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Expanded clinical spectrum of enhanced S-cone syndrome.

ABSTRACT: New funduscopic findings in patients with enhanced S-cone syndrome (ESCS) may help clinicians in diagnosing this rare autosomal recessive retinal dystrophy.To expand the clinical spectrum of ESCS due to mutations in the NR2E3 gene.Retrospective, noncomparative case series of 31 patients examined between 1983 and 2012.Academic and private ophthalmology practices specialized in retinal dystrophies.A cohort of patients diagnosed with ESCS and harboring known NR2E3 mutations.Patients had ophthalmic examinations including visual function testing that led to the original diagnosis.New fundus features captured with imaging modalities.New clinical observations in ESCS include (1) torpedo-like, deep atrophic lesions with a small hyperpigmented rim, variably sized and predominantly located along the arcades; (2) circumferential fibrotic scars in the posterior pole with a spared center and large fibrotic scars around the optic nerve head; and (3) yellow dots in areas of relatively normal-appearing retina.Enhanced S-cone syndrome has more pleiotropy than previously appreciated. While the nummular type of pigmentation at the level of the retinal pigment epithelium and cystoid or schisis-like maculopathy with typical functional findings remain classic hallmarks of the disease, changes such as circumferential fibrosis of the macula or peripapillary area and "torpedo-like" lesions along the vascular arcades may also direct the clinical diagnosis and focus on screening the NR2E3 gene for a molecular diagnosis.

SUBMITTER: Yzer S

PROVIDER: S-EPMC4405536 | biostudies-literature | 2013 Oct

REPOSITORIES: biostudies-literature

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Expanded clinical spectrum of enhanced S-cone syndrome.

Yzer Suzanne S Barbazetto Irene I Allikmets Rando R van Schooneveld Mary J MJ Bergen Arthur A Tsang Stephen H SH Jacobson Samuel G SG Yannuzzi Lawrence A LA

JAMA ophthalmology 20131001 10

<h4>Importance</h4>New funduscopic findings in patients with enhanced S-cone syndrome (ESCS) may help clinicians in diagnosing this rare autosomal recessive retinal dystrophy.<h4>Objective</h4>To expand the clinical spectrum of ESCS due to mutations in the NR2E3 gene.<h4>Design</h4>Retrospective, noncomparative case series of 31 patients examined between 1983 and 2012.<h4>Setting</h4>Academic and private ophthalmology practices specialized in retinal dystrophies.<h4>Participants</h4>A cohort of ...[more]

PMID: 23989059

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Project description:PurposeTo describe the detailed phenotype, long-term clinical course, clinical variability, and genotype of patients with enhanced S-cone syndrome (ESCS).DesignRetrospective case series.ParticipantsFifty-six patients with ESCS.MethodsClinical history, examination, imaging, and electrophysiologic findings of 56 patients (age range, 1-75 years) diagnosed with ESCS were reviewed. Diagnosis was established by molecular confirmation of disease-causing variants in the NR2E3 gene (n = 38) or by diagnostic full-field electroretinography findings (n = 18).Main outcome measuresAge at onset of visual symptoms, best-corrected visual acuity (BCVA), quantitative age-related electrophysiologic decline, and imaging findings.ResultsMean age at onset of visual symptoms was 4.0 years, and median age at presentation was 20.5 years, with mean follow-up interval being 6.1 years. Six patients were assessed once. Disease-causing variants in NR2E3 were identified in 38 patients. Mean BCVA of the better-seeing eye was 0.32 logarithm of the minimum angle of resolution (logMAR) at baseline and 0.39 logMAR at follow-up. In most eyes (76% [76/100]), BCVA remained stable, with a mean BCVA change of 0.07 logMAR during follow-up. Nyctalopia was the most common initial symptom, reported in 92.9% of patients (52/56). Clinical findings were highly variable and included foveomacular schisis (41.1% [26/56]), yellow-white dots (57.1% [32/56]), nummular pigmentation (85.7% [48/56]), torpedo-like lesions (10.7% [6/56]), and circumferential subretinal fibrosis (7.1% [4/56]). Macular and peripheral patterns of autofluorescence were classified as (1) minimal change, (2) hypoautofluorescent (mild diffuse, moderate speckled, moderate diffuse, or advanced), or (3) hyperautofluorescent flecks. One patient showed undetectable electroretinography findings; quantification of main electroretinography components in all other patients revealed amplitude and peak time variability but with pathognomonic electroretinography features. The main electroretinography components showed evidence of age-related worsening over 6.7 decades, at a rate indistinguishable from that seen in unaffected control participants. Eighteen sequence variants in NR2E3 were identified, including 4 novel missense changes.ConclusionsEnhanced S-cone syndrome has a highly variable phenotype with relative clinical and imaging stability over time. Most electroretinography findings have pathognomonic features, but quantitative assessment reveals variability and a normal mean rate of age-related decline, consistent with largely nonprogressive peripheral retinal dysfunction.

Project description:Enhanced S-cone syndrome (ESCS) is mainly associated with mutations in the NR2E3 gene. However, rare mutations in the NRL gene have been reported in patients with ESCS. We report on an ESCS phenotype in additional patients with autosomal recessive NRL (arNRL) mutations. Three Moroccan patients of two different families with arNRL mutations were enrolled in this study. The mutation in the DNA of one patient, from a consanguineous marriage, was detected by homozygosity mapping. The mutation in the DNA of two siblings from a second family was detected in a targeted next-generation sequencing project. Full ophthalmic examination was performed, including best-corrected visual acuity, slit-lamp biomicroscopy, funduscopy, Goldmann kinetic perimetry, optical coherence tomography, fundus autofluorescence, and extended electroretinography including an amber stimulus on a blue background and a blue stimulus on an amber background. One patient carried a homozygous missense mutation (c.508C>A; p.Arg170Ser) in the NRL gene, whereas the same mutation was identified heterozygously in the two siblings of a second family, in combination with a one base-pair deletion (c.654del; p.Cys219Valfs*4) on the other allele. All patients had reduced visual acuity and showed a typical clumped pigmentary retinal degeneration (CPRD). Foveal schisis-like changes were observed in the oldest patient. An electroretinogram (ERG) under dark-adapted conditions showed absent responses for low stimulus strengths and reduced responses for high stimulus strengths, with constant b-wave latencies despite increasing stimulus strength. A relatively high amplitude was detected with a blue stimulus on an amber background, while an amber stimulus on a blue background showed reduced responses. The arNRL mutations cause a phenotype with typical CPRD. This phenotype has previously been described in patients with ESCS caused by NR2E3 mutations, and rarely by NRL mutations. Based on our findings in ERG testing, we conclude that S-cone function is enhanced in our patients in a similar manner as in patients with NR2E3-associated ESCS, confirming previous reports of NRL as a second gene to cause ESCS.

Project description:The purpose of this study was to evaluate pupillary light reflexes (PLRs) mediated by rod, cone, and intrinsically photosensitive retinal ganglion cell pathways as indices of outer- and inner-retinal function in patients who have enhanced S-cone syndrome (ESCS) due to NR2E3 mutations.Four patients with ESCS (ages 16-23 years) participated in the study. Subjects were tested with long- and short-wavelength single-flash full-field ERG stimuli under light-adapted conditions. They were also tested with an established pupillometry protocol involving 1-s duration, long- and short-wavelength stimuli under dark- and light-adapted conditions. The PLR was measured as a function of stimulus luminance. Transient PLRs were measured under all conditions, and sustained PLRs were measured under the highest luminance dark-adapted condition.Two-color light-adapted full-field ERGs demonstrated larger amplitude responses for short-wavelength stimuli relative to long-wavelength stimuli of the same photopic luminance, with three of four ESCS patients having super-normal a-wave amplitudes to the short-wavelength stimulus. b/a wave ratios were reduced in all four cases. Transient PLRs elicited by low-luminance stimuli under dark-adapted conditions (rod-mediated) were unrecordable, whereas the sustained PLRs elicited by high-luminance stimuli (melanopsin-mediated) were normal. Cone-mediated PLRs were recordable for all four patients, but generally lower than normal in amplitude. However, the cone-mediated PLR was larger for the short-wavelength stimulus compared to the photopically matched long-wavelength stimulus at high luminances, a pattern that was not observed for control subjects. None of the PLR conditions demonstrated "super-normal" responses.ESCS patients appear to have generally well-preserved cone- and melanopsin-mediated PLRs, indicating intact inner-retinal function. Two-color pupillometry demonstrates greater sensitivity to short-wavelength light under higher-luminance conditions and could complement the ERG as a tool for evaluating retinal function in ESCS.

Project description:SCN2A-related disorders secondary to altered function in the voltage-gated sodium channel NaV1.2 are rare with clinically heterogeneous expressions that include epilepsy, autism, and multiple severe to profound impairments and other conditions. To advance understanding of the clinical phenotypes and their relation to channel function, 81 patients (36, 44% female, median age 5.4 years) with 69 unique SCN2A variants were systematically phenotyped and their NaV1.2 channel function systematically assessed. Participants were recruited through the FamileSCN2A Foundation. Primary phenotype (epilepsy of neonatal-onset, N=27; infant onset, N=18; and later onset N=24; and autism without seizures, (N=12) was strongly correlated with a non-seizure severity index (p=0.002), which was based on presence of severe impairments in gross motor, fine motor, communication abilities, gastrostomy tube dependence, and diagnosis of cortical visual impairment and scoliosis. Non-seizure severity was greatest in the neonatal-onset group and least in the autism group (p=0.002). Children with the lowest severity indices were still severely impaired, as reflected by an average Vineland adaptive behavior composite score of 49.5 (>3 SD below the test's norm-referenced mean). Epileptic spasms were significantly more common in infant onset (67%) than in neonatal (22%) or later-onset (29%) epilepsy (p=0.007). Primary phenotype also strongly correlated with variant function (p<0.0001); gain of function and mixed function variants predominated in neonatal-onset epilepsy, shifting to moderate loss of function in infant-onset epilepsy, and severe and complete loss of function in later-onset epilepsy and autism groups. Exploratory cluster analysis identified five groups representing (1) primarily later-onset epilepsy with moderate loss of function variants and low severity indices, (2) mostly infant-onset epilepsy with moderate loss of function variants but higher severity indices, (3) late-onset and autism only with the lowest severity indices (mostly 0) and severe/complete loss of function variants. Two exclusively neonatal clusters were distinguished from each other largely on non-seizure severity scores and secondarily on variant function. The relation between primary phenotype and variant function emphasizes the role of developmental factors in the differential clinical expression of SCN2A variants based on their effects on NaV1.2 channel function. The non-seizure severity of SCN2A disorders depends on a combination of the age at seizure onset (primary phenotype) and variant function. As precision therapies for SCN2A-related disorders advance toward clinical trials, knowledge of the relationship between variant function and clinical disease expression will be valuable for identifying appropriate patients for these trials and in selecting efficient clinical outcomes.

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Expanded clinical spectrum of enhanced S-cone syndrome.

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Expanded clinical spectrum of enhanced S-cone syndrome.

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