EAR General Assembly,Vienna, 8 March, 1995

News of the EAR

EAR General Assembly, Vienna, 8 March 1995President's Report     

Gene transfer in the RPE65 null mutation dog: relationship between construct volume,visual behavior and electroretinographic (ERG) results

In vivo gene transfer in a large group of RPE65 null mutation dogs have been recently performed. The present study was aimed at determining, through visual behavioral and electroretinographic (ERG) testing, if there is a volume effect of the gene construct administered. Eleven Beagle-Briard dogs homozygous for the RPE65 null mutation and two unaffected control dogs were included. Affected animals were unilaterally treated with either a high (70–100 l; N = 6) or a low volume (30–60 l; N = 5) of subretinally injected rAAV.RPE65 construct, at the age of 4 months to 2.5 years. Fellow eyes were treated with a subretinal injection of rAAV.GFP or sham operated and used as internal controls. Retinal function was measured pre- and 10–12 weeks post-surgically, using simultaneous bilateral full-field flash ERGs. A significant improvement in all ERG responses studied was identified for the high volume treated group compared to pre-surgical parameters. A significant improvement for the high intensity scotopic a-wave response for the low volume rAAV.RPE65 treated group was also found. Objective and subjective dim and day light visual maze testing, in eight of the affected treated animals, and the two control dogs, revealed better vision in daylight than in dim light for all animals. Vision in dogs treated with the high volume of gene construct was significantly better in day light than in dim light. No significant difference was noted between day and dim light testing for the control group or those animals treated with a low volume of the gene construct. Significantly better vision was noted in the control group when compared with the low volume group under dim light conditions, and the high volume group under day light conditions. No significant difference in functional vision could be identified between the high volume treated animals and control animals in day light conditions. These findings support the hypothesis that functional vision is improved by subretinal rAAV.RPE65 injection in a volume-dependent manner.     

A whole genome association study in Icelandic multiple sclerosis patients with 4804 markers

Multiple sclerosis (MS) is a demyelinating disorder of the central nervous system (CNS) with a complex genetic background. Here we use a genome-wide association strategy with 4804 microsatellite markers successfully typed in separately pooled DNA from 200 patients and 200 controls. A total of 91 markers showed evidence of association. When compared to our in-house physical map of the genome, six 2-Mb regions containing at least two of these markers were detected. Of those, three regions have one or more markers among the 20 most strongly associated: chromosomes 3q25, 6p21.3 (the MHC region) and 19q13.     

A whole genome association study in multiple sclerosis patients from north Portugal

Genetic factors are known to influence susceptibility to multiple sclerosis (MS) but the genes involved are largely undefined. Here, we report an association study based on 200 patients and 200 controls from the Porto region in Portugal. A total of 3974 markers were successfully typed from which we have identified 46 markers showing evidence of association. When compared to a physical map three regions were found with two of these markers less than 1.5 Mb apart: chromosomes 6p21.3 (the MHC region), 6q14.1 and 7q34.     

Interval training compared with continuous training in patients with COPD

The aim of this study was to compare the effects of interval training (3-min intervals) with continuous training on peak exercise capacity (W peak), physiological response, functional capacity, dyspnoea, mental health and health-related quality of life (HRQoL) in patients with moderate or severe COPD. Sixty patients exercised twice weekly for 16 weeks after randomisation to interval- or continuous training. Target intensity was 80% of baseline W peak in the interval group (I-group) and 65% in the continuous group (C-group). Patients were tested by spirometry, ergometer cycle test, cardiopulmonary test and a 12 min walk test. Dyspnoea was measured by the dyspnoea scale from Chronic Obstructive Disease Questionnaire (CRDQ), mental health by Hospital Anxiety and Depression scale (HAD) and HRQoL by the Medical Outcomes Survey Short Form 36 (SF-36). After training, W peak, peak oxygen uptake (VO(2) peak) and exhaled carbon dioxide (VCO(2) peak) increased significantly in both groups, no significant differences between the groups. Minute ventilation (V(E) peak) increased only in the C-group. At identical work rates (isotime) VO(2), VCO(2) and V(E) were significantly more decreased in the I-group than in the C-group (p<0.05). Functional capacity, dyspnoea, mental health, and HRQoL improved significantly in both groups, no difference between the groups. Interval training and continuous training were equally potent in improving peak exercise capacity, functional exercise capacity, dyspnoea, mental health and HRQoL in patients with moderate or severe COPD. At isotime, the physiological response to training differed between the groups, in favour of the interval training.     

Pregnancy outcome in women with polycystic ovary syndrome in relation to second-trimester testosterone levels

Research questionDo women with polycystic ovary syndrome (PCOS) have higher testosterone levels during pregnancy and what role does high testosterone play in the development of obstetric complications?DesignRetrospective cohort study from Uppsala University Hospital, Sweden. The study population consisted of women with PCOS (n = 159) and a comparison group of women without PCOS matched for body mass index (n = 320). Plasma testosterone levels were measured in the early second trimester by liquid chromatography with tandem mass spectrometry, and women with PCOS were grouped into tertiles according to their testosterone levels. Possible associations with obstetric complications, maternal metabolic factors and offspring birth weight were explored by multivariable logistic and linear regression models.ResultsCompared with women who do not have PCOS, women with PCOS had higher total testosterone (median 1.94, interquartile range [IQR] 1.21–2.64 versus 1.41, IQR 0.89–1.97; P < 0.001), and free androgen index (median 0.25, IQR 0.15–0.36 versus 0.18, IQR 0.11–0.28; P < 0.001). Women with PCOS who had the highest levels of testosterone had increased risk for preeclampsia, even when adjusted for age, parity, country of birth and smoking (adjusted OR 6.16, 95% CI 1.82 to 20.91). No association was found between high testosterone in women with PCOS and other obstetric complications.ConclusionsWomen with PCOS have higher levels of total testosterone and free androgen index during pregnancy than women without PCOS matched for body mass index. Preliminary evidence shows that women with PCOS and the highest maternal testosterone levels in early second trimester had the highest risk of developing preeclampsia. This finding, however, is driven by a limited number of cases and should be interpreted with caution.     

No association between a common single nucleotide polymorphism,rs4141463, in the MACROD2 gene and autism spectrum disorder

The Autism Genome Project (AGP) Consortium recently reported genome‐wide significant association between autism and an intronic single nucleotide polymorphism marker, rs4141463, within the MACROD2 gene. In the present study we attempted to replicate this finding using an independent case–control design of 1,170 cases with autism spectrum disorder (ASD) (874 of which fulfilled narrow criteria for Autism (A)) from five centers within Europe (UK, Germany, the Netherlands, Italy, and Iceland), and 35,307 controls. The combined sample size gave us a non‐centrality parameter (NCP) of 11.9, with 93% power to detect allelic association of rs4141463 at an alpha of 0.05 with odds ratio of 0.84 (the best odds ratio estimate of the AGP Consortium data), and for the narrow diagnosis of autism, an NCP of 8.9 and power of 85%. Our case–control data were analyzed for association, stratified by each center, and the summary statistics were combined using the meta‐analysis program, GWAMA. This resulted in an odds ratio (OR) of 1.03 (95% CI 0.944–1.133), with a P‐value of 0.5 for ASD and OR of 0.99 (95% CI 0.88–1.11) with P‐value = 0.85 for the Autism (A) sub‐group. Therefore, this study does not provide support for the reported association between rs4141463 and autism. © 2011 Wiley‐Liss, Inc.     

Autosomal dominant retinitis pigmentosa in Norway: a 20-year clinical follow-up study with molecular genetic analysis. Two novel rhodopsin mutations: 1003delG and I179F

PURPOSE: To examine the clinical picture and molecular genetics of 12 Norwegian families with autosomal dominant retinitis pigmentosa (adRP) in order to achieve a genotype-phenotype correlation. METHODS: In addition to a clinical ophthalmological examination, fundus photography, dark adaptometry and electroretinography were performed. Four genes were analysed: rhodopsin (RHO); retinitis pigmentosa 1 (RP1); retinal degeneration slow/peripherin (RDS/peripherin), and inosine monophosphate dehydrogenase 1 (IMPDH1). Seven of the families had been examined about 20 years previously. A total of 63 patients or first-degree relatives (aged 18-79 years) were examined. RESULTS: Mutations were found only in the RHO gene. Seven families were given a diagnosis of classical RP. Two of them had novel mutation 1003delG, and one family had the mutation V345M. Four families had pericentral retinal dystrophy (PRD), two families with the mutation A164V and one with novel mutation I179F. One family was given a diagnosis of central and pericentral retinal dystrophy (CPRD), a special type of cone/rod dystrophy, and no mutation was found. CONCLUSIONS: Six of 12 families had an RHO mutation. The mutation V345M and the novel mutation 1003delG both caused classical RP, the former indicating the most unfavourable prognosis. Two of the families with PRD had the A164V mutation with a favourable prognosis, whereas the novel mutation I179F caused PRD with extremely variable expressivity.