3 has on retinal degenerations we screened 163 patients from Denmark, Germany, the UK, and USA. Four sequence variants, two missence mutations and two intronic changes were identified in the screen. Thus, mutations in PITPNM3 do not appear to be a major cause of cone or cone-rod dystrophy.
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| 32. |
- Lange, C., et al.
(författare)
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Perspectives for personalized therapy for patients with multidrug-resistant tuberculosis
- 2018
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Ingår i: Journal of Internal Medicine. - : WILEY. - 0954-6820 .- 1365-2796. ; 284:2, s. 163-188
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Forskningsöversikt (refereegranskat)abstract
- According to the World Health Organization (WHO), tuberculosis is the leading cause of death attributed to a single microbial pathogen worldwide. In addition to the large number of patients affected by tuberculosis, the emergence of Mycobacterium tuberculosis drug-resistance is complicating tuberculosis control in many high-burden countries. During the past 5years, the global number of patients identified with multidrug-resistant tuberculosis (MDR-TB), defined as bacillary resistance at least against rifampicin and isoniazid, the two most active drugs in a treatment regimen, has increased by more than 20% annually. Today we experience a historical peak in the number of patients affected by MDR-TB. The management of MDR-TB is characterized by delayed diagnosis, uncertainty of the extent of bacillary drug-resistance, imprecise standardized drug regimens and dosages, very long duration of therapy and high frequency of adverse events which all translate into a poor prognosis for many of the affected patients. Major scientific and technological advances in recent years provide new perspectives through treatment regimens tailor-made to individual needs. Where available, such personalized treatment has major implications on the treatment outcomes of patients with MDR-TB. The challenge now is to bring these adances to those patients that need them most.
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| 33. |
- Merker, Matthias, et al.
(författare)
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Phylogenetically informative mutations in genes implicated in antibiotic resistance in Mycobacterium tuberculosis complex
- 2020
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Ingår i: Genome Medicine. - : BMC. - 1756-994X. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- Background A comprehensive understanding of the pre-existing genetic variation in genes associated with antibiotic resistance in the Mycobacterium tuberculosis complex (MTBC) is needed to accurately interpret whole-genome sequencing data for genotypic drug susceptibility testing (DST). Methods We investigated mutations in 92 genes implicated in resistance to 21 anti-tuberculosis drugs using the genomes of 405 phylogenetically diverse MTBC strains. The role of phylogenetically informative mutations was assessed by routine phenotypic DST data for the first-line drugs isoniazid, rifampicin, ethambutol, and pyrazinamide from a separate collection of over 7000 clinical strains. Selected mutations/strains were further investigated by minimum inhibitory concentration (MIC) testing. Results Out of 547 phylogenetically informative mutations identified, 138 were classified as not correlating with resistance to first-line drugs. MIC testing did not reveal a discernible impact of a Rv1979c deletion shared by M. africanum lineage 5 strains on resistance to clofazimine. Finally, we found molecular evidence that some MTBC subgroups may be hyper-susceptible to bedaquiline and clofazimine by different loss-of-function mutations affecting a drug efflux pump subunit (MmpL5). Conclusions Our findings underline that the genetic diversity in MTBC has to be studied more systematically to inform the design of clinical trials and to define sound epidemiologic cut-off values (ECOFFs) for new and repurposed anti-tuberculosis drugs. In that regard, our comprehensive variant catalogue provides a solid basis for the interpretation of mutations in genotypic as well as in phenotypic DST assays.
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| 34. |
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| 35. |
- Weisschuh, Nicole, et al.
(författare)
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Mutation Detection in Patients with Retinal Dystrophies Using Targeted Next Generation Sequencing.
- 2016
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- Retinal dystrophies (RD) constitute a group of blinding diseases that are characterized by clinical variability and pronounced genetic heterogeneity. The different nonsyndromic and syndromic forms of RD can be attributed to mutations in more than 200 genes. Consequently, next generation sequencing (NGS) technologies are among the most promising approaches to identify mutations in RD. We screened a large cohort of patients comprising 89 independent cases and families with various subforms of RD applying different NGS platforms. While mutation screening in 50 cases was performed using a RD gene capture panel, 47 cases were analyzed using whole exome sequencing. One family was analyzed using whole genome sequencing. A detection rate of 61% was achieved including mutations in 34 known and two novel RD genes. A total of 69 distinct mutations were identified, including 39 novel mutations. Notably, genetic findings in several families were not consistent with the initial clinical diagnosis. Clinical reassessment resulted in refinement of the clinical diagnosis in some of these families and confirmed the broad clinical spectrum associated with mutations in RD genes.
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| 36. |
- Weisschuh, Nicole, et al.
(författare)
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Mutations in the gene PDE6C encoding the catalytic subunit of the cone photoreceptor phosphodiesterase in patients with achromatopsia
- 2018
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Ingår i: Human Mutation. - : John Wiley & Sons. - 1059-7794 .- 1098-1004. ; 39:10, s. 1366-1371
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Tidskriftsartikel (refereegranskat)abstract
- Biallelic PDE6C mutations are a known cause for rod monochromacy, better known as autosomal recessive achromatopsia (ACHM), and early-onset cone photoreceptor dysfunction. PDE6C encodes the catalytic alpha'-subunit of the cone photoreceptor phosphodiesterase, thereby constituting an essential part of the phototransduction cascade. Here, we present the results of a study comprising 176 genetically preselected patients who remained unsolved after Sanger sequencing of the most frequent genes accounting for ACHM, and were subsequently screened for exonic and splice site variants in PDE6C applying a targeted next generation sequencing approach. We were able to identify potentially pathogenic biallelic variants in 15 index cases. The mutation spectrum comprises 18 different alleles, 15 of which are novel. Our study significantly contributes to the mutation spectrum of PDE6C and allows for a realistic estimate of the prevalence of PDE6C mutations in ACHM since our entire ACHM cohort comprises 1,074 independent families.
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| 37. |
- Wilson, Stephen A., et al.
(författare)
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New materials for micro-scale sensors and actuators An engineering review
- 2007
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Ingår i: Materials science & engineering. R, Reports. - : Elsevier BV. - 0927-796X .- 1879-212X. ; 56:06-jan, s. 1-129
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Forskningsöversikt (refereegranskat)abstract
- This paper provides a detailed overview of developments in transducer materials technology relating to their current and future applications in micro-scale devices. Recent advances in piezoelectric, magnetostrictive and shape-memory alloy systems are discussed and emerging transducer materials such as magnetic nanoparticles, expandable micro-spheres and conductive polymers are introduced. Materials properties, transducer mechanisms and end applications are described and the potential for integration of the materials with ancillary systems components is viewed as an essential consideration. The review concludes with a short discussion of structural polymers that are extending the range of micro-fabrication techniques available to designers and production engineers beyond the limitations of silicon fabrication technology.
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| 38. |
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| 39. |
- Zobor, Ditta, et al.
(författare)
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The clinical phenotype of CNGA3-related achromatopsia : Pretreatment characterization in preparation of a gene replacement therapy trial
- 2017
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Ingår i: Investigative Ophthalmology and Visual Science. - : Association for Research in Vision and Ophthalmology (ARVO). - 0146-0404. ; 58:2, s. 821-832
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE. The purpose of this study was to clinically characterize patients with CNGA3-linked achromatopsia (CNGA3-ACHM) in preparation of a gene therapy trial. METHODS. Thirty-six patients (age 7-56 years) with complete (cACHM) or incomplete (iACHM) CNGA3-ACHM were examined, including detailed psychophysical tests, extended electrophysiology, and assessment of morphology by fundus autofluorescence and spectral-domain optical coherence tomography (SD-OCT). RESULTS. Mean best-corrected visual acuity was 0.78 ± 0.14 logMAR. Color vision tests were consistent with a rod-dominated function in every cACHM patient. Microperimetry indicated an overall lowered retinal sensitivity within 20° of visual field. In electroretinography (ERG), photopic responses were nondetectable in cACHM patients, but residual cone responses were observed in the iACHM patients. Scotopic responses were altered referring to anomalies of photoreceptor and postreceptor signaling, whereas in voltage versus intensity functions, V was significantly below normal values (P < 0.05). In contrast, slope (n) and semisaturation intensity (K) were found to be within normal limits. Spectral-domain OCT examination showed no specific changes in 14.7%, disruption of the ellipsoid zone (EZ) at the fovea in 38.2%, absent EZ in 17.7%, a hyporeflective zone in 20.5%, and outer retinal atrophy in 8.9% of all cases and foveal hypoplasia in 29 patients (85%). No correlation of retinal morphology with visual function or with a specific genotype was found. The severity of morphologic and functional changes lacked a robust association with age. CONCLUSIONS. Our extended investigations prove that even among such a genetically homogenous group of patients, no specific correlations regarding function and morphology severity and age can be observed. Therefore, the therapeutic window seems to be wider than previously indicated.
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