Recognizing differentiating clinical signs of CLN3 disease (Batten disease) at presentation

Purpose To help differentiate CLN3 (Batten) disease, a devastating childhood metabolic disorder, from the similarly presenting early-onset Stargardt disease (STGD1). Early clinical identification of children with CLN3 disease is essential for adequate referral, counselling and rehabilitation. Methods Medical chart review of 38 children who were referred to a specialized ophthalmological centre because of rapid vision loss. The patients were subsequently diagnosed with either CLN3 disease (18 patients) or early-onset STGD1 (20 patients). Results Both children who were later diagnosed with CLN3 disease, as children who were later diagnosed with early-onset STGD1, initially presented with visual acuity (VA) loss due to macular dystrophy at 5-10 years of age. VA in CLN3 disease decreased significantly faster than in STGD1 (p = 0.01). Colour vision was often already severely affected in CLN3 disease while unaffected or only mildly affected in STGD1. Optic disc pallor on fundoscopy and an abnormal nerve fibre layer on optical coherence tomography were common in CLN3 disease compared to generally unaffected in STGD1. In CLN3 disease, dark-adapted (DA) full-field electroretinogram (ERG) responses were either absent or electronegative. In early-onset STGD1, DA ERG responses were generally unaffected. None of the STGD1 patients had an electronegative ERG. Conclusion Already upon presentation at the ophthalmologist, the retina in CLN3 disease is more extensively and more severely affected compared to the retina in early-onset STGD1. This results in more rapid VA loss, severe colour vision abnormalities and abnormal DA ERG responses as the main differentiating early clinical features of CLN3 disease

Multisensory Integration and Attention in Autism Spectrum Disorder: Evidence from Event-Related Potentials

Successful integration of various simultaneously perceived perceptual signals is crucial for social behavior. Recent findings indicate that this multisensory integration (MSI) can be modulated by attention. Theories of Autism Spectrum Disorders (ASDs) suggest that MSI is affected in this population while it remains unclear to what extent this is related to impairments in attentional capacity. In the present study Event-related potentials (ERPs) following emotionally congruent and incongruent face-voice pairs were measured in 23 high-functioning, adult ASD individuals and 24 age- and IQ-matched controls. MSI was studied while the attention of the participants was manipulated. ERPs were measured at typical auditory and visual processing peaks, namely, P2 and N170. While controls showed MSI during divided attention and easy selective attention tasks, individuals with ASD showed MSI during easy selective attention tasks only. It was concluded that individuals with ASD are able to process multisensory emotional stimuli, but this is differently modulated by attention mechanisms in these participants, especially those associated with divided attention. This atypical interaction between attention and MSI is also relevant to treatment strategies, with training of multisensory attentional control possibly being more beneficial than conventional sensory integration therapy

Defining inclusion criteria and endpoints for clinical trials: a prospective cross-sectional study in CRB1-associated retinal dystrophies

Purpose: To investigate the retinal structure and function in patients with CRB1-associated retinal dystrophies (RD) and to explore potential clinical endpoints. Methods: In this prospective cross-sectional study, 22 patients with genetically confirmed CRB1-RD (aged 6–74 years), and who had a decimal best-corrected visual acuit

The Detection Of Misrouting In Albinism : Evaluation of Different VEP Procedures in a Heterogeneous Cohort

Purpose: To investigate the optimal procedures for multichannel visually evoked potentials (VEPs) to detect misrouting in albinism subjects. Methods: Investigations were done in a phenotypically heterogeneous group of 180 albinism subjects and 187 controls with and without ocular pathology. We retrospectively compared standard flash VEP (fVEP), high-frequency fVEP with a handheld device (hh fVEP), pattern-onset VEP (poVEP), and short-onset acuity sweep VEP. The diagnostic power of these stimuli were estimated by calculating the area under the curve (AUC). Subjects were divided in three age groups (0.3 logMAR). Results: The optimal stimulus was hh fVEP, standard fVEP, and poVEP 60' for subjects 0.3 logMAR. Remarkably, some albinism subjects showed misrouting on full-field stimulation but normal routing of the central retina, suggesting that not the whole line of decussation is shifted temporally

Correction: Littink, K. W.; et al. Autosomal Recessive NRL Mutations in Patients with Enhanced S-Cone Syndrome. Genes 2018, 9, 68

The authors wish to make the following correction to this paper [1]. [...

Recognizing differentiating clinical signs of CLN3 disease (Batten disease) at presentation

Purpose: To help differentiate CLN3 (Batten) disease, a devastating childhood metabolic disorder, from the similarly presenting early-onset Stargardt disease (STGD1). Early clinical identification of children with CLN3 disease is essential for adequate referral, counselling and rehabilitation. Methods: Medical chart review of 38 children who were referred to a specialized ophthalmological centre because of rapid vision loss. The patients were subsequently diagnosed with either CLN3 disease (18 patients) or early-onset STGD1 (20 patients). Results: Both children who were later diagnosed with CLN3 disease, as children who were later diagnosed with early-onset STGD1, initially presented with visual acuity (VA) loss due to macular dystrophy at 5–10 years of age. VA in CLN3 disease decreased significantly faster than in STGD1 (p = 0.01). Colour vision was often already severely affected in CLN3 disease while unaffected or only mildly affected in STGD1. Optic disc pallor on fundoscopy and an abnormal nerve fibre layer on optical coherence tomography were common in CLN3 disease compared to generally unaffected in STGD1. In CLN3 disease, dark-adapted (DA) full-field electroretinogram (ERG) responses were either absent or electronegative. In early-onset STGD1, DA ERG responses were generally unaffected. None of the STGD1 patients had an electronegative ERG. Conclusion: Already upon presentation at the ophthalmologist, the retina in CLN3 disease is more extensively and more severely affected compared to the retina in early-onset STGD1. This results in more rapid VA loss, severe colour vision abnormalities and abnormal DA ERG responses as the main differentiating early clinical features of CLN3 disease

A Rare Form of Retinal Dystrophy Caused by Hypomorphic Nonsense Mutations in CEP290

Purpose: To identify the gene defect and to study the clinical characteristics and natural course of disease in a family originally diagnosed with oligocone trichromacy (OT), a rare congenital cone dysfunction syndrome. Methods: Extensive clinical and ophthalmologic assessment was performed on two siblings with OT and long-term follow up data were analyzed. Subsequently, whole exome sequencing (WES) and Sanger sequence analysis of CEP290 was performed in the two siblings. Additionally, the identified CEP290 mutations were analyzed in persons with achromatopsia (ACHM) (n = 23) and autosomal recessive or isolated cone dystrophy (CD; n = 145). Results: In the first decade of life, the siblings were diagnosed with OT based on low visual acuity, photophobia, nystagmus, and absent cone response on electroretinography , but with normal color discrimination. Over time, the phenotype of OT evolved to a progressive degenerative disease without any CEP290-associated non-ocular features. In both siblings, two nonsense mutations (c.451C>T; p.(Arg151*) and c.4723A>T; p.(Lys1575*)) in CEP290 were found. Previously, p.(Arg151*) was demonstrated to induce nonsense-mediated alternative splicing events leading to intact open reading frames of the resulting mRNA products (p.(Leu148_Glu165del) and p.(Leu148_Lys172del)). mRNA analysis for p.(Lys1575*) confirmed a suspected hypomorphic character, as exon 36 skipping was observed in a small fraction of CEP290 mRNA, resulting in a 36 aa in-frame deletion (p.(Glu1569_Trp1604del)). No additional cases carrying these variants were identified in the ACHM and CD cohorts. Conclusions: Compound heterozygous hypomorphic mutations in CEP290 may lead to a rare form of cone-dominated retinal dystrophy, a novel phenotype belonging to the CEP290-associated spectrum of ciliopathies. These findings provide insight into the effect of CEP290 mutations on the clinical phenotype

Defining inclusion criteria and endpoints for clinical trials: a prospective cross-sectional study in CRB1-associated retinal dystrophies

Purpose: To investigate the retinal structure and function in patients with CRB1-associated retinal dystrophies (RD) and to explore potential clinical endpoints. Methods: In this prospective cross-sectional study, 22 patients with genetically confirmed CRB1-RD (aged 6–74 years), and who had a decimal best-corrected visual acuity (BCVA) ≥ 0.05 at the last visit, were studied clinically with ETDRS BCVA, corneal topography, spectral-domain optical coherence tomography (SD-OCT), fundus autofluorescence, Goldmann visual field (VF), microperimetry, full-field electroretinography (ERG) and full-field stimulus testing (FST). Ten patients were from a genetic isolate (GI). Results: Patients had retinitis pigmentosa (n = 19; GI and non-GI), cone-rod dystrophy (n = 2; GI) or macular dystrophy (n = 1; non-GI). Median age at first symptom onset was 3 years (range 0.8–49). Median decimal BCVA in the better and worse-seeing eye was 0.18 (range 0.05–0.83) and 0.08 (range light perception-0.72), respectively. Spectral-domain optical coherence tomography (SD-OCT) showed cystoid maculopathy in 8 subjects; inner retinal thickening (n = 20), a well-preserved (para)foveal outer retina (n = 7) or severe (para)foveal outer retinal atrophy (n = 14). All retinal layers were discernible in 13/21 patients (62%), with mild to moderate laminar disorganization in the others. Nanophthalmos was observed in 8 patients (36%). Full-field stimulus testing (FST) provided a subjective outcome measure for retinal sensitivity in eyes with (nearly) extinguished ERG amplitudes. Conclusions: Despite the generally severe course of CRB1-RDs, symptom onset and central visual function are variable, even at advanced ages. Phenotypes may vary within the same family. Imaging and functional studies in a prospective longitudinal setting should clarify which endpoints may be most appropriate in a clinical trial

CRB1-Associated Retinal Dystrophies: A Prospective Natural History Study in Anticipation of Future Clinical Trials

PURPOSE: To investigate the natural disease course of retinal dystrophies associated with crumbs cell polarity complex component 1 (CRB1) and identify clinical end points for future clinical trials. DESIGN: Single-center, prospective case series. METHODS: An investigator-initiated nationwide collaborative study that included 22 patients with CRB1-associated retinal dystrophies. Patients underwent ophthalmic assessment at baseline and 2 years after baseline. Clinical examination included best-corrected visual acuity (BCVA) using Early Treatment Diabetic Retinopathy Study charts, Goldmann kinetic perimetry (V4e isopter seeing retinal areas), microperimetry, full-field electroretinography, full-field stimulus threshold (FST), fundus photography, spectral-domain optical coherence tomography, and fundus autofluorescence imaging. RESULTS: Based on genetic, clinical, and electrophysiological data, patients were diagnosed with retinitis pigmentosa (19 [86%]), cone-rod dystrophy (2 [9%]), or isolated macular dystrophy (1 [5%]). Analysis of the entire cohort at 2 years showed no significant changes in BCVA (P = .069) or V4e isopter seeing retinal areas (P = .616), although signs of clinical progression were present in individual patients. Macular sensitivity measured on microperimetry revealed a significant reduction at the 2-year follow-up (P < .001). FST responses were measurable in patients with nonrecordable electroretinograms. On average, FST responses remained stable during follow-up. CONCLUSION: In CRB1-associated retinal dystrophies, visual acuity and visual field measures remain relatively stable over the course of 2 years. Microperimetry showed a significant decrease in retinal sensitivity during follow-up and may be a more sensitive progression marker. Retinal sensitivity on microperimetry may serve as a functional clinical end point in future human treatment trials for CRB1-associated retinal dystrophies