Occult retinopathy following treatment of Hepatitis C with glecaprevir/pibrentasvir (Mavyret).

BACKGROUND/PURPOSE: Medication-induced ocular toxicity is an important consideration in the differential diagnosis of unexplained visual disturbance. We present a case of visual disturbance after starting treatment with glecaprevir/pibrentasvir (Mavyret), a therapy for Hepatitis C virus approved by the FDA in 2017. METHODS: A 50-year-old male with no significant ocular history experienced bilateral visual disturbance, including visual field and acuity loss, shortly after initiating treatment with Mavyret for Hepatitis C. Examination of the anterior and posterior segments was unremarkable, and no abnormalities could be identified on multimodal imaging of the eye and brain, including MRI, SD-OCT, and fundus autofluorescence. Extensive testing for inflammatory, infectious, nutritional, and genetic etiologies for optic neuropathy and retinopathy was negative. RESULTS: Electrophysiology testing was pursued to narrow the broad differential diagnosis. Full-field electroretinography and multi-focal electroretinography detected deficiencies in the rod and cone visual pathways and attenuated electrophysiologic responses in the fovea. Pattern electroretinography and visually-evoked potentials demonstrated macula dysfunction. Taken together, electrophysiologic data suggested diffuse retinal dysfunction, which was most pronounced in the macula. CONCLUSIONS: Given the temporal relationship between Mavyret administration and vision loss in our patient, and the absence of an underlying cause after extensive evaluation, we propose that Mavyret may be associated with a toxic occult retinopathy characterized by panretinal dysfunction without clinically apparent structural findings.

Large Internal Limiting Membrane Tears: Prevalence, Clinical Characteristics, and Surgical Utility.

PURPOSE: To describe the prevalence, clinical and imaging characteristics, and surgical utility of large internal limiting membrane (ILM) tears in eyes with epiretinal membrane (ERM). DESIGN: Retrospective interventional case series. METHODS: This was a single-institution study including 71 eyes of 70 consecutive patients that underwent ERM peeling by a single vitreoretinal surgeon between 2016 and 2019. Demographic and clinical data were collected from the medical record. ERMs and large ILM tears were identified and analyzed on multimodal imaging. The main outcome measures were the prevalence and characteristics of large ILM tears in eyes undergoing ERM peeling. RESULTS: Large ILM tears were present in 23 of 71 eyes (32.4%) with ERM that underwent surgical management. A review of patients with ERM during the same period who did not undergo surgical management found large ILM tears in 8 of 100 eyes (8.0%). Large ILM tears were commonly associated with other signs of ERM-induced retinal traction, including retinal nerve fiber layer schisis in 20 of 23 eyes (87.0%), inner retinal dimpling in 8 of 23 eyes (34.8%), and discrete paravascular red lesions in 16 of 19 eyes (84.2%). In all eyes stained with brilliant blue G, the preoperative diagnosis of large ILM tear was confirmed and the scrolled ILM edge was used successfully to initiate ILM peeling. CONCLUSIONS: Large ILM tears are often present in eyes undergoing surgery for ERM and are likely caused by ERM contracture. Careful preoperative identification of these tears is helpful for surgical planning because the scrolled flap of ILM provides a convenient and safe "handle" for initiating membrane peeling.

Two-Color Dark-Adapted Perimetry Implemented With a Commercially Available Perimeter to Characterize Rod-Pathway Sensitivity.

BACKGROUND AND OBJECTIVE: To characterize rod-pathway function across the visual field using 2-color dark-adapted perimetry (2cDAP) implemented with conventional Octopus 900 Pro perimeters. PATIENTS AND METHODS: Eighteen visually normal individuals and two retinitis pigmentosa (RP) patients participated. Thresholds were measured under dark-adapted conditions at 15 locations along the horizontal meridian using short (450 nm) and long (610 nm) wavelength stimuli. Threshold differences between the two wavelengths were used to determine rod- vs cone-mediated function. RESULTS: Among controls, peripheral and perifoveal thresholds for the short-wavelength stimulus were approximately 2 log units lower than for the long-wavelength stimulus. Foveal thresholds for the two wavelengths were similar. RP threshold profiles differed considerably from the controls, with normal foveal thresholds and high peripheral thresholds for both wavelengths. CONCLUSIONS: 2cDAP can be performed with an unmodified Octopus perimeter to evaluate rod function across the visual field and obtain information that is not available with standard automated perimetry. [Ophthalmic Surg Lasers Imaging Retina 2022;53:692-696.].

Spatial and Temporal Integration Abnormalities in X-Linked Retinoschisis.

Purpose: To evaluate spatial and temporal integration across the visual field in individuals with juvenile X-linked retinoschisis (XLRS). Methods: Nine subjects with XLRS and 10 visually normal individuals participated. Luminance thresholds were measured at 15 locations along the horizontal visual field meridian. Locations were grouped into four regions for analysis: foveal, parafoveal (2°), perifoveal (5°-10°), and peripheral (10°-60°). For spatial integration measurements, stimulus duration was 100 ms, and size ranged from 0.01 to 2.32 deg2 (Goldmann I-V). For temporal integration measurements, stimulus size was 0.15 deg2 (Goldmann III), and duration ranged from 12 to 800 ms. The effect of stimulus size and duration on the subjects' threshold was described using integration models. Results: Luminance thresholds for the XLRS group were more elevated for small targets (2.0×-12.6×) than for large targets (1.25×-3.2×) compared to controls for all locations. Likewise, thresholds for the XLRS group were more elevated for short durations (6.3×) than for long durations (4.0×) in the fovea and parafovea but were similarly elevated at all durations (2.0×-2.5×) in the perifovea and periphery. For both the size and duration experiments, thresholds measured in the fovea, parafovea, and perifovea of XLRS subjects were highly similar to those measured from the peripheral field of the controls. Conclusions: Spatial and temporal integration characteristics of the XLRS fovea, parafovea, and perifovea are similar to those of the normal periphery. The results also indicate that scaling stimulus size equates thresholds for the XLRS and control subjects throughout the visual field, but scaling duration does not.

Contrast Sensitivity and Equivalent Intrinsic Noise in X-Linked Retinoschisis.

Purpose: To define relationships among contrast sensitivity (CS), equivalent intrinsic noise (Neq; a measure of noise within the visual pathway), and retinal thickness in X-linked retinoschisis (XLRS). Methods: Nine XLRS and 10 visually-normal subjects participated. CS was measured in the presence and absence of luminance noise. These data were fit with a standard model to estimate Neq and sampling efficiency (an estimate of the ability to use stimulus information). Optical coherence tomography images were obtained to quantify outer nuclear layer (ONL+) and outer segment (OS+) thickness. A linear structure-function model was used to describe the relationship between CS and the product of ONL+ and OS+ thickness. Results: CS in the absence of noise (CS0) for the XLRS subjects ranged from normal to as much as 1.5× below the lower limit of normal. Four of the nine subjects with XLRS had abnormally high Neq, whereas two others had sampling efficiency that was borderline abnormal. Log CS0 for the subjects with XLRS was correlated significantly with log Neq (r = -0.78, P = 0.01), but not with log efficiency (r = 0.19, P = 0.63). CS0 and Neq, but not efficiency, conformed to the linear ONL+ × OS+ structure-function model. Conclusions: The XLRS subjects in this study who had elevated internal noise had abnormally low CS; both internal noise and CS fell within the predicted limits of a structure-function model. Translational Relevance: Internal noise measurements can provide insight into a source of CS loss in some individuals with XLRS.

SEROLOGY NEGATIVE BARTONELLA NEURORETINITIS IN AN IMMUNOCOMPROMISED PATIENT.

BACKGROUND/PURPOSE: To report a case of serology-negative severe disseminated Bartonella neuroretinitis in an immunocompromised patient in which diagnosis was made by detection of B. henselae DNA by universal polymerase chain reaction of brain tissue. METHODS: Case report. RESULTS: A 57-year-old man with immunoglobulin A vasculitis on immunosuppressive therapy presented with lethargy, weight loss, and bilateral decreased vision. Fundus examination revealed bilateral mild vitritis, marked optic disc edema, vascular sheathing, and numerous white inner retinal and preretinal lesions. Brain magnetic resonance imaging revealed multiple foci of restricted diffusion and a ring-enhancing focus in the left parietal lobe. Serologies, cerebrospinal fluid, and vitreous biopsies were all negative for Bartonella. A brain biopsy was performed and B. henselae DNA was detected by universal polymerase chain reaction of the specimen. The patient demonstrated resolution of fundus findings with antibiotic treatment. Repeat serological testing demonstrated seroconversion. CONCLUSION: In immunocompromised patients, infection by Bartonella henselae can present as severe disseminated disease. Establishing the diagnosis can be challenging as serologic testing is often unrevealing in the setting of a blunted immune response. Polymerase chain reaction has been used in select cases to establish the diagnosis.

Cone pathway dysfunction in Jalili syndrome due to a novel familial variant of CNNM4 revealed by pupillometry and electrophysiologic investigations.

PURPOSE: To evaluate retinal function in a family presenting with Jalili syndrome due to a previously unreported variant in CNNM4. METHODS: A family of three sisters with a novel CNNM4 variant, c.482 T > C p.(Leu161Pro), and ten visually normal, age-similar controls participated in this study. The subjects underwent detailed dental examinations and comprehensive ophthalmological examinations that included color vision testing, retinal imaging, and electroretinography. Full-field light- and dark-adapted luminance thresholds were obtained, in addition to light- and dark-adapted measures of the pupillary light reflex (PLR; pupil constriction elicited by a flash of light) across a range of stimulus luminance. RESULTS: Clinical findings of cone dysfunction and amelogenesis imperfecta were observed, consistent with Jalili syndrome. Light-adapted ERGs were non-detectable in CNNM4 subjects, whereas dark-adapted ERGs were generally normal. Full-field luminance thresholds were normal under dark-adapted conditions and were elevated, but measurable, under light-adapted conditions. The CNNM4 subjects had large PLRs under dark-adapted conditions and responses near the lower limit of normal, or slightly subnormal, under light-adapted conditions. CONCLUSION: CNNM4 variants can result in Jalili syndrome with cone dystrophy and generally preserved rod function. The PLR may be a useful measure for evaluating cone function in these individuals, as robust cone-mediated PLRs were recordable despite non-detectable light-adapted ERGs.

Effect of Pharmacological Pupil Dilation on Dark-Adapted Perimetric Sensitivity in Healthy Subjects Using an Octopus 900 Perimeter.

Purpose: To determine whether dilation status has a clinically meaningful effect on sensitivity in normal subjects undergoing two-color dark-adapted perimetry, which can be useful to assess rod function. Methods: A perimeter measured naturally and pharmacologically dilated scotopic sensitivities using a test grid consisting of 16 points across the horizontal meridian ranging from 60° temporal to 45° nasal using cyan (500 nm wavelength) or red (650 nm wavelength) stimuli. The primary outcome was average overall sensitivity based on dilation status, which was compared using a linear mixed effect model for each color stimuli. A difference of 2 dB or more was considered clinically significant. Results: Twenty-nine eyes from 15 subjects (nine female) ages 23 to 63 with no known retinal pathology were included. Pharmacologically dilated eyes were 0.54 dB (95% confidence interval [CI], 0.05 dB to 1.03 dB; P = 0.032) more sensitive to a red stimulus than naturally dilated eyes, but this was not statistically significant after correction for multiple comparisons. Pharmacologically dilated eyes were 0.03 dB (95% CI, -0.20 dB to 0.14 dB; P = 0.734) less sensitive to a cyan stimulus compared to naturally dilated eyes. Conclusions: These findings show no clinically significant differences in sensitivity of scotopic perimetry in eyes without retinal pathology based on dilation status for both cyan and red stimuli. Translational Relevance: In this study, pharmacological dilation did not have a clinically meaningful effect on sensitivity, suggesting that this is not necessary when using two-color dark-adapted perimetry to assess for rod function.

Luminance Thresholds and Their Correlation With Retinal Structure in X-Linked Retinoschisis.

Purpose: To provide a comprehensive analysis of light- and dark-adapted luminance thresholds and their associations with retinal structure in X-linked retinoschisis (XLRS). Methods: Nine subjects with XLRS and 10 visually-normal individuals participated. Threshold was measured at 15 locations along the horizontal meridian of the visual field at several adaptation levels (5 × 10-5 to 50 cd/m2) after dark-adaptation. The relationship between threshold and adaptation level across the field was described using a standard "threshold-versus-illuminance" model. Optical coherence tomography images were obtained and segmented to quantify outer nuclear layer (ONL+) and outer segment (OS+) thickness. A linear structure-function model was used to describe the relationship between threshold and the product of ONL+ and OS+ thickness. Results: For peripheral field measurements, thresholds were generally normal for most subjects with XLRS. All subjects had perifoveal and parafoveal threshold elevations under dark-adapted and high illuminance conditions, with thresholds at moderate illuminances being closer to normal. For foveal measurements, seven of nine subjects with XLRS had normal dark-adapted thresholds, and all had abnormally elevated high illuminance thresholds. Threshold-versus-illuminance curves in the fovea, parafovea, and perifovea were abnormally steep for subjects with XLRS, appearing similar to the normal peripheral field shape. Under both dark- and light-adapted conditions, threshold was predicted by ONL+ × OS+ thickness at nearly all field locations. Conclusions: Threshold elevation in XLRS is complex, depending on both the adaptation level and the visual field location. The pattern of threshold-versus-illuminance suggests that macular function in XLRS is similar to the periphery of controls.

Toxoplasma Retinochoroiditis with Chorioretinal Neovascularization in a Young Patient.

We present a pediatric case to highlight the clinical appearance and management of choroidal neovascularization in the setting of active toxoplasma retinochoroiditis (TRC). A 17-year-old female presented with 2 days of blurry vision in her left eye. Retinal examination demonstrated a pigmented chorioretinal lesion with associated subretinal fluid, vessel sheathing, and adjacent intraretinal hemorrhage. She was diagnosed with active choroidal neovascularization and successful treatment with bevacizumab revealed an underlying active toxoplasmosis lesion. Choroidal neovascularization may rarely present during an acute case of TRC. Dual therapy with anti-vascular endothelial growth factor antibody and anti-parasitic agents leads to improved visual outcomes.

The Diagnostic Conundrum of Retinitis and a Pigmented Scar.

We report a finding of a pigmented chorioretinal scar with acute retinal necrosis (ARN) caused by herpes simplex virus 2 (HSV-2) infection rather than toxoplasma, creating an initial diagnostic dilemma. A 53-year-old functionally monocular male presented with painless floaters and blurry vision in his seeing eye over a period of 4 days. An exam demonstrated anterior chamber (AC) reaction, vitritis, multifocal patches of whitening, and an occlusive retinal vasculitis. A superior pigmented chorioretinal scar with overlying contracted vitreous was noted in the periphery with no adjacent retinal whitening. The patient was treated for both ARN and toxoplasma chorioretinitis until PCR study of the vitreous and AC returned positive for HSV-2 and negative for toxoplasmosis. Management consisted of a dual therapy regimen of both oral and intravitreal antiviral agents as well as oral corticosteroids. The patient's clinical course was complicated by rhegmatogenous retinal detachment within 2 weeks after symptom onset, requiring pars plana vitrectomy with silicone oil and intraoperative intraocular incubation with foscarnet. We review emerging evidence for pigmented chorioretinal scars in ARN specifically caused by HSV-2, as well as diagnostic and treatment dilemmas in the management of ARN and ARN detachments.

Evaluation of the underlying causes of papilledema in children.

OBJECTIVE: The purpose of this retrospective study was to identify the types and relative frequencies of intracranial disorders in pediatric patients who present with papilledema. DESIGN: Retrospective case series. PARTICIPANTS AND METHODS: This study was conducted in 2 pediatric ophthalmology clinics, both providing community-based care in a large inner-city urban center in the U.S. Pediatric patients aged between 0 and 16 years diagnosed with papilledema and who had an underlying etiology identified were included in the study. Patient demographic data, ophthalmologic examination findings, and diagnostic work-up results were identified from clinical records. RESULTS: The mean age of 38 study patients (19 female, 19 male) was 8.6 ± 4.8 years. Of the 38 patients, 16 (42.1%) had idiopathic intracranial hypertension (IIH) as the underlying cause of the papilledema, 7 (18.4%) had a craniosynostosis disorder, 6 (15.8%) had intracranial tumours, 2 (5.3%) had primary hydrocephalus, and 1 (2.6%) patient each had transverse sinus thrombosis related to sinusitis, hypertensive crisis, subdural hematoma, intracranial abscess, Lyme disease, presumed neurosarcoidosis, and acute disseminated encephalomyelitis. Of the 6 intracranial tumours, 2 (33.3%) presented in the sellar/parasellar region, 2 (33.3%) in the posterior fossa, and 2 (33.3%) were in cortical locations. CONCLUSION: Clinicians should have a high index of suspicion for IIH and brain tumours in children presenting with papilledema. Patients with craniosynostosis should have routine eye examinations to monitor for asymptomatic papilledema. Understanding the relative incidence of etiologies for papilledema highlights the urgency of appropriate work-up and the need to consider low-frequency etiologies.

Late detachment of Descemet's membrane after penetrating keratoplasty for pellucid marginal degeneration.

PURPOSE: we report a case of late spontaneous large detachment of Descemet's membrane in recurrent pellucid marginal degeneration after penetrating keratoplasty. OBSERVATIONS: a 73-year-old man presented to clinic with spontaneous detachment of his Descemet's membrane 30 years after penetrating keratoplasty for pellucid marginal degeneration. Efforts were made to bubble the membrane back into place without success. The patient then underwent endothelial keratoplasty with successful restoration of cornea clarity. CONCLUSIONS AND IMPORTANCE: this condition may cause diagnostic and treatment dilemmas if not properly identified and managed. In addition this case has information for both the use of scleral contact lens and the success of endothelial keratoplasty in an extremely steep cornea.

Solitary fibrous tumor of the orbit with growth during pregnancy: a case report.

We report the case of an anterior orbital tumor in a young woman that enlarged during pregnancy. The mass was excised and found to be a spindle cell tumor with immunohistochemical reactivity consistent with a solitary fibrous tumor, a rare entity in the spectrum of fibroblastic mesenchymal tumors. The tumor was strongly positive for the progesterone receptor, consistent with its clinical growth during the antenatal and postnatal periods. To our knowledge, a primary orbital tumor with these characteristics has rarely been reported in the literature.

Primary Baerveldt Shunt Implantation: Outcomes and Complications.

INTRODUCTION: This study is a retrospective case series to evaluate the outcomes and complications of Baerveldt glaucoma implant surgery (BGI) in patients without prior cataract or incisional glaucoma surgery. METHODS: Patients who underwent 350-mm2 BGI through the Glaucoma Service of the University of Illinois at Chicago between 2010 and 2015 were included in this study. Outcome measures included age, sex, ethnicity, operated eye, preoperative diagnosis, preoperative, and sequential postoperative intraocular pressure (IOP), visual acuity, glaucoma medications, and postoperative complication and interventions. Statistical analyses were performed using the two-sided Student t test for continuous variables. RESULTS: Thirty-seven patients were studied. IOP was consistently and statistically significantly lower at 3 months (17.4 ± 6.4, p = 3 × 10-7), 6 months (13.9 ± 5.1, p = 2 × 10-11), 1 year (12.2 ± 4.0, p = 9 × 10-10), and 2 years (14.6 ± 3.3, p = 0.0004) postoperatively compared to IOP at baseline (27.5 ± 8.1). Fewer glaucoma medications were used at 3 months (2.8 ± 1.3, p = 0.04), 6 months (2.6 ± 1.2, p = 0.02), 1 year (2.7 ± 1.7, p = 0.04), and 2 years (2.0 ± 1.2, p = 0.03) postoperatively compared to baseline (3.4 ± 1.1). A total of six cases (16%) had failure. A total of five patients (15%) had postoperative complications. Mean Snellen visual acuity was not statistically different at 6 months (0.5 ± 0.6, p = 0.88) or 1 year (0.4 ± 0.4, p = 0.57) postoperatively from baseline (0.5 ± 0.6). CONCLUSIONS: Primary BGI is effective at reducing IOP and the medication burden in patients suffering glaucomatous optic neuropathy. Further randomized prospective studies are needed to compare various procedures in the primary surgical management of patients with uncontrolled glaucoma. FUNDING: This study was funded by an unrestricted grant from Research to Prevent Blindness.

Dynamics of robust pattern separability in the hippocampal dentate gyrus.

The dentate gyrus (DG) is thought to perform pattern separation on inputs received from the entorhinal cortex, such that the DG forms distinct representations of different input patterns. Neuronal responses, however, are known to be variable, and that variability has the potential to confuse the representations of different inputs, thereby hindering the pattern separation function. This variability can be especially problematic for tissues such as the DG, in which the responses can persist for tens of seconds following stimulation: the long response duration allows for variability from many different sources to accumulate. To understand how the DG can robustly encode different input patterns, we investigated a recently developed in vitro hippocampal DG preparation that generates persistent responses to transient electrical stimulation. For 10-20 s after stimulation, the responses are indicative of the pattern of stimulation that was applied, even though the responses exhibit significant trial-to-trial variability. Analyzing the dynamical trajectories of the evoked responses, we found that, following stimulation, the neural responses follow distinct paths through the space of possible neural activations, with a different path associated with each stimulation pattern. The neural responses' trial-to-trial variability shifts the responses along these paths rather than between them, maintaining the separability of the input patterns. Manipulations that redistributed the variability more isotropically over the space of possible neural activations impeded the pattern separation function. Consequently, we conclude that the confinement of neuronal variability to these one-dimensional paths mitigates the impacts of variability on pattern encoding and, thus, may be an important aspect of the DG's ability to robustly encode input patterns.

Mnemonic representations of transient stimuli and temporal sequences in the rodent hippocampus in vitro.

A primary function of the brain is the storage and retrieval of information. Except for working memory, where extracellular recordings have shown persistent discharges during delay-response tasks, it has been difficult to link memories with changes in individual neurons or specific synaptic connections. We found that transient stimuli are reliably encoded in the ongoing activity of brain tissue in vitro. Patterns of synaptic input onto dentate hilar neurons predicted which of four pathways were stimulated with an accuracy of 76% and performed significantly better than chance for >15 s. Dentate gyrus neurons were also able to accurately encode temporal sequences using population representations that were robust to variation in sequence interval. These results demonstrate direct neural encoding of temporal sequences in the spontaneous activity of brain tissue and suggest a local circuit mechanism that may contribute to diverse forms of short-term memory.

Optogenetic control of motor coordination by Gi/o protein-coupled vertebrate rhodopsin in cerebellar Purkinje cells.

G protein-coupled receptors are involved in the modulation of complex neuronal networks in the brain. To investigate the impact of a cell-specific G(i/o) protein-mediated signaling pathway on brain function, we created a new optogenetic mouse model in which the G(i/o) protein-coupled receptor vertebrate rhodopsin can be cell-specifically expressed with the aid of Cre recombinase. Here we use this mouse model to study the functional impact of G(i/o) modulation in cerebellar Purkinje cells (PCs). We show that in vivo light activation of vertebrate rhodopsin specifically expressed in PCs reduces simple spike firing that is comparable with the reduction in firing observed for the activation of cerebellar G(i/o)-coupled GABA(B) receptors. Notably, the light exposure of the cerebellar vermis in freely moving mice changes the motor behavior. Thus, our studies directly demonstrate that spike modulation via G(i/o)-mediated signaling in cerebellar PCs affects motor coordination and show a new promising approach for studying the physiological function of G protein-coupled receptor-mediated signaling in a cell type-specific manner.

Delayed postnatal loss of P/Q-type calcium channels recapitulates the absence epilepsy, dyskinesia, and ataxia phenotypes of genomic Cacna1a mutations.

Inherited loss of P/Q-type calcium channel function causes human absence epilepsy, episodic dyskinesia, and ataxia, but the molecular "birthdate" of the neurological syndrome and its dependence on prenatal pathophysiology is unknown. Since these channels mediate transmitter release at synapses throughout the brain and are expressed early in embryonic development, delineating the critical circuitry and onset underlying each of the emergent phenotypes requires targeted control of gene expression. To visualize P/Q-type Ca(2+) channels and dissect their role in neuronal networks at distinct developmental stages, we created a novel conditional Cacna1a knock-in mouse by inserting the floxed green fluorescent protein derivative Citrine into the first exon of Cacna1a and then crossed it with a postnatally expressing PCP2-Cre line for delayed Purkinje cell (PC) gene deletion within the cerebellum and sparsely in forebrain (purky). PCs in purky mice lacked P/Q-type calcium channel protein and currents within the first month after birth, displayed altered spontaneous firing, and showed impaired neurotransmission. Unexpectedly, adult purky mice exhibited the full spectrum of neurological deficits seen in mice with genomic Cacna1a ablation. Our results show that the ataxia, dyskinesia, and absence epilepsy caused by inherited disorders of the P/Q-type channel arise from signaling defects beginning in late infancy, revealing an early window of opportunity for therapeutic intervention.