Comparison of Scheimpflug Corneal Tomography and Anterior Segment Optical Coherence Tomography Measurements in Corneal Cystinosis: A Case Series.

PURPOSE: To report the clinical course and compare the utility of Scheimpflug tomography (ST) and anterior segment optical coherence tomography (AS-OCT) for central corneal thickness (CCT) and corneal densitometry (CD) assessment in patients with corneal crystals owing to nephropathic cystinosis. METHODS: A retrospective chart analysis of three patients with nephropathic cystinosis and the presence of corneal cystine crystals in both eyes was performed. All patients underwent clinical examination and anterior segment photography, ST, and AS-OCT scans. Corneal densitometry was exported from built-in proprietary software for ST and from custom-made validated software for AS-OCT. Anterior segment optical coherence tomography images were rescaled to grayscale units from 0 (maximum transparency) to 100 (minimum transparency) to match built-in ST densitometry readings. Furthermore, the mean pixel intensity, representative of CD, was calculated from the pixels corresponding to the segmented cornea. RESULTS: All three patients had pathognomonic cystine crystals deposits in the cornea and were treated with cysteamine medications that resulted in clinical improvement. The CCT measured using ST exhibited a range from 560 to 958 µm. Conversely, when assessed with AS-OCT, the CCT varied within the range of 548 to 610 µm. Both examinations could be performed, but in the more severe cases, AS-OCT showed far greater utility to estimate CD. In four of six eyes examined, ST showed disproportionate CCT values, compared with the AS-OCT, whereas reliable CD measurements were only available in AS-OCT. CONCLUSION: The AS-OCT could be considered a baseline ocular measurement in cystinosis and in the evaluation of disease progression and treatment efficacy.

ABCA4-associated disease as a model for missing heritability in autosomal recessive disorders: novel noncoding splice, cis-regulatory, structural, and recurrent hypomorphic variants.

PURPOSE: ABCA4-associated disease, a recessive retinal dystrophy, is hallmarked by a large proportion of patients with only one pathogenic ABCA4 variant, suggestive for missing heritability. METHODS: By locus-specific analysis of ABCA4, combined with extensive functional studies, we aimed to unravel the missing alleles in a cohort of 67 patients (p), with one (p = 64) or no (p = 3) identified coding pathogenic variants of ABCA4. RESULTS: We identified eight pathogenic (deep-)intronic ABCA4 splice variants, of which five are novel and six structural variants, four of which are novel, including two duplications. Together, these variants account for the missing alleles in 40.3% of patients. Furthermore, two novel variants with a putative cis-regulatory effect were identified. The common hypomorphic variant c.5603A>T p.(Asn1868Ile) was found as a candidate second allele in 43.3% of patients. Overall, we have elucidated the missing heritability in 83.6% of our cohort. In addition, we successfully rescued three deep-intronic variants using antisense oligonucleotide (AON)-mediated treatment in HEK 293-T cells and in patient-derived fibroblast cells. CONCLUSION: Noncoding pathogenic variants, novel structural variants, and a common hypomorphic allele of the ABCA4 gene explain the majority of unsolved cases with ABCA4-associated disease, rendering this retinopathy a model for missing heritability in autosomal recessive disorders.

Mutations in the gene PDE6C encoding the catalytic subunit of the cone photoreceptor phosphodiesterase in patients with achromatopsia.

Biallelic PDE6C mutations are a known cause for rod monochromacy, better known as autosomal recessive achromatopsia (ACHM), and early-onset cone photoreceptor dysfunction. PDE6C encodes the catalytic α'-subunit of the cone photoreceptor phosphodiesterase, thereby constituting an essential part of the phototransduction cascade. Here, we present the results of a study comprising 176 genetically preselected patients who remained unsolved after Sanger sequencing of the most frequent genes accounting for ACHM, and were subsequently screened for exonic and splice site variants in PDE6C applying a targeted next generation sequencing approach. We were able to identify potentially pathogenic biallelic variants in 15 index cases. The mutation spectrum comprises 18 different alleles, 15 of which are novel. Our study significantly contributes to the mutation spectrum of PDE6C and allows for a realistic estimate of the prevalence of PDE6C mutations in ACHM since our entire ACHM cohort comprises 1,074 independent families.

Visual sensory and perceptive functioning in 5-year-old very preterm/very-low-birthweight children.

AIM: To examine visual sensory and perceptive functions, study their interrelations, and explore associations between visual dysfunctions and intelligence in very preterm/very-low-birthweight (VP/VLBW) children. METHOD: One-hundred and sixteen VP/VLBW children (57 males, 59 females; mean gestational age 30.1 wks, SD 2.3; mean corrected age 5 y 6 mo, SD 1 mo) and 73 term-born children (40 males, 33 females; mean gestational age 39.9 wks, SD 1.3; mean age 5 y 6 mo, SD 3 mo) completed visual sensory (acuity, visual field, contrast-, color-, and stereovision), perceptive (visual coherence, and Developmental Test of Visual Perception non-motor scale), and intelligence assessments. RESULTS: Compared with term-born children, VP/VLBW children had reduced acuity (d=0.70, p<0.001), inferior visual field (d=0.67, p<0.001), and stereovision (v=0.19, p=0.008). VP/VBLW children showed weaker static coherence (d=0.49, p=0.001) and Position in Space (d=0.41, p=0.006) performance, independent of visual sensory deficits, and showed lower Verbal IQ (VIQ) and Performance IQ (PIQ; p<0.001). Visual perceptive functioning accounted for 13% of variance in VIQ, and for 35% of variance in PIQ. INTERPRETATION: Visual sensory and perceptive dysfunctions are present in VP/VLBW children and occur largely independently of each other. Visual perceptive dysfunctions are moderately associated with PIQ, and weakly with VIQ.

Visual impairment due to retinopathy of prematurity and concomitant disabilities in the Netherlands.

AIM: Determine incidence of visual impairment due to retinopathy of prematurity (ROP) and concomitant disabilities between 2009 and 2018 in the Netherlands and compare data to four former similar studies. Secondly, monitor if infants were missed for ROP-screening since the adoption of stricter, risk factor guided criteria (2013). METHODS: Retrospective inventory on anonymous data of infants diagnosed with ROP from Dutch visual impairment-institutes. Data including: best corrected visual acuity, ROP-treatment and concomitant disabilities: bronchopulmonary dysplasia, behavioral abnormalities, epilepsy, hearing deficit, developmental delay, cerebral palsy and cerebral visual impairment. During the study period, lower age limit for neonatal life support (2010) and higher oxygen saturation targets (2014) were implemented. RESULTS: Records of 53 infants were analyzed. Visual impairment incidence due to ROP was 2.02 per 100.000 live births (2000-2009: 1.84, p = 0.643). Compared to earlier periods (1975-2000), a significant decrease was observed. The incidence of concomitant disabilities remained stable. Mean gestational age (GA) continued to decrease to 26.6 ± 1.9 weeks (2000-2009: 27.4 ± 2.0 weeks, p = 0.047). All patients met the screening inclusion criteria. CONCLUSION: The incidence of visual impairment due to ROP and concomitant disabilities between 2009 and 2018 has not increased, despite lower GA and higher oxygen saturation targets. None of the infants were missed for ROP screening following introduction of more restricted screening inclusion criteria.