Purpose: The cytosolic enzyme N-glycanase 1, encoded by NGLY1, catalyzes cleavage of the β-aspartyl glycosylamine bond of N-linked glycoproteins, releasing intact N-glycans from proteins bound for degradation. In this study, we describe the clinical spectrum of NGLY1 deficiency (NGLY1-CDDG). Methods: Prospective natural history protocol. Results: In 12 individuals ages 2 to 21 years with confirmed, biallelic, pathogenic NGLY1 mutations, we identified previously unreported clinical features, including optic atrophy and retinal pigmentary changes/cone dystrophy, delayed bone age, joint hypermobility, and lower than predicted resting energy expenditure. Novel laboratory findings include low cerebral spinal fluid (CSF) total protein and albumin and unusually high antibody titers toward rubella and/or rubeola following vaccination. We also confirmed and further quantified previously reported findings noting that decreased tear production, transient transaminitis, small feet, a complex hyperkinetic movement disorder, and varying degrees of global developmental delay with relatively preserved socialization are the most consistent features. Conclusion: Our prospective phenotyping expands the clinical spectrum of NGLY1-CDDG, offers prognostic information, and provides baseline data for evaluating therapeutic interventions. Genet Med 19 2, 160–168.

Joubert syndrome (JS) is caused by mutations in >34 genes that encode proteins involved with primary (nonmotile) cilia and the cilium basal body. This study describes the varying ocular phenotypes in JS patients, with correlation to systemic findings and genotype. Patients were systematically and prospectively examined at the National Institutes of Health (NIH) Clinical Center in the setting of a dedicated natural history clinical trial. Ninety-nine patients with JS examined at a single center. All patients underwent genotyping for JS, followed by complete age-appropriate ophthalmic examinations at the NIH Clinical Center, including visual acuity (VA), fixation behavior, lid position, motility assessment, slit-lamp biomicroscopy, dilated fundus examination with an indirect ophthalmoscope, and retinoscopy. Color and fundus autofluorescence imaging, Optos wide-field photography (Dunfermline, Scotland, UK), and electroretinography (ERG) were performed when possible. The VA (with longitudinal follow-up where possible), ptosis, extraocular muscle function, retinal and optic nerve status, and retinal function as measured by ERG. Among patients with JS with quantifiable VA (68/99), values ranged from 0 logarithm of the minimum angle of resolution (logMAR) (Snellen 20/20) to 1.5 logMAR (Snellen 20/632). Strabismus (71/98), nystagmus (66/99), oculomotor apraxia (60/77), ptosis (30/98), coloboma (28/99), retinal degeneration (20/83), and optic nerve atrophy (8/86) were identified. We recommend regular monitoring for ophthalmological manifestations of JS beginning soon after birth or diagnosis. We demonstrate delayed visual development and note that the amblyogenic time frame may last significantly longer in JS than is typical. In general, patients with coloboma were less likely to display retinal degeneration, and those with retinal degeneration did not have coloboma. Severe retinal degeneration that is early and aggressive is seen in disease caused by specific genes, such as CEP290- and AHI1-associated JS. Retinal degeneration in INPP5E-, MKS1-, and NPHP1-associated JS was generally milder. Finally, ptosis surgery can be helpful in a subset of patients with JS; decisions as to timing and benefit/risk ratio need to be made on an individual basis according to expert consultation.

We aimed to characterize the ocular phenotype of patients with ROSAH (retinal dystrophy, optic nerve edema, splenomegaly, anhidrosis, and headache) syndrome and their response to therapy. Single-center observational case study. Eleven patients with a diagnosis of ROSAH syndrome and mutation in ALPK1 were included. Patients with molecularly confirmed ROSAH syndrome underwent ophthalmic evaluation, including visual acuity testing, slit-lamp and dilated examinations, color fundus and autofluorescence imaging, fluorescein angiography, OCT, and electrophysiologic testing. Visual acuity, electrophysiology, fluorescein angiography, and OCT findings. Eleven individuals (6 female and 5 male patients) from 7 families ranging in age from 7.3 to 60.2 years at the time of the initial evaluation were included in this study. Seven patients were followed up for a mean of 2.6 years (range, 0.33–5.0 years). Best-corrected visual acuity at baseline ranged from 20/16 to no light perception. Variable signs or sequelae of intraocular inflammation were observed in 9 patients, including keratic precipitates, band keratopathy, trace to 2+ anterior chamber cells, cystoid macular edema, and retinal vasculitis on fluorescein angiography. Ten patients were observed to show optic disc elevation and demonstrated peripapillary thickening on OCT. Seven patients showed retinal degeneration consistent with a cone–rod dystrophy, with atrophy tending to involve the posterior pole and extending peripherally. One patient with normal electroretinography findings and visual evoked potential was found to have decreased Arden ratio on electrooculography. Leveraging insights from the largest single-center ROSAH cohort described to date, this study identified 3 main factors as contributing to changes in visual function of patients with ROSAH syndrome: optic nerve involvement; intraocular inflammation, including cystoid macular edema; and retinal degeneration. More work is needed to determine how to arrest the progressive vision loss associated with ROSAH syndrome. Proprietary or commercial disclosure may be found after the references.

Usher syndrome has classically been described as a combination of hearing loss and rod-cone dystrophy; vestibular dysfunction is present in many patients. Three distinct clinical subtypes were documented in the late 1970s. Genotyping efforts have led to the identification of several genes associated with the disease. Recent literature has seen multiple publications referring to “atypical” Usher syndrome presentations. This manuscript reviews the molecular etiology of Usher syndrome, highlighting rare presentations and molecular causes. Reports of “atypical” disease are summarized noting the wide discrepancy in the spectrum of phenotypic deviations from the classical presentation. Guidelines for establishing a clear nomenclature system are suggested.

BACKGROUND: Outcome measures sensitive to disease progression are needed for ATP-binding cassette, sub-family A, member 4–associated ( ABCA4 -associated) retinopathy. We aimed to quantify ellipsoid zone (EZ) loss and photoreceptor degeneration beyond EZ-loss in ABCA4 -associated retinopathy and investigate associations between photoreceptor degeneration, genotype, and age. METHODS: We analyzed 132 eyes from 66 patients (of 67 enrolled) with molecularly confirmed ABCA4 -associated retinopathy from a prospective natural history study with a median [IQR] follow-up of 4.2 years [3.1, 5.1]. Longitudinal spectral-domain optical coherence tomography volume scans (37 B-scans, 30° × 15°) were segmented using a deep learning (DL) approach. For genotype-phenotype analysis, a model of ABCA4 variants was applied with the age of criterion EZ-loss (6.25 mm ² ) as the dependent variable. RESULTS: Patients exhibited an average (square-root-transformed) EZ-loss progression rate of [95% CI] 0.09 mm/y [0.06, 0.11]. Outer nuclear layer (ONL) thinning extended beyond the area of EZ-loss . The average distance from the EZ-loss boundary to normalization of ONL thickness (to ±2 z score units) was 3.20° [2.53, 3.87]. Inner segment (IS) and outer segment (OS) thinning was less pronounced, with an average distance from the EZ-loss boundary to layer thickness normalization of 1.20° [0.91, 1.48] for the IS and 0.60° [0.49, 0.72] for the OS. An additive model of allele severity explained 52.7% of variability in the age of criterion EZ-loss . CONCLUSION: Patients with ABCA4 -associated retinopathy exhibited significant alterations of photoreceptors outside of EZ-loss . DL-based analysis of photoreceptor laminae may help monitor disease progression and estimate the severity of ABCA4 variants. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01736293. FUNDING: National Eye Institute Intramural Research Program and German Research Foundation grant PF950/1-1.