Eyetracking-enhanced VEP for nystagmus.

Visual evoked potentials (VEPs) are an important prognostic indicator of visual ability in patients with nystagmus. However, VEP testing requires stable fixation, which is impossible with nystagmus. Fixation instability reduces VEP amplitude, and VEP reliability is therefore low in this important patient group. We investigated whether VEP amplitude can be increased using an eye tracker by triggering acquisition only during slow periods of the waveform. Data were collected from 10 individuals with early-onset nystagmus. VEP was obtained under continuous (standard) acquisition, or triggered during periods of low eye velocity, as detected by an eye tracker. VEP amplitude was compared using Bonferroni corrected paired samples t-tests. VEP amplitude is significantly increased when triggered during low eye velocity (95% CI 1.42-6.83 µV, t(15) = 3.25, p = 0.0053). This study provides proof-of-concept that VEP amplitude (and therefore prognostic reliability) can be increased in patients with early onset nystagmus by connecting an eye tracker and triggering acquisition during periods of lower eye velocity.

Comparison of the handheld RETeval ERG system with a routine ERG system in healthy adults and in paediatric patients.

BACKGROUND: Electroretinograms (ERG) are necessary for the evaluation of retinal function, however testing children is challenging and only performed at a few specialised centres. The handheld RETeval ERG instrument could prove a valuable tool for clinicians in assessing retinal function. This study evaluates this device using an ISCEV approved modified paediatric protocol and compares it to standard methods using a photic stimulator. SUBJECTS AND METHOD: Cone and rod ERGs were recorded using a standard photic stimulator (Grass) and the RETeval device. Both methods involve using skin electrodes, without mydriasis and under dark and light conditions. Two groups of participants were recruited: 44 healthy adult subjects (mean age = 39 years) and 37 paediatric patients (mean = 5 years). Three of the paediatric patients were not sufficiently compliant to undertake the RETeval recording. RESULTS: Adult ERG reference range data are presented for the RETeval and compared to the standard system. There is lack of absolute agreement in the measurements between the two devices, highlighting the need for device-specific reference data. In the paediatric group there is a high level of diagnostic agreement between both systems (Cohen's Kappa k = 0.80). The relative sensitivity and specificity of the RETeval was 1.0 and 0.91. Qualitative patient and user feedback is discussed. CONCLUSIONS: ERGs are similar between the two methodologies. This study demonstrates that the RETeval device is a useful tool for assessing retinal function in children. Importantly, it is quick, relatively easy to use and can potentially reduce the burden and costs of paediatric electrodiagnostic assessments.

A small gene sequencing panel realises a high diagnostic rate in patients with congenital nystagmus following basic phenotyping.

Nystagmus is a disorder of uncontrolled eye movement and can occur as an isolated trait (idiopathic INS, IINS) or as part of multisystem disorders such as albinism, significant visual disorders or neurological disease. Eighty-one unrelated patients with nystagmus underwent routine ocular phenotyping using commonly available phenotyping methods and were grouped into four sub-cohorts according to the level of phenotyping information gained and their findings. DNA was extracted and sequenced using a broad utility next generation sequencing (NGS) gene panel. A clinical subpanel of genes for nystagmus/albinism was utilised and likely causal variants were prioritised according to methods currently employed by clinical diagnostic laboratories. We determine the likely underlying genetic cause for 43.2% of participants with similar yields regardless of prior phenotyping. This study demonstrates that a diagnostic workflow combining basic ocular phenotyping and a clinically available targeted NGS panel, can provide a high diagnostic yield for patients with infantile nystagmus, enabling access to disease specific management at a young age and reducing the need for multiple costly, often invasive tests. By describing diagnostic yield for groups of patients with incomplete phenotyping data, it also permits the subsequent design of 'real-world' diagnostic workflows and illustrates the changing role of genetic testing in modern diagnostic workflows for heterogeneous ophthalmic disorders.

Long term follow-up of a family with GUCY2D dominant cone dystrophy.

AIM: To describe long term follow-up in a family with GUCY2D dominant cone dystrophy. METHODS: Optical coherence tomography scans and fundus autofluorescence images were obtained. Flash and pattern electroretinograms (ERGs) and occipital pattern reversal visual evoked potentials were recorded. RESULTS: Two members of the same family (father and son) were identified to have the heterozygous R838C mutation in the GUCY2D gene. The father presented at the age of 45 with bilateral bull's eye maculopathy and temporal disc pallor. Over 13y of serial follow up visits, the bull's eye maculopathy progressed gradually into macular atrophy. Electrophysiological tests were significantly degraded suggesting poor macular function. Spectral-domain optical coherence tomography (SD-OCT) scans showed progressive loss and disruption of the ellipsoid layer at the foveal level. His son presented at the age of 16 with bilateral granular retinal pigment epithelial changes in both maculae. Electrophysiological testing was initially borderline normal but has gradually deteriorated to show reduced cone ERGs and macula function. SD-OCT demonstrated gradual macular thinning and atrophy bilaterally. Unlike his father, there was no disruption of the ellipsoid layer. CONCLUSION: Both family members exhibited gradual changes in their fundi, electrophysiological testing and multimodal imaging. Changes were milder than those observed in other mutations of the same gene.

Identification of a functionally significant tri-allelic genotype in the Tyrosinase gene (TYR) causing hypomorphic oculocutaneous albinism (OCA1B).

Oculocutaneous albinism (OCA) and ocular albinism (OA) are inherited disorders of melanin biosynthesis, resulting in loss of pigment and severe visual deficits. OCA encompasses a range of subtypes with overlapping, often hypomorphic phenotypes. OCA1 is the most common cause of albinism in European populations and is inherited through autosomal recessive mutations in the Tyrosinase (TYR) gene. However, there is a high level of reported missing heritability, where only a single heterozygous mutation is found in TYR. This is also the case for other OCA subtypes including OCA2 caused by mutations in the OCA2 gene. Here we have interrogated the genetic cause of albinism in a well phenotyped, hypomorphic albinism population by sequencing a broad gene panel and performing segregation studies on phenotyped family members. Of eighteen probands we can confidently diagnose three with OA and OCA2, and one with a PAX6 mutation. Of six probands with only a single heterozygous mutation in TYR, all were found to have the two common variants S192Y and R402Q. Our results suggest that a combination of R402Q and S192Y with a deleterious mutation in a 'tri-allelic genotype' can account for missing heritability in some hypomorphic OCA1 albinism phenotypes.

Retinitis pigmentosa and bilateral cystoid macular oedema in a patient heterozygous for the RIM1 mutation previously associated with cone-rod dystrophy 7.

BACKGROUND: Autosomal dominant cone-rod dystrophy 7 (CORD7) has been previously associated with the RIM1 c.2459G>A (Arg820His) mutation. Cystoid macular oedema (CMO) is a rare feature of CORD and has not been described in CORD7. We report a patient who was heterozygous for the RIM1 mutation with bilateral CMO and who manifested a retinitis pigmentosa phenotype. MATERIALS AND METHODS: The patient's medical notes were retrospectively reviewed over an 18-month period. Genetic testing was performed by next generation sequencing for a panel of 176 genes associated with retinal dystrophy. RESULTS: A 34-year-old man presented with a 5-year history of bilateral floaters and blurred vision. Visual acuity was 20/23 and 20/33 in the right and left eyes, respectively. Optical coherence tomography scans revealed bilateral CMO. Goldmann visual field tests detected mid-peripheral ring scotomas. Electrodiagnostic testing was overall consistent with a primary photoreceptor abnormality involving both rods and cones. Subsequent genetic testing identified heterozygosity for the RIM1 c.2459G>A (Arg820His) mutation. Various treatments for CMO were trialled unsuccessfully. However, at his latest clinic appointment the CMO had partially improved following topical brinzolamide therapy. Most recent visual acuity was 20/25 in the right eye and 20/24 in the left eye. CONCLUSIONS: This is the first reported case of bilateral CMO in association with the RIM1 mutation. Overall, our findings were more consistent with a phenotype of retinitis pigmentosa. This could imply that the RIM1 mutation causes diverse retinal dystrophies, or that the previously described CORD7 phenotype resulted from a different variant on the same haplotype.

Common spectral domain OCT and electrophysiological findings in different pattern dystrophies.

OBJECTIVES: (1) To investigate and integrate the tomographic, angiographic and electrodiagnostic findings in pattern dystrophy. (2) To correlate visual acuity (VA) with central macular thickness (CMT), the electrooculogram (EOG) and pattern electroretinogram (PERG). DESIGN: A retrospective study of patients with pattern dystrophy. 52 eyes of 26 patients were examined. RESULTS: Thirty-three eyes had adult-onset foveomacular vitelliform dystrophy, 8 had multifocal pattern dystrophy, 6 had butterfly pattern dystrophy and 2 had reticular pattern dystrophy. SD-OCT demonstrated hyperreflectivity between the retinal pigment epithelium (RPE)/ Bruch's complex, and the junction of the inner and outer segments (IS/OS) of the photoreceptors. Disruption of the IS/OS was observed in 20, and disruption of the end tips of photoreceptors was clearly visible in eight eyes. 11 eyes showed abnormal focal hyper-reflectivity originating from the RPE towards the outer nuclear layer (ONL), and in two eyes this appeared to originate from the junction of the IS/OS towards the ONL. EDTs revealed borderline or a reduced EOG in 25 (51%) and a degraded PERG in 41eyes (83.6%) with the P50 component reduced in 23 and N95 in 18. CMT and Arden ratio did not show any significant correlation with VA. CONCLUSIONS: We observed relatively consistent features between different types of pattern dystrophies. In addition we observed novel findings on 3D-OCT. We also report 3D-OCT features of reticular, multifocal and butterfly pattern dystrophies. The degraded PERG results observed in our study indicate that the disease process in this condition is not limited to the RPE.

Allelic variation of the FRMD7 gene in congenital idiopathic nystagmus.

OBJECTIVES: To perform a genotype-phenotype correlation study in an X-linked congenital idiopathic nystagmus pedigree (pedigree 1) and to assess the allelic variance of the FRMD7 gene in congenital idiopathic nystagmus. METHODS: Subjects from pedigree 1 underwent detailed clinical examination including nystagmology. Screening of FRMD7 was undertaken in pedigree 1 and in 37 other congenital idiopathic nystagmus probands and controls. Direct sequencing confirmed sequence changes. X-inactivation studies were performed in pedigree 1. RESULTS: The nystagmus phenotype was extremely variable in pedigree 1. We identified 2 FRMD7 mutations. However, 80% of X-linked families and 96% of simplex cases showed no mutations. X-inactivation studies demonstrated no clear causal link between skewing and variable penetrance. CONCLUSIONS: We confirm profound phenotypic variation in X-linked congenital idiopathic nystagmus pedigrees. We demonstrate that other congenital nystagmus genes exist besides FRMD7. We show that the role of X inactivation in variable penetrance is unclear in congenital idiopathic nystagmus. Clinical Relevance We demonstrate that phenotypic variation of nystagmus occurs in families with FRMD7 mutations. While FRMD7 mutations may be found in some cases of X-linked congenital idiopathic nystagmus, the diagnostic yield is low. X-inactivation assays are unhelpful as a test for carrier status for this disease.

Fine mapping of the X-linked recessive congenital idiopathic nystagmus locus at Xq24-q26.3.

PURPOSE: To refine the interval for X-linked congenital idiopathic nystagmus at Xq24-q26.3 and to evaluate a novel candidate gene (Muscleblind-like 3 gene [MBNL3]). METHODS: A single pedigree with congenital idiopathic nystagmus (CIN) inherited as an X-linked recessive trait underwent detailed clinical examination including nystagmology and electrophysiological investigation in selected subjects. Following detailed phenotyping, genotyping was performed using 52 microsatellite markers spaced at an average of 5 cM along the X chromosome. Subsequent two-point and multipoint linkage analysis were performed and a candidate gene was screened for mutations by conventional sequencing. RESULTS: Linkage mapping located the disease gene to a 15.5cM interval at Xq24-q26.3, between markers DXS1212 and DXS1062 with a maximum two-point LOD score of 4.24 with both markers DXS8044 and DXS994 (theta=0). Multipoint analysis indicated a LOD score of 4.54 and a critical gene interval of 8.0 cM. No mutations were found in the MBNL3 gene in this pedigree. CONCLUSIONS: We describe a family with an unusual inheritance pattern most consistent with X-linked recessive inheritance with X inactivation causing manifesting females. We refine the linkage interval for X-linked recessive congenital idiopathic nystagmus and exclude MBNL3 as the causative gene in this family.

Joubert syndrome: long-term follow-up.

Twenty-nine patients (16 males, 13 females) with Joubert syndrome were identified from ophthalmology, neurology, and genetic databases covering a 15-year period at Great Ormond Street Hospital, London. Criteria for diagnosis included absent or markedly hypoplastic cerebellar vermis, abnormal eye movements, and developmental delay. Five patients had died. Scans and notes were available for 22 patients, and 18 cases were clinically reviewed. The median age was 10 years 10 months (range 3mo to 19y) and the median follow-up was 8 years 5 months (range 3mo to 19y, with one new patient seen at 3mo of age). Cerebellar vermis hypoplasia/aplasia with 'molar tooth sign' in the axial plane was present in 22 of 22 patients, coloboma in 6 of 22, and polydactyly in 6 of 22. In the 18 clinically reviewed, apnoea occurred in 13 patients. Five had renal problems with cysts and 4 of 5 had abnormal electroretinograms (ERGs). Visual electrophysiology was abnormal in 14 of 18 patients, and in 6 there was evidence of deterioration in the ERG. Blood investigations of organic acids, phytanic acid, very-long-chain fatty acid, and transferrin were normal in 12 patients tested. Developmental assessment showed that 6 of 15 patients aged more than 5 years were at mainstream school, and 12 of 18 had started walking between 22 months and 10 years. Speech difficulties and behavioural problems were prominent.