KCNV2-associated retinopathy: genotype-phenotype correlations - KCNV2 study group report 3.

BACKGROUND/AIMS: To investigate genotype-phenotype associations in patients with KCNV2 retinopathy. METHODS: Review of clinical notes, best-corrected visual acuity (BCVA), molecular variants, electroretinography (ERG) and retinal imaging. Subjects were grouped according to the combination of KCNV2 variants-two loss-of-function (TLOF), two missense (TM) or one of each (MLOF)-and parameters were compared. RESULTS: Ninety-two patients were included. The mean age of onset (mean±SD) in TLOF (n=55), TM (n=23) and MLOF (n=14) groups was 3.51±0.58, 4.07±2.76 and 5.54±3.38 years, respectively. The mean LogMAR BCVA (±SD) at baseline in TLOF, TM and MLOF groups was 0.89±0.25, 0.67±0.38 and 0.81±0.35 for right, and 0.88±0.26, 0.69±0.33 and 0.78±0.33 for left eyes, respectively. The difference in BCVA between groups at baseline was significant in right (p=0.03) and left eyes (p=0.035). Mean outer nuclear layer thickness (±SD) at baseline in TLOF, MLOF and TM groups was 37.07±15.20 µm, 40.67±12.53 and 40.38±18.67, respectively, which was not significantly different (p=0.85). The mean ellipsoid zone width (EZW) loss (±SD) was 2051 µm (±1318) for patients in the TLOF, and 1314 µm (±965) for MLOF. Only one patient in the TM group had EZW loss at presentation. There was considerable overlap in ERG findings, although the largest DA 10 ERG b-waves were associated with TLOF and the smallest with TM variants. CONCLUSIONS: Patients with missense alterations had better BCVA and greater structural integrity. This is important for patient prognostication and counselling, as well as stratification for future gene therapy trials.

Three-year results of phase I retinal gene therapy trial for CNGA3-mutated achromatopsia: results of a non randomised controlled trial.

AIMS: To determine long-term safety and efficacy outcomes of a subretinal gene therapy for CNGA3-associated achromatopsia. We present data from an open-label, nonrandomised controlled trial (NCT02610582). METHODS: Details of the study design have been previously described. Briefly, nine patients were treated in three escalating dose groups with subretinal AAV8.CNGA3 gene therapy between November 2015 and October 2016. After the first year, patients were seen on a yearly basis. Safety assessment constituted the primary endpoint. On a secondary level, multiple functional tests were carried out to determine efficacy of the therapy. RESULTS: No adverse or serious adverse events deemed related to the study drug occurred after year 1. Safety of the therapy, as the primary endpoint of this trial, can, therefore, be confirmed. The functional benefits that were noted in the treated eye at year 1 were persistent throughout the following visits at years 2 and 3. While functional improvement in the treated eye reached statistical significance for some secondary endpoints, for most endpoints, this was not the case when the treated eye was compared with the untreated fellow eye. CONCLUSION: The results demonstrate a very good safety profile of the therapy even at the highest dose administered. The small sample size limits the statistical power of efficacy analyses. However, trial results inform on the most promising design and endpoints for future clinical trials. Such trials have to determine whether treatment of younger patients results in greater functional gains by avoiding amblyopia as a potential limiting factor.

BBS1 mutations in a wide spectrum of phenotypes ranging from nonsyndromic retinitis pigmentosa to Bardet-Biedl syndrome.

OBJECTIVE: To investigate the involvement of the Bardet-Biedl syndrome (BBS) gene BBS1 p.M390R variant in nonsyndromic autosomal recessive retinitis pigmentosa (RP). METHODS: Homozygosity mapping of a patient with isolated RP was followed by BBS1 sequence analysis. We performed restriction fragment length polymorphism analysis of the p.M390R allele in 2007 patients with isolated RP or autosomal recessive RP and in 1824 ethnically matched controls. Patients with 2 BBS1 variants underwent extensive clinical and ophthalmologic assessment. RESULTS: In an RP proband who did not fulfill the clinical criteria for BBS, we identified a large homozygous region encompassing the BBS1 gene, which carried the p.M390R variant. In addition, this variant was detected homozygously in 10 RP patients and 1 control, compound heterozygously in 3 patients, and heterozygously in 5 patients and 6 controls. The 14 patients with 2 BBS1 variants showed the entire clinical spectrum, from nonsyndromic RP to full-blown BBS. In 8 of 14 patients, visual acuity was significantly reduced. In patients with electroretinographic responses, a rod-cone pattern of photoreceptor degeneration was observed. CONCLUSIONS: Variants in BBS1 are significantly associated with nonsyndromic autosomal recessive RP and relatively mild forms of BBS. As exemplified in this study by the identification of a homozygous p.M390R variant in a control individual and in unaffected parents of BBS patients in other studies, cis - or trans -acting modifiers may influence the disease phenotype. CLINICAL RELEVANCE: It is important to monitor patients with an early diagnosis of mild BBS phenotypes for possible life-threatening conditions.

ISCEV Standard for Clinical Electro-oculography (EOG) 2006.

The Clinical Electro-oculogram (EOG) is an electrophysiological test of function of the outer retina and retinal pigment epithelium (RPE) in which the change in the electrical potential between the cornea and the ocular fundus is recorded during successive periods of dark and light adaptation. This document sets out a Standard Method for performance of the test, and also gives detailed guidance on technical and practical issues, and on reporting test results. The main object of the Standard is to promote consistent quality of testing and reporting within and between centres. This 2006 Standard, from the International Society for Clinical Electrophysiology of Vision (ISCEV: www.iscev.org ), is a revision of the previous Standard published in 1993, and reviewed and re-issued in 1998.

MfERG waveform characteristics in the RS1h mouse model featuring a 'negative' ERG.

Several retinal disorders lead to a relatively greater attenuation of the b-wave compared to the a-wave of the electroretinogram (ERG), a constellation called 'negative' ERG. To determine the waveform characteristics of multifocal ERGs (mfERGs) and their dependence on recording parameters in such a case, we studied the Rs1h(-/Y) mouse, the model for x-linked juvenile retinoschisis. mfERGs were recorded with a VERIS 4 system connected to a piggyback stimulator prototype that added the stimulus to the optical pathway of a HRA scanning-laser ophthalmoscope (SLO) by means of a wavelength-sensitive mirror. Real-time fundus visualization was achieved with the infrared laser of the SLO (835 nm). High-pass filter settings and the time interval used by the 'artefact removal' feature were varied to study their influence on the waveform. The mfERG in the Rs1h(-/Y) mouse had a 'negative' shape. However, the high-pass filter setting had to be lowered from the usual 10 Hz down to about 2 Hz in order to obtain that result, otherwise the negative shape was lost and mainly a positive peak remained. Similarly, a short time interval used by the 'artefact removal' feature also removed the negative shape. The Rs1h(-/Y) mouse was found to be a valuable model of diseases with a 'negative' waveform shape also in mfERG. Our results underline the importance of a lower high-pass filter cutoff frequency when recording mfERGs in such disorders. In addition, if the 'artefact removal' feature is used, it should be verified that it doesn't distort the waveform shape.