Search

BACKGROUND: Usher syndrome is the most common hereditary syndrome combining deafness and blindness (1, 2). In the 2017 National Child Count of Children and Youth who are Deaf-Blind, Usher syndrome represented 329 of 10,000 children, but there were also at least 70 other etiologies of deaf-blindness documented (3). The purpose of this study was to analyze the work-up and ultimate diagnoses of 21 consecutive families who presented to the Genetic Eye-Ear Clinic (GEEC) at the University of Iowa. Our hypothesis was that most families referred to the GEEC would have initial and final diagnoses of Usher syndrome. MATERIALS AND METHODS: Patients were identified through an IRB approved retrospective chart review of referrals to the GEEC between 2012 and 2019. Details about each patient’s history, exam, and clinical and genetic work-up were recorded. RESULTS: From 2012 to 2019, 21 families (25 patients) were referred to the collaborative GEEC. Overall molecular diagnostic rate in this cohort was 14/21 (67%). Evaluation resulted in a change of diagnosis in 11/21 (52%) families. Ultimately, there were eleven unique diagnoses including hereditary, non-hereditary, and independent causes of combined visual impairment and hearing loss. The most common diagnosis was Usher Syndrome, which represented 6/21 (29%) families. CONCLUSIONS: Providing a correct diagnosis for patients with visual impairment and hearing loss can be challenging for clinicians and their patients, but it can greatly improve clinical care and outcomes. We recommend an algorithm that includes multidisciplinary collaboration, careful clinical evaluation, strategic molecular testing, and consideration of a broad differential diagnosis.

CEP290-associated Leber congenital amaurosis type 10 (LCA10) is a retinal disease resulting in childhood blindness. Sepofarsen is an RNA antisense oligonucleotide targeting the c.2991+1655A>G variant in the CEP290 gene to treat LCA10. In this open-label, phase 1b/2 (NCT03140969), 12-month, multicenter, multiple-dose, dose-escalation trial, six adult patients and five pediatric patients received ≤4 doses of intravitreal sepofarsen into the worse-seeing eye. The primary objective was to evaluate sepofarsen safety and tolerability via the frequency and severity of ocular adverse events (AEs); secondary objectives were to evaluate pharmacokinetics and efficacy via changes in functional outcomes. Six patients received sepofarsen 160 µg/80 µg, and five patients received sepofarsen 320 µg/160 µg. Ten of 11 (90.9%) patients developed ocular AEs in the treated eye (5/6 with 160 µg/80 µg; 5/5 with 320 µg/160 µg) versus one of 11 (9.1%) in the untreated eye; most were mild in severity and dose dependent. Eight patients developed cataracts, of which six (75.0%) were categorized as serious (2/3 with 160 µg/80 µg; 4/5 with 320 µg/160 µg), as lens replacement was required. As the 160-µg/80-µg group showed a better benefit–risk profile, higher doses were discontinued or not initiated. Statistically significant improvements in visual acuity and retinal sensitivity were reported (post hoc analysis). The manageable safety profile and improvements reported in this trial support the continuation of sepofarsen development.

Photoreceptor ciliopathies constitute the most common molecular mechanism of the childhood blindness Leber congenital amaurosis. Ten patients with Leber congenital amaurosis carrying the c.2991+1655A>G allele in the ciliopathy gene centrosomal protein 290 (CEP290) were treated (ClinicalTrials.gov no. NCT03140969 ) with intravitreal injections of an antisense oligonucleotide to restore correct splicing. There were no serious adverse events, and vision improved at 3 months. The visual acuity of one exceptional responder improved from light perception to 20/400. RNA antisense oligonucleotide therapy to restore normal splicing of a ciliopathy gene shows promising safety and efficacy results in a clinical trial to treat a form of childhood blindness.

Purpose To present a series of patients diagnosed with oculocutaneous albinism (OCA) based on clinical presentation who were later proven to have a different diagnosis. Methods The medical records of patients seen at the Pediatric Inherited Eye Disease Clinic of the University of Iowa from 1980 to 2018 who were eventually discovered to have an incorrect diagnosis of OCA were reviewed retrospectively. Results Eight pediatric patients presenting with clinical features suggestive of OCA which changed to a different diagnosis over time were identified. Presenting clinical features included fair pigmentation of the skin and adnexa (8/8), congenital nystagmus (6/8), decreased visual acuity (8/8), iris transillumination defects (8/8), and foveal hypoplasia (7/8). Of the 8 patients, 4 manifested progressive, preschool-age-onset myopia. Other associated clinical features included hearing loss (3), seizures (1), abnormal chest x-ray (1) and easy bruising (2). During follow-up, additional clinical features and genetic testing proved that they have different clinical entities, namely, Knobloch syndrome, Jeune syndrome, Donnai-Barrow syndrome, Waardenburg syndrome, Aniridia syndrome, Stickler syndrome, and Hermansky-Pudlak syndrome, one of the syndromic types of OCA. Conclusions Clinical features used to diagnose OCA also occur in other disorders. For a definitive diagnosis of OCA, ancillary/genetic testing must be performed. Clinical features not typically found in association with albinism, such as hearing loss, or early onset, or progressive myopia, may indicate the need for more extensive investigation.

Background: Sepofarsen is an RNA antisense oligonucleotide (AON) targeting the common c.2991+1655A>G mutation in the CEP290 gene to treat Leber congenital amaurosis type 10 (LCA10), a condition with severe childhood-onset vision loss or blindness. Methods: In this 12-month, multicenter, open-label, multiple-dose, dose-escalation, phase 1b/2 trial, patients with LCA10 received up to four doses of intravitreal sepofarsen in the worse-seeing eye. Primary end point was safety; secondary end points included vision outcome measures. Findings: Of 11 patients enrolled (8–44 years of age), six received loading/maintenance doses of sepofarsen of 160 µg/80 µg and five received 320 µg/160 µg. Reported cases of cataracts, mild cystoid macular edema, and retinal thinning were 3, 0, and 0, respectively, in the 160-µg/80-µg group and 5, 2, and 2 in the 320-µg/160-µg group. Pooled data (n=11) showed improvements from baseline to Month 12 in treated eyes vs untreated eyes in mean ± standard error of the mean best-corrected visual acuity (BCVA: −0·55 ± 0·26 vs −0·12 ± 0·07 logarithm of the minimum angle of resolution [logMAR], p

Purpose GUCY2D has been associated with autosomal recessive Leber congenital amaurosis and autosomal dominant cone-rod dystrophy. This report expands the phenotype of autosomal recessive mutations to congenital night blindness, which may slowly progress to mild retinitis pigmentosa. Design Retrospective case series. Methods Multicenter study of 5 patients (3 male, 2 female). Results All patients presented with night blindness since childhood. Age at referral was 9–45 years. Length of follow-up was 1–7 years. Best-corrected visual acuity at presentation ranged from 20/15 to 20/30 and at most recent visit averaged 20/25. No patient had nystagmus or high refractive error. ISCEV standard electroretinography revealed nondetectable dark-adapted dim flash responses and reduced amplitude but not electronegative dark-adapted bright flash responses with similar waveforms to the reduced-amplitude light-adapted single flash responses. The 30 Hz flicker responses were relatively preserved. Macular optical coherence tomography revealed normal lamination in 3 patients, with abnormalities in 2. Goldmann visual fields were normal at presentation in children but constricted in 1 adult. One child showed loss of midperipheral fields over time. Fundus appearance was normal in childhood; the adult had sparse bone spicule–like pigmentation. Full-field stimulus testing (FST) revealed markedly decreased retinal sensitivity to light. Dark adaptation demonstrated lack of rod-cone break. Two patients had tritanopia. All 5 had compound heterozygous mutations in GUCY2D . Three of the 5 patients harbor the Arg768Trp mutation reported in GUCY2D -associated Leber congenital amaurosis. Conclusions Autosomal recessive GUCY2D mutations may cause congenital night blindness with normal acuity and refraction, and unique electroretinography. Progression to mild retinitis pigmentosa may occur.

Juvenile Neuronal Ceroid Lipofuscinosis (JNCL) presents with progressive vision loss at 4–7 years of age. Blindness results within 2 years, followed by inexorable neurologic decline and death. There is no treatment or cure. Neuroinflammation is postulated to play a role in the neurodegeneration. The JNCL mouse model demonstrated decreased neuroinflammation and improved motor skills with immunosuppression. Based on this work, a short-term human clinical trial of mycophenolate mofetil has begun, however longer term effects, and whether immunosuppression modulates vision loss, have not been studied. We report a JNCL patient treated with immunosuppressive therapy in whom visual function was comprehensively characterized over 2 years.

Purpose To present the largest cohort of preschool children screened by the MTI PhotoScreener over a 9-year period from a single, statewide vision screening effort. Design Cross-sectional study. Participants We included 147 809 children screened between May 1, 2000, and April 30, 2009 by a photoscreening program. Methods Retrospective review of results from the Iowa photoscreening program using the MTI PhotoScreener. The photographs were taken by volunteers from local Lions clubs and sent to the University of Iowa for interpretation. Children who failed the photoscreening were referred to local eye care professionals, who preformed a comprehensive eye evaluation and forwarded the results to the Iowa KidSight program. Main Outcome Measures Number of screenings, referral rate, positive predictive value (PPV), follow-up rate, and associated costs per year are described. Results Over the 9 years of the continuously operating program, 147 809 children underwent photoscreens to detect amblyopic risk factors at 9746 sites. Because of abnormal photoscreen results, 6247 children (4.2%) were referred. Of the children, 24.3% were evaluated by local ophthalmologists and 76.7% were seen by local optometrists. Between 2000 and 2009, the follow-up rate ranged from a low of 36.1% to a high of 89.5%, with an overall program follow-up rate after the addition of the follow-up coordinator of 81.3%. The overall PPV of the MTI PhotoScreener was 94.2%. Taking into account overall operating budget including salaries and associated costs, the cost of screening 1 child has been reduced to $US9 per child. Conclusions The addition of a part-time follow-up coordinator to the photoscreening program produced 89.5% follow-up rate when screening 147 809 children for amblyopia risk factors over a 9-year period. Financial Disclosure(s) The authors have no proprietary or commercial interest in any of the materials discussed in this article.

Infantile nystagmus has many causes, some life threatening. We determined the most common diagnoses in order to develop a testing algorithm.Retrospective chart review. Exclusion criteria were no nystagmus, acquired after 6 months, or lack of examination.pediatric eye examination findings, ancillary testing, order of testing, referral, and final diagnoses. Final diagnosis was defined as meeting published clinical criteria and/or confirmed by diagnostic testing. Patients with a diagnosis not meeting the definition were "unknown." Patients with incomplete testing were "incomplete." Patients with multiple plausible etiologies were "multifactorial." Patients with negative complete workup were "motor."A total of 284 charts were identified; 202 met inclusion criteria. The three most common causes were Albinism (19%), Leber Congenital Amaurosis (LCA; 14%), and Non-LCA retinal dystrophy (13%). Anatomic retinal disorders comprised 10%, motor another 10%. The most common first test was MRI (74/202) with a diagnostic yield of 16%. For 28 MRI-first patients, nystagmus alone was the indication; for 46 MRI-first patients other neurologic signs were present. 0/28 nystagmus-only patients had a diagnostic MRI while 14/46 (30%) with neurologic signs did. The yield of ERG as first test was 56%, OCT 55%, and molecular genetic testing 47%. Overall, 90% of patients had an etiology identified.The most common causes of infantile nystagmus were retinal disorders (56%), however the most common first test was brain MRI. For patients without other neurologic stigmata complete pediatric eye examination, ERG, OCT, and molecular genetic testing had a higher yield than MRI scan. If MRI is not diagnostic, a complete ophthalmologic workup should be pursued.

OBJECTIVE: Recent US Preventive Services Task Force recommendations on vision screening reported insufficient data to recommend vision screening in children METHODS: A retrospective review of results from the Iowa KidSight database using the MTI PhotoScreener containing results of children screened between May 1, 2000, and April 30, 2011. RESULTS: During the 11 years of the study, 210 695 photoscreens on children were performed at 13 750 sites. In the CONCLUSIONS: No statistically significant difference was found in screening children from 1 to 3 years old compared with screening children >3 years old. These results confirm that early screening, before amblyopia is more pronounced, can reliably detect amblyogenic risk factors in children younger than 3 years of age, and we recommend initiation of photoscreening in children aged 1 year and older.

Purpose: To investigate the incidence and characteristics of occlusion amblyopia with prescribed full-time patching and determine its effect on long-term visual acuity outcomes. Methods: The records of patients younger than 10 years diagnosed as having amblyopia between 1970 and 2000 were retrospectively reviewed. Patients were prescribed full-time occlusion and observed until completion of therapy. Results: Of 597 patients treated for amblyopia by full-time patching, 115 were diagnosed as having occlusion amblyopia (19.3%). Seventy-five percent (86 of 115) developed occlusion amblyopia during the first episode of full-time patching. Occlusion amblyopia occurred more frequently in children prescribed full-time patching at an earlier age ( P = .0002), with an odds ratio of 8.56 (95% confidence interval: 2.73, 26.84) in children younger than 36 months and 2.66 (95% confidence interval: 0.96, 7.37) in children between 36 and 59 months old. Seven of the patients with occlusion amblyopia did not reverse fixation and continued to fixate with the initially amblyopic eye after treatment. Final visual acuity in these eyes with occlusion amblyopia was 20/30 or better. After cessation of treatment, the final interocular difference in visual acuity was less in patients with a history of occlusion amblyopia ( P = .003). Conclusion: Occlusion amblyopia occurred at all ages, but the incidence decreased with increasing age. Patients who developed occlusion amblyopia with prescribed full-time occlusion had less interocular visual acuity difference than patients who did not, suggesting that development of occlusion amblyopia can indicate the potential for the development of better vision in the originally amblyopic eye. [J Pediatr Ophthalmol Strabismus 2013;50:94–101.]