Correlation Between Fundus Autofluorescence Pattern and Retinal Function on Microperimetry in Choroideremia.

Purpose: In patients with choroideremia, it is not known how smooth and mottled patterns on short-wavelength fundus autofluorescence (AF) imaging relate to retinal function. Methods: A retrospective case-note review was undertaken on 190 patients with choroideremia at two specialist centers for retinal genetics. Twenty patients with both smooth and mottled zones on short-wavelength AF imaging and concurrent mesopic microperimetry assessments were included. Mean retinal sensitivities within the smooth and mottled zones were compared between choroideremia patients, and identical points on mesopic microperimetry collected from 12 age-matched controls. Longitudinal analyses were undertaken at 2 and 5 years in a subset of patients. Results: In patients with choroideremia, mean retinal sensitivities at baseline were significantly greater in the smooth zone (26.1 ± 2.0 dB) versus the mottled zone (20.5 ± 4.2 dB) (P < 0.0001). Mean retinal sensitivities at baseline were similar in the smooth zone between choroideremia patients and controls (P = 0.054) but significantly impaired in the mottled zone in choroideremia compared to controls (P < 0.0001). The rate of decline in total sensitivity over 5 years was not significant in either the smooth or mottled zone in a small subset of choroideremia patients (n = 7; P = 0.344). Conclusions: In choroideremia, retinal sensitivity as determined by microperimetry correlates with patterns on AF imaging: retinal function in the smooth zone, where the retinal pigment epithelium is anatomically preserved, is similar to controls, but retinal sensitivity in the mottled zone is impaired. Translational Relevance: Patterns on AF imaging may represent a novel, objective outcome measure for clinical trials in choroideremia as a surrogate for retinal function.

MERTK missense variants in three patients with retinitis pigmentosa.

BACKGROUND: MERTK (MER proto-oncogene, tyrosine kinase) is a transmembrane protein essential in regulating photoreceptor outer segment phagocytosis. Biallelic mutations in MERTK cause retinal degeneration. Here we present the retinal phenotype of three patients with missense variants in MERTK. MATERIALS AND METHODS: All patients underwent a full clinical examination, fundus photography, short-wavelength fundus autofluorescence and optical coherence tomography imaging. Two patients also underwent Goldmann visual field testing and electroretinography was undertaken for the third patient. Molecular genetic testing was undertaken using next generation or whole-exome sequencing with all variants confirmed by Sanger sequencing. RESULTS: The first patient was a 29-year-old female heterozygous for a missense variant (c.1133C>T, p.Thr378 Met) and a nonsense variant (c.1744_1751delinsT, p.Ile582Ter) in MERTK. The second patient was a 26-year-old male homozygous for a c.2163T>A, p.His721Gln variant in MERTK. The third patient was an 11-year-old female heterozygous for a deletion of exons 5-19 and a missense variant (c.1866 G>C, p.Lys622Asn) in MERTK. Reduced night vision was the initial symptom in all patients. Fundoscopy revealed typical signs of retinitis pigmentosa (RP) with early-onset macular atrophy. All three MERTK missense variants affect highly conserved residues within functional domains, have low population frequencies and are predicted to be pathogenic in silico. CONCLUSIONS: We report three missense variants in MERTK and present the associated phenotypic data, which are supportive of non-syndromic RP. MERTK is a promising candidate for viral-mediated gene replacement therapy. Moreover, one variant represents a single nucleotide transition, which is theoretically targetable with CRISPR-Cas9 base-editing.

The reliability and feasibility of non-contrast adenosine stress cardiovascular magnetic resonance T1 mapping in patients on haemodialysis.

BACKGROUND: Identifying coronary artery disease (CAD) in patients with end-stage renal disease (ESRD) is challenging. Adenosine stress native T1 mapping with cardiovascular magnetic resonance (CMR) may accurately detect obstructive CAD and microvascular dysfunction in the general population. This study assessed the feasibility and reliability of adenosine stress native T1 mapping in patients on haemodialysis. METHODS: The feasibility of undertaking rest and adenosine stress native T1 mapping using the single-shot Modified Look-Locker inversion recovery (MOLLI) sequence was assessed in 58 patients on maintenance haemodialysis using 3 T CMR. Ten patients underwent repeat stress CMR within 2 weeks for assessment of test-retest reliability of native T1, stress T1 and delta T1 (ΔT1). Interrater and intrarater agreement were assessed in 10 patients. Exploratory analyses were undertaken to assess associations between clinical variables and native T1 values in 51 patients on haemodialysis. RESULTS: Mean age of participants was 55 ± 15 years, 46 (79%) were male, and median dialysis vintage was 21 (8; 48) months. All patients completed the scan without complications. Mean native T1 rest, stress and ΔT1 were 1261 ± 57 ms, 1297 ± 50 ms and 2.9 ± 2.5%, respectively. Interrater and intrarater agreement of rest T1, stress T1 and ΔT1 were excellent, with intraclass correlation coefficients (ICC) > 0.9 for all. Test-retest reliability of rest and stress native T1 were excellent or good (CoV 1.2 and 1.5%; ICC, 0.79 and 0.69, respectively). Test-retest reliability of ΔT1 was moderate to poor (CoV 27.4%, ICC 0.55). On multivariate analysis, CAD, diabetes mellitus and resting native T1 time were independent determinants of ΔT1 (ß = - 0.275, p = 0.019; ß = - 0.297, p = 0.013; ß = - 0.455; p < 0.001, respectively). CONCLUSIONS: Rest and adenosine stress native T1 mapping is feasible and well-tolerated amongst patients with ESRD on haemodialysis. Although rater agreement of the technique is excellent, test-retest reliability of ΔT1 is moderate to poor. Prospective studies should evaluate the relationship between this technique and established methods of CAD assessment and association with outcomes.

The assessment of coronary artery disease in patients with end-stage renal disease.

Cardiovascular disease (CVD) remains the leading cause of morbidity and mortality among patients with end-stage renal disease (ESRD). Clustering of traditional atherosclerotic and non-traditional risk factors drive the excess rates of coronary and non-coronary CVD in patients with ESRD. Coronary artery disease (CAD) is a key disease process, present in ∼50% of the haemodialysis population ≥65 years of age. Patients with ESRD are more likely to be asymptomatic, posing a challenge to the correct identification of CAD, which is essential for appropriate risk stratification and management. Given the lack of randomized clinical trial evidence in this population, current practice is informed by observational data with a significant potential for bias. For this reason, the most appropriate approach to the investigation of CAD is the subject of considerable discussion, with practice patterns largely varying between different centres. Traditional imaging modalities are limited in their diagnostic accuracy and prognostic value for cardiac events and survival in patients with ESRD, demonstrated by the large number of adverse cardiac outcomes among patients with negative test results. This review focuses on the current understanding of CAD screening in the ESRD population, discussing the available evidence for the use of various imaging techniques to refine risk prediction, with an emphasis on their strengths and limitations.