Association of variants in the CP, ATOX1 and COMMD1 genes with Wilson disease symptoms in Latvia

Funding Information: This study was partially financed by a grant of Riga Stradins University, Department of Doctoral studies and grant of Roche Academy. Funding Information: Funding . This study was partially financed by a grant of Riga Stradiņš University, Department of Doctoral studies and grant of Roche Academy. Publisher Copyright: © 2019 Zarina A, Tolmane I, Krumina Z, Tutane AI, Gailite L, published by Sciendo.Wilson's disease (WD) is a copper metabolism disorder, caused by allelic variants in the ATP7B gene. Wilson's disease can be diagnosed by clinical symptoms, increased copper and decreased cerulopasmin levels, which could all also be by other genetic variants beyond the ATP7B gene, e.g., disturbed ceruloplasmin biosynthesis can be caused by pathogenic allelic variants of the CP gene. Copper metabolism in the organism is affected by several molecules, but pathogenic variants and related phenotypes are described with COMMD1 and ATOX1 genes. The aim of the study was to test other genes, CP, ATOX1 and COMMD1, for possible influence to the manifestation of WD. Patients were enrolled on the basis of Leipzig's diagnostic criteria, 64 unrelated patients with confirmed WD. Direct sequencing of promoter region of the CP gene and ATOX1 and COMMD1 gene exons was conducted. Statistically significant differences were found between the two variants in the CP gene and the ATP7B genotype (rs66508328 variant AA genotype and the rs11708215 variant GG genotype) were more common in WD patients with an unconfirmed ATP7B genotype. One allelic (intronic) variant was found in the ATOX1 gene without causing the functional changes of the gene. Three allelic variants were identified in the COMMD1 gene. No statistically significant differences were found between allele and genotype frequencies and the first clinical manifestations of WD. Different variants of the CP gene contributed to a WD-like phenotype in clinically confirmed WD patients with neurological symptoms and without identified pathogenic variants in the ATP7B gene. Allelic variants in the ATOX1 and COMMD1 genes do not modify the clinical manifestation of WD in Latvian patients.publishersversionPeer reviewe

Solar retinopathy: a new setting of red, green, and blue channels

PURPOSE: To introduce a new color imaging technique using improved settings of red, green, and blue channels for improved delineation of retinal damage in patients with solar retinopathy. METHODS: A retrospective case series of patients with poor vision secondary to solar retinopathy were analyzed. All patients underwent visual acuity, refraction, and dilated fundus examination. A spectral domain–optical coherence tomography of the macula and color fundus imaging using optimized red, green, and blue color setting was performed. Patients were reviewed over a 6-month period. The data were analyzed for statistical significance using an independent t test and a receiver operating characteristic curve. RESULTS: In total, 20 eyes of 10 patients were included between 2009 and 2017. The mean age was 24.9 ± 18.1 years. Best corrected visual acuity at first consultation was 0.78 ± 0.11 and after 6 months was 0.83 ± 0.09. Spectral domain–optical coherence tomography demonstrated retinal abnormalities at the myoid zone, ellipsoid zone, and the outer segment of photoreceptors. Receiver operating characteristic curve analysis showed an improving effect (area under the curve = 0.62; 95% confidence interval = 0.42–0.79). The color channels parameters, which improve visualization of the lesions were found to be 67-0.98-255 for the R-guided setting, 19-0.63-121 for the B-guided setting, and 7-1.00-129 for the G-guided setting. The ideal red, green, and blue setting was in 24-0.82-229. CONCLUSIONS: The use of a new setting of red, green, and blue channels could improve the diagnosis and monitoring of solar retinopathy, hence improving patient care

Myalgic encephalomyelitis/chronic fatigue Syndrome (ME/CFS) : Investigating care practices pointed out to disparities in diagnosis and treatment across European Union

ME/CFS is a chronic, complex, multisystem disease that often limits the health and functioning of the affected patients. Diagnosing patients with ME/CFS is a challenge, and many different case definitions exist and are used in clinical practice and research. Even after diagnosis, medical treatment is very challenging. Symptom relief and coping may affect how patients live with their disease and their quality of life. There is no consensus on which diagnostic criteria should be used and which treatment strategies can be recommended for patients. The purpose of the current project was to map the landscape of the Euromene countries in respect of national guidelines and recommendations for case definition, diagnosis and clinical approaches for ME/CFS patients. A 23 items questionnaire was sent out by email to the members of Euromene. The form contained questions on existing guidelines for case definitions, treatment/management of the disease, tests and questionnaires applied, and the prioritization of information for data sampling in research. We obtained information from 17 countries. Five countries reported having national guidelines for diagnosis, and five countries reported having guidelines for clinical approaches. For diagnostic purposes, the Fukuda criteria were most often recommended, and also the Canadian Consensus criteria, the International Consensus Criteria and the Oxford criteria were used. A mix of diagnostic criteria was applied within those countries having no guidelines. Many different questionnaires and tests were used for symptom registration and diagnostic investigation. For symptom relief, pain and anti-depressive medication were most often recommended. Cognitive Behavioral Therapy and Graded Exercise treatment were often recommended as disease management and rehabilitative/palliative strategies. The lack of consistency in recommendations across European countries urges the development of regulations, guidance and standards. The results of this study will contribute to the harmonization of diagnostic criteria and treatment for ME/CFS in Europe

The comparative responsiveness of Hospital Universitario Princesa Index and other composite indices for assessing rheumatoid arthritis activity

Objective To evaluate the responsiveness in terms of correlation of the Hospital Universitario La Princesa Index (HUPI) comparatively to the traditional composite indices used to assess disease activity in rheumatoid arthritis (RA), and to compare the performance of HUPI-based response criteria with that of the EULAR response criteria. Methods Secondary data analysis from the following studies: ACT-RAY (clinical trial), PROAR (early RA cohort) and EMECAR (pre-biologic era long term RA cohort). Responsiveness was evaluated by: 1) comparing change from baseline (Delta) of HUPI with Delta in other scores by calculating correlation coefficients; 2) calculating standardised effect sizes. The accuracy of response by HUPI and by EULAR criteria was analyzed using linear regressions in which the dependent variable was change in global assessment by physician (Delta GDA-Phy). Results Delta HUPI correlation with change in all other indices ranged from 0.387 to 0.791); HUPI's standardized effect size was larger than those from the other indices in each database used. In ACT-RAY, depending on visit, between 65 and 80% of patients were equally classified by HUPI and EULAR response criteria. However, HUPI criteria were slightly more stringent, with higher percentage of patients classified as non-responder, especially at early visits. HUPI response criteria showed a slightly higher accuracy than EULAR response criteria when using Delta GDA-Phy as gold standard. Conclusion HUPI shows good responsiveness in terms of correlation in each studied scenario (clinical trial, early RA cohort, and established RA cohort). Response criteria by HUPI seem more stringent than EULAR''s

Association of variants in the CP, ATOX1 and COMMD1 genes with Wilson disease symptoms in Latvia

Wilson’s disease (WD) is a copper metabolism disorder, caused by allelic variants in the ATP7B gene. Wilson’s disease can be diagnosed by clinical symptoms, increased copper and decreased cerulopasmin levels, which could all also be by other genetic variants beyond the ATP7B gene, e.g., disturbed ceruloplasmin biosynthesis can be caused by pathogenic allelic variants of the CP gene. Copper metabolism in the organism is affected by several molecules, but pathogenic variants and related phenotypes are described with COMMD1 and ATOX1 genes. The aim of the study was to test other genes, CP, ATOX1 and COMMD1, for possible influence to the manifestation of WD. Patients were enrolled on the basis of Leipzig’s diagnostic criteria, 64 unrelated patients with confirmed WD. Direct sequencing of promoter region of the CP gene and ATOX1 and COMMD1 gene exons was conducted. Statistically significant differences were found between the two variants in the CP gene and the ATP7B genotype (rs66508328 variant AA genotype and the rs11708215 variant GG genotype) were more common in WD patients with an unconfirmed ATP7B genotype. One allelic (intronic) variant was found in the ATOX1 gene without causing the functional changes of the gene. Three allelic variants were identified in the COMMD1 gene. No statistically significant differences were found between allele and genotype frequencies and the first clinical manifestations of WD. Different variants of the CP gene contributed to a WD-like phenotype in clinically confirmed WD patients with neurological symptoms and without identified pathogenic variants in the ATP7B gene. Allelic variants in the ATOX1 and COMMD1 genes do not modify the clinical manifestation of WD in Latvian patients. (266 words

Solar retinopathy: a new setting of red, green, and blue channels

9siPurpose: To introduce a new color imaging technique using improved settings of red, green, and blue channels for improved delineation of retinal damage in patients with solar retinopathy. Method: A retrospective case series of patients with poor vision secondary to solar retinopathy were analyzed. All patients underwent visual acuity, refraction, and dilated fundus examination. A spectral domain–optical coherence tomography of the macula and color fundus imaging using optimized red, green, and blue color setting was performed. Patients were reviewed over a 6-month period. The data were analyzed for statistical significance using an independent t test and a receiver operating characteristic curve. Results: In total, 20 eyes of 10 patients were included between 2009 and 2017. The mean age was 24.9 ± 18.1 years. Best corrected visual acuity at first consultation was 0.78 ± 0.11 and after 6 months was 0.83 ± 0.09. Spectral domain–optical coherence tomography demonstrated retinal abnormalities at the myoid zone, ellipsoid zone, and the outer segment of photoreceptors. Receiver operating characteristic curve analysis showed an improving effect (area under the curve = 0.62; 95% confidence interval = 0.42–0.79). The color channels parameters, which improve visualization of the lesions were found to be 67-0.98-255 for the R-guided setting, 19-0.63-121 for the B-guided setting, and 7-1.00-129 for the G-guided setting. The ideal red, green, and blue setting was in 24-0.82-229. Conclusion: The use of a new setting of red, green, and blue channels could improve the diagnosis and monitoring of solar retinopathy, hence improving patient care.reservedmixedBorroni D.; Erts R.; Vallabh N.A.; Bonzano C.; Sepetiene S.; Krumina Z.; Romano V.; Parekh M.; Iannetta D.Borroni, D.; Erts, R.; Vallabh, N. A.; Bonzano, C.; Sepetiene, S.; Krumina, Z.; Romano, V.; Parekh, M.; Iannetta, D

Novel FOXG1 mutations associated with the congenital variant of Rett syndrome.

Background: Rett syndrome is a severe neurodevelopmental disorder representing one of the most common genetic causes of mental retardation in girls. The classic form is caused by MECP2 mutations. In two patients affected by the congenital variant of Rett we have recently identified mutations in the FOXG1 gene encoding a brain specific transcriptional repressor, essential for early development of the telencephalon. Methods: 60 MECP2/CDKL5 mutation negative European Rett patients (classic and variants), 43 patients with encephalopathy with early onset seizures, and four atypical Rett patients were analysed for mutations in FOXG1. Results and conclusions: Mutations have been identified in four patients, independently classified as congenital Rett variants from France, Spain and Latvia. Clinical data have been compared with the two previously reported patients with mutations in FOXG1. In all cases hypotonia, irresponsiveness and irritability were present in the neonatal period. At birth, head circumference was normal while a deceleration of growth was recognised soon afterwards, leading to severe microcephaly. Motor development was severely impaired and voluntary hand use was absent. In contrast with classic Rett, patients showed poor eye contact. Typical stereotypic hand movements with hand washing and hand mouthing activities were present continuously. Some patients showed abnormal movements of the tongue and jerky movements of the limbs. Brain magnetic resonance imaging showed corpus callosum hypoplasia in most cases, while epilepsy was a variable sign. Scoliosis was present and severe in the older patients. Neurovegetative symptoms typical of Rett were frequently present

Eyes on MEGDEL: Distinctive basal ganglia involvement in dystonia deafness syndrome

PubMed ID: 25642805Pediatric movement disorders are still a diagnostic challenge, as many patients remain without a (genetic) diagnosis. Magnetic resonance imaging (MRI) pattern recognition can lead to the diagnosis. MEGDEL syndrome (3-MethylGlutaconic aciduria, Deafness, Encephalopathy, Leigh-like syndrome MIM #614739) is a clinically and biochemically highly distinctive dystonia deafness syndrome accompanied by 3-methylglutaconic aciduria, severe developmental delay, and progressive spasticity. Mutations are found in SERAC1, encoding a phosphatidylglycerol remodeling enzyme essential for both mitochondrial function and intracellular cholesterol trafficking. Based on the homogenous phenotype, we hypothesized an accordingly characteristic MRI pattern. A total of 43 complete MRI studies of 30 patients were systematically reevaluated. All patients presented a distinctive brain MRI pattern with five characteristic disease stages affecting the basal ganglia, especially the putamen. In stage 1, T2 signal changes of the pallidum are present. In stage 2, swelling of the putamen and caudate nucleus is seen. The dorsal putamen contains an eye that shows no signal alteration and (thus) seems to be spared during this stage of the disease. It later increases, reflecting progressive putaminal involvement. This eye was found in all patients with MEGDEL syndrome during a specific age range, and has not been reported in other disorders, making it pathognomonic for MEDGEL and allowing diagnosis based on MRI findings. © 2015 Georg Thieme Verlag KG Stuttgart New York

Effects of reducing frequency of intrinsic knowledge of results on the learning of a motor skill

WOS: 000351954400006PubMed ID: 25642805Pediatric movement disorders are still a diagnostic challenge, as many patients remain without a (genetic) diagnosis. Magnetic resonance imaging (MRI) pattern recognition can lead to the diagnosis. MEGDEL syndrome (3-MethylGlutaconic aciduria, Deafness, Encephalopathy, Leigh-like syndrome MIM #614739) is a clinically and biochemically highly distinctive dystonia deafness syndrome accompanied by 3-methylglutaconic aciduria, severe developmental delay, and progressive spasticity. Mutations are found in SERAC1, encoding a phosphatidylglycerol remodeling enzyme essential for both mitochondrial function and intracellular cholesterol trafficking. Based on the homogenous phenotype, we hypothesized an accordingly characteristic MRI pattern. A total of 43 complete MRI studies of 30 patients were systematically reevaluated. All patients presented a distinctive brain MRI pattern with five characteristic disease stages affecting the basal ganglia, especially the putamen. In stage 1, T2 signal changes of the pallidum are present. In stage 2, swelling of the putamen and caudate nucleus is seen. The dorsal putamen contains an "eye" that shows no signal alteration and (thus) seems to be spared during this stage of the disease. It later increases, reflecting progressive putaminal involvement. This "eye" was found in all patients with MEGDEL syndrome during a specific age range, and has not been reported in other disorders, making it pathognomonic for MEDGEL and allowing diagnosis based on MRI findings.Ministry of Science, Education and Sport, Republic of CroatiaMinistry of Science, Education and Sports, Republic of Croatia [108-1081870-1885]I.B. was supported by Ministry of Science, Education and Sport, Republic of Croatia (Grant No: 108-1081870-1885)