ABSTRACT:The Smith-Lemli-Opitz syndrome (SLOS) is the firstdescribed in a growing family of hereditary defects in cholesterol biosynthesis, and presents with a spectrum of serious abnormalities, including multiple dysmorphologies, failure to thrive, cognitive and behavioral impairments, and retinopathy. Using a pharmacologically induced rat model of SLOS that exhibits key hallmarks of the disease, including progressive retinal degeneration and dysfunction, we show that a high-cholesterol diet can substantially correct abnormalities in retinal sterol composition, with concomitant improvement of visual function, particularly within the cone pathway. Although histologic degeneration still occurred, a high-cholesterol diet reduced the number of pyknotic photoreceptor nuclei, relative to animals on a cholesterol-free diet. These findings demonstrate that cholesterol readily crosses the blood-retina barrier (unlike the blood-brain barrier) and suggest that cholesterol supplementation may be efficacious in treating SLOS-associated retinopathy. H ereditary abnormalities in cholesterol biosynthesis underlie a family of human birth defects associated with specific enzyme defects and phenotypes (1-3). The first described and most common of these is SLOS (4), a multiple congenital anomalies syndrome involving the inability to efficiently convert 7DHC to Chol (5,6). The enzyme responsible for catalyzing this biosynthetic step (3␤-hydroxysterol-⌬ 7 -reductase; DHCR7; EC 1.3.1.21) is encoded by the DHCR7 gene localized to human chromosome 11q12-q13 (7-9). More than 100 mutations in DHCR7 have been identified in association with SLOS; many result in abnormally low levels of cholesterol and abnormally high levels of 7DHC in bodily tissues (8,9). With an estimated global incidence of 1 in 20,000 to 1 in 60,000 live births, SLOS is likely the fourth most common human recessive disease, after cystic fibrosis, phenylketonuria, and hemochromatosis (8,9). However, a recent study (10) estimates the SLOS carrier frequency to be 1 in 30, suggesting a much higher actual disease frequency, e.g. approximately 1 in 1,590 to 1 in 13,500. The SLOS phenotype displays a spectrum of clinical manifestations, from mild to lethal, and may include such findings as moderate to severe mental retardation, autism, dysmorphic craniofacial and skeletal malformations, and failure to thrive (1-3).We previously reported progressive retinal degeneration in a pharmacological rat model of SLOS (11) characterized by shortening and eventual loss of retinal ROS, pyknosis and thinning of the ONL, accumulation of membranous inclusions and lipid droplets in the retinal pigment epithelium (RPE), defects in rod and cone photoresponses, together with SLOSlike accumulation of 7DHC and diminished cholesterol levels in retina, brain, liver, and serum. The SLOS rat model (11-13) is induced by treatment of pregnant rats and their progeny with AY9944, a selective inhibitor of 3␤-hydroxysterol-⌬ 7 -reductase (14,15), the enzyme defective in SLOS. The clinical relevance of the S...

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SIGNIFICANCE Clinicians can better diagnose and manage vision problems of autism spectrum disorder (ASD) children by establishing a standard of care for this population. Results also reinforce the importance of a comprehensive binocular vision evaluation in all patients with ASD. PURPOSE The purposes of this study were to compare near-point and ocular motility test findings in ASD children and typically developing (TD) peers and to compare findings among ASD children by level of verbal communication. METHODS Sixty-one children and adolescents (ASD, 34; TD, 27) aged 9 to 17 years completed an eye examination protocol including tests of distance and near phoria, near point of convergence, near fusional convergence and divergence, accommodative response, and Northeastern State University College of Optometry oculomotor testing. Testing was completed through refractive correction. Parents of ASD children provided information regarding subjects' verbal communication level (nonverbal, uses short words, verbal). RESULTS Distance phoria did not differ significantly between groups. Near phoria of ASD subjects was more exophoric (difference, 2.8 prism diopters). Mean near point of convergence break and recovery were 7.0 and 8.02 cm, respectively, in ASD subjects and 2.19 and 3.99 cm in TD subjects. Near fusional divergence and convergence showed no significant difference. Autism spectrum disorder subjects had significantly poorer stereoacuity ( P < .0001) and, on Northeastern State University College of Optometry Oculomotor Testing, reduced fixation, poorer accuracy and stamina/ability, and increased head and body movement. Monocular estimation method retinoscopy results did not differ significantly between ASD and TD subjects. No significant differences in phoria, near point of convergence, and near fusional divergence or convergence were observed between ASD subgroups (nonverbal, uses short words, verbal). CONCLUSIONS Autism spectrum disorder children are more likely to show receded near point of convergence, poor fixation, inaccurate saccades, erratic pursuits, and exophoric posture. These differences occur, regardless of reported verbal communication level.

Purpose To determine the effectiveness of office‐based vergence/accommodative therapy for improving accommodative amplitude and accommodative facility in children with symptomatic convergence insufficiency and accommodative dysfunction. Methods We report changes in accommodative function following therapy among participants in the Convergence Insufficiency Treatment Trial – Attention and Reading Trial with decreased accommodative amplitude (115 participants in vergence/accommodative therapy; 65 in placebo therapy) or decreased accommodative facility (71 participants in vergence/accommodative therapy; 37 in placebo therapy) at baseline. The primary analysis compared mean change in amplitude and facility between the vergence/accommodative and placebo therapy groups using analyses of variance models after 4, 8, 12 and 16 weeks of treatment. The proportions of participants with normal amplitude and facility at each time point were calculated. The average rate of change in amplitude and facility from baseline to week 4, and from weeks 4 to 16, were determined in the vergence/accommodative therapy group. Results From baseline to 16 weeks, the mean improvement in amplitude was 8.6 dioptres (D) and 5.2 D in the vergence/accommodative and placebo therapy groups, respectively (mean difference = 3.5 D, 95% confidence interval (CI): 1.5 to 5.5 D; p = 0.01). The mean improvement in facility was 13.5 cycles per minute (cpm) and 7.6 cpm in the vergence/accommodative and placebo therapy groups, respectively (mean difference = 5.8 cpm, 95% CI: 3.8 to 7.9 cpm; p < 0.0001). Significantly greater proportions of participants treated with vergence/accommodative therapy achieved a normal amplitude (69% vs. 32%, difference = 37%, 95% CI: 22 to 51%; p < 0.0001) and facility (85% vs. 49%, difference = 36%, 95% CI: 18 to 55%; p < 0.0001) than those who received placebo therapy. In the vergence/accommodative therapy group, amplitude increased at an average rate of 1.5 D per week during the first 4 weeks (p < 0.0001), then slowed to 0.2 D per week (p = 0.002) from weeks 4 to 16. Similarly, facility increased at an average rate of 1.5 cpm per week during the first 4 weeks (p < 0.0001), then slowed to 0.6 cpm per week from weeks 4 to 16 (p < 0.0001). Conclusion Office‐based vergence/accommodative therapy is effective for improving accommodative function in children with symptomatic convergence insufficiency and coexisting accommodative dysfunction.

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