Visual experience shapes the Bouba-Kiki effect and the size-weight illusion upon sight restoration from congenital blindness.

The Bouba-Kiki effect is the systematic mapping between round/spiky shapes and speech sounds ("Bouba"/"Kiki"). In the size-weight illusion, participants judge the smaller of two equally-weighted objects as being heavier. Here we investigated the contribution of visual experience to the development of these phenomena. We compared three groups: early blind individuals (no visual experience), individuals treated for congenital cataracts years after birth (late visual experience), and typically sighted controls (visual experience from birth). We found that, in cataract-treated participants (tested visually/visuo-haptically), both phenomena are absent shortly after sight onset, just like in blind individuals (tested haptically). However, they emerge within months following surgery, becoming statistically indistinguishable from the sighted controls. This suggests a pivotal role of visual experience and refutes the existence of an early sensitive period: A short period of experience, even when gained only years after birth, is sufficient for participants to visually pick-up regularities in the environment, contributing to the development of these phenomena.

Grasping behavior does not recover after sight restoration from congenital blindness.

We investigated whether early visual input is essential for establishing the ability to use predictions in the control of actions and for perception. To successfully interact with objects, it is necessary to pre-program bodily actions such as grasping movements (feedforward control). Feedforward control requires a model for making predictions, which is typically shaped by previous sensory experience and interaction with the environment.1 Vision is the most crucial sense for establishing such predictions.2,3 We typically rely on visual estimations of the to-be-grasped object's size and weight in order to scale grip force and hand aperture accordingly.4,5,6 Size-weight expectations play a role also for perception, as evident in the size-weight illusion (SWI), in which the smaller of two equal-weight objects is misjudged to be heavier.7,8 Here, we investigated predictions for action and perception by testing the development of feedforward controlled grasping and of the SWI in young individuals surgically treated for congenital cataracts several years after birth. Surprisingly, what typically developing individuals do easily within the first years of life, namely to adeptly grasp new objects based on visually predicted properties, cataract-treated individuals did not learn after years of visual experience. Contrary, the SWI exhibited significant development. Even though the two tasks differ in substantial ways, these results may suggest a potential dissociation in using visual experience to make predictions about an object's features for perception or action. What seems a very simple task-picking up small objects-is in truth a highly complex computation that necessitates early structured visual input to develop.

The development of oscillatory and aperiodic resting state activity is linked to a sensitive period in humans.

Congenital blindness leads to profound changes in electroencephalographic (EEG) resting state activity. A well-known consequence of congenital blindness in humans is the reduction of alpha activity which seems to go together with increased gamma activity during rest. These results have been interpreted as indicating a higher excitatory/inhibitory (E/I) ratio in visual cortex compared to normally sighted controls. Yet it is unknown whether the spectral profile of EEG during rest would recover if sight were restored. To test this question, the present study evaluated periodic and aperiodic components of the EEG resting state power spectrum. Previous research has linked the aperiodic components, which exhibit a power-law distribution and are operationalized as a linear fit of the spectrum in log-log space, to cortical E/I ratio. Moreover, by correcting for the aperiodic components from the power spectrum, a more valid estimate of the periodic activity is possible. Here we analyzed resting state EEG activity from two studies involving (1) 27 permanently congenitally blind adults (CB) and 27 age-matched normally sighted controls (MCB); (2) 38 individuals with reversed blindness due to bilateral, dense, congenital cataracts (CC) and 77 age-matched sighted controls (MCC). Based on a data driven approach, aperiodic components of the spectra were extracted for the low frequency (Lf-Slope 1.5 to 19.5 Hz) and high frequency (Hf-Slope 20 to 45 Hz) range. The Lf-Slope of the aperiodic component was significantly steeper (more negative slope), and the Hf-Slope of the aperiodic component was significantly flatter (less negative slope) in CB and CC participants compared to the typically sighted controls. Alpha power was significantly reduced, and gamma power was higher in the CB and the CC groups. These results suggest a sensitive period for the typical development of the spectral profile during rest and thus likely an irreversible change in the E/I ratio in visual cortex due to congenital blindness. We speculate that these changes are a consequence of impaired inhibitory circuits and imbalanced feedforward and feedback processing in early visual areas of individuals with a history of congenital blindness.

A tactile pain evaluation scale for persons with visual deficiencies.

OBJECTIVE: Pain evaluation scales often rely on the sense of sight. There is so far no pain assessment scale designed specifically for persons with visual impairment. DESIGN: This study aims to validate a tactile pain evaluation scale, Visiodol (Copyright Prof Pickering), in blind or visually impaired persons, by correlation with a numeric pain scale. SETTING: The study took place at University Hospital Clermont-Ferrand, France. METHODS: Pain intensity for a range of thermal stimuli (Pathway Medoc) was evaluated with Visiodol and a numeric pain scale. Secondary outcomes, including pain thresholds, catastrophizing, emotion, and quality of life, were compared in persons who were blind or visually impaired and in sighted persons. Lin's concordance correlation coefficient was estimated. Weighted Cohen's κ accounted for degrees of disagreement between scales with 95% confidence intervals (95% CI). SUBJECTS: Sixteen healthy sighted and 21 healthy nonsighted volunteers (n = 13 congenital, n = 8 acquired) were included. RESULTS: Lin's correlation coefficient for repeated data was 0.967 (95% CI, 0.956-0.978; P < 0.001) for visually impaired participants, with a good agreement at each temperature plateau. A weighted Cohen's κ of 0.90 (95% CI, 0.84-0.92) and 92.9% percentage of agreement for visually impaired participants were satisfactory. Pain perception, psychological components, and quality of life were more impaired in persons who were blind or visually impaired than in sighted persons. CONCLUSIONS: This study validates Visiodol, a tactile scale for persons who are blind or visually impaired, and addresses health care inequalities in the context of pain evaluation. Visiodol will now be tested in a larger population of patients to give the millions of persons worldwide who are blind or visually impaired an option for pain intensity evaluation in clinical situations. TRIAL REGISTRATION: French National Agency for the Safety of Medicines and Healthcare Products (2018-A03370-55) and www.ClinicalTrials.gov (NCT03968991).

Narrativas de mães de crianças cegas congênitas sobre itinerários terapêuticos, arranjos de cuidados e experiências maternas: uma pesquisa no Instituto Benjamin Constant / Narratives of mothers of congenitally blind children on therapeutic pathways, care arrangements and maternal experiences: a study at the Benjamin Constant Institute

O objetivo da tese é analisar as narrativas de oito mães de crianças cegas congênitas, matriculadas no Instituto Benjamin Constant. O estudo abrange itinerários terapêuticos, arranjos de cuidados e experiências maternas. Utilizaram-se os postulados teóricos sobre narrativas de Ricoeur e a análise foi feita sob o marco teórico de Bardin. Optou-se pelo itinerário terapêutico como método de pesquisa, por valorizar as histórias de vidas das mães que participaram da pesquisa. A narrativa reforçou a utilização de metodologias participativas e inclusivas, baseadas no respeito, na solidariedade e na cooperação. As narrativas mostraram que as mães, após o primeiro itinerário, que é na maternidade, encontram na figura do médico pediatra o auxílio que as orienta sobre quais os itinerários a percorrer. Em seguida, elas procuram o oftalmologista, mais especificamente o retinólogo e, também, o neuropediatra. A chegada ao IBC acontece depois da confirmação derradeira da cegueira do filho. As mães das crianças e adolescentes matriculados no IBC permanecem no espaço do Instituto, diariamente, enquanto seus filhos estão em aula ou em algum atendimento. Essa permanência se justifica por razão da distância entre o IBC e suas casas. A espera permite compartilharem, com outras mães, situações vivenciadas para o fortalecimento de vínculos de afetos, mas também existem tensões. O estudo apontou, ainda, que o discurso iatrogênico, com palavras ou ações de alguns médicos, causou ansiedade, desconfiança, confusão e sentimento de desrespeito. Outro dado relevante, encontrado por meio das narrativas, foi a dificuldade que encontraram ao transitarem nos espaços públicos com seus filhos, por causa de barreiras atitudinais. Ainda segundo as narrativas, o cuidado que elas dispensam quase que integralmente aos seus filhos (as), apesar de toda a sobrecarga que relatam, não é considerado um trabalho, pelo fato de não ser remunerado. As mães entendem que a tarefa de cuidar é um ato de amor para com o filho e, não, um trabalho. Por fim, a pesquisa também investigou os impactos que a pandemia de COVID 19 ocasionou nas vidas das mães e de seus filhos, surgindo como principais desafios o afastamento do espaço da escola e o manejo das aulas on-line. (AU)

The objective of the thesis is to study the narratives of eight mothers of congenitally blind children enrolled at the Benjamin Constant Institute. The study covers therapeutic journeys, care arrangements, and maternal experiences. Theoretical postulates on narratives by Ricoeur were utilized, and the analysis was conducted within the theoretical framework of Bardin. The therapeutic journey was chosen as the research method, as it values the life stories of the participating mothers. The narrative reinforced the use of participatory and inclusive methodologies based on respect, solidarity, and cooperation. The narratives showed that mothers, after the initial journey in maternity, seek guidance from pediatricians on the paths to take. They then consult ophthalmologists, specifically retinologists, and neuropediatricians. Arrival at the IBC occurs after the final confirmation of the child's blindness. Mothers of children and adolescents enrolled at the IBC stay at the Institute daily while their children are in class or receiving some form of assistance. This stay is due to the distance between the IBC and their homes. Waiting allows them to share experiences with other mothers, strengthening emotional bonds, but tensions also exist. The study also pointed out that iatrogenic discourse, with words or actions from some doctors, caused anxiety, mistrust, confusion, and feelings of disrespect. Another significant finding from the narratives was the difficulty they encountered when navigating public spaces with their children due to attitudinal barriers. According to the narratives, the care they provide to their children, despite the reported burden, is not considered work because it is unpaid. Mothers view caregiving as an act of love for their children, not as a job. Finally, the research also investigated the impacts of the COVID-19 pandemic on the lives of the mothers and their children, with the main challenges being the separation from the school environment and the management of online classes. (AU)

Intelligibility of speech produced by sighted and blind adults.

PURPOSE: It is well known that speech uses both the auditory and visual modalities to convey information. In cases of congenital sensory deprivation, the feedback language learners have access to for mapping visible and invisible orofacial articulation is impoverished. Although the effects of blindness on the movements of the lips, jaw, and tongue have been documented in francophone adults, not much is known about their consequences for speech intelligibility. The objective of this study is to investigate the effects of congenital visual deprivation on vowel intelligibility in adult speakers of Canadian French. METHOD: Twenty adult listeners performed two perceptual identification tasks in which vowels produced by congenitally blind adults and sighted adults were used as stimuli. The vowels were presented in the auditory, visual, and audiovisual modalities (experiment 1) and at different signal-to-noise ratios in the audiovisual modality (experiment 2). Correct identification scores were calculated. Sequential information analyses were also conducted to assess the amount of information transmitted to the listeners along the three vowel features of height, place of articulation, and rounding. RESULTS: The results showed that, although blind speakers did not differ from their sighted peers in the auditory modality, they had lower scores in the audiovisual and visual modalities. Some vowels produced by blind speakers are also less robust in noise than those produced by sighted speakers. CONCLUSION: Together, the results suggest that adult blind speakers have learned to adapt to their sensory loss so that they can successfully achieve intelligible vowel targets in non-noisy conditions but that they produce less intelligible speech in noisy conditions. Thus, the trade-off between visible (lips) and invisible (tongue) articulatory cues observed between vowels produced by blind and sighted speakers is not equivalent in terms of perceptual efficiency.

Long-Term Anatomic and Visual Outcomes of Planned Preterm Delivery and Treatment of Norrie Disease.

We previously reported that planned preterm delivery at 34 weeks gestational age provided an opportunity to treat Norrie disease in the vasoproliferative phase, prevented infantile retinal detachment, and preserved functional vision without further treatment after infancy. Although retinal vascularization did not proceed postnatally, after 8 years of follow-up, the retinas remained attached, and rudimentary foveal development was observed by optical coherence tomography. Best corrected visual acuity gradually improved to 20/80 with both eyes, and visual fields and real-world visual performance were remarkably functional. Global development progressed appropriately, and no long-term sequelae of premature delivery were observed. [Ophthalmic Surg Lasers Imaging Retina 2022;53:464-467.].

A Survey of Multigenic Protein-Altering Variant Frequency in Familial Exudative Vitreo-Retinopathy (FEVR) Patients by Targeted Sequencing of Seven FEVR-Linked Genes.

While Inherited Retinal Diseases (IRDs) are typically considered rare diseases, Familial Exudative Vitreo-Retinopathy (FEVR) and Norrie Disease (ND) are more rare than retinitis pigmentosa. We wanted to determine if multigenic protein-altering variants are common in FEVR subjects within a set of FEVR-related genes. The potential occurrence of protein-altering variants in two different genes has been documented in a very small percentage of patients, but potential multigenic contributions to FEVR remain unclear. Genes involved in these orphan pediatric retinal diseases are not universally included in available IRD targeted-sequencing panels, and cost is also a factor limiting multigenic-sequence-based testing for these rare conditions. To provide an accurate solution at lower cost, we developed a targeted-sequencing protocol that includes seven genes involved in Familial Exudative Vitreo-Retinopathy (FEVR) and Norrie disease. Seventy-six DNA samples from persons refered to clinic with possible FEVR and some close relatives were sequenced using a novel Oakland-ERI orphan pediatric retinal disease panel (version 2) providing 900 times average read coverage. The seven genes involved in FEVR/ND were: NDP (ChrX), CTNNB1 (Chr3); TSPAN12 (Chr7); KIF11 (Chr10), FZD4 (Chr11), LRP5 (Chr11), ZNF408 (Chr11). A total of 33 variants were found that alter protein sequence, with the following relative distribution: LRP5 13/33 (40%), FZD4 9/33 (27%), ZNF408 6/33 (18%), (KIF11 3/33 (9%), NDP 1/33 (3%), CTNNB1 1/33 (3%). Most protein-altering variants, 85%, were found in three genes: FZD4, LRP5, and ZNF408. Four previously known pathogenic variants were detected in five families and two unrelated individuals. Two novel, likely pathogenic variants were detected in one family (FZD4: Cys450ter), and a likely pathogenic frame shift termination variant was detected in one unrelated individual (LRP5: Ala919CysfsTer67). The average number of genes with protein-altering variants was greater in subjects with confirmed FEVR (1.46, n = 30) compared to subjects confirmed unaffected by FEVR (0.95, n = 20), (p = 0.009). Thirty-four percent of persons sequenced had digenic and trigenic protein-altering variants within this set of FEVR genes, which was much greater than expected in the general population (3.6%), as derived from GnomAD data. While the potential contributions to FEVR are not known for most of the variants in a multigenic context, the high multigenic frequency suggests that potential multigenic contributions to FEVR severity warrant future investigation. The targeted-sequencing format developed will support such exploration by reducing the testing cost to $250 (US) for seven genes and facilitating greater access to genetic testing for families with this very rare inherited retinal disease.

The timing of auditory sensory deficits in Norrie disease has implications for therapeutic intervention.

Norrie disease is caused by mutation of the NDP gene, presenting as congenital blindness followed by later onset of hearing loss. Protecting patients from hearing loss is critical for maintaining their quality of life. This study aimed to understand the onset of pathology in cochlear structure and function. By investigating patients and juvenile Ndp-mutant mice, we elucidated the sequence of onset of physiological changes (in auditory brainstem responses, distortion product otoacoustic emissions, endocochlear potential, blood-labyrinth barrier integrity) and determined the cellular, histological, and ultrastructural events leading to hearing loss. We found that cochlear vascular pathology occurs earlier than previously reported and precedes sensorineural hearing loss. The work defines a disease mechanism whereby early malformation of the cochlear microvasculature precedes loss of vessel integrity and decline of endocochlear potential, leading to hearing loss and hair cell death while sparing spiral ganglion cells. This provides essential information on events defining the optimal therapeutic window and indicates that early intervention is needed. In an era of advancing gene therapy and small-molecule technologies, this study establishes Ndp-mutant mice as a platform to test such interventions and has important implications for understanding the progression of hearing loss in Norrie disease.

Superior verbal but not nonverbal memory in congenital blindness.

Previous studies suggest that people who are congenitally blind outperform sighted people on some memory tasks. Whether blindness-associated memory advantages are specific to verbal materials or are also observed with nonverbal sounds has not been determined. Congenitally blind individuals (n = 20) and age and education matched blindfolded sighted controls (n = 22) performed a series of auditory memory tasks. These included: verbal forward and backward letter spans, a complex letter span with intervening equations, as well as two matched recognition tasks: one with verbal stimuli (i.e., letters) and one with nonverbal complex meaningless sounds. Replicating previously observed findings, blind participants outperformed sighted people on forward and backward letter span tasks. Blind participants also recalled more letters on the complex letter span task despite the interference of intervening equations. Critically, the same blind participants showed larger advantages on the verbal as compared to the nonverbal recognition task. These results suggest that blindness selectively enhances memory for verbal material. Possible explanations for blindness-related verbal memory advantages include blindness-induced memory practice and 'visual' cortex recruitment for verbal processing.

A novel frameshift c.22_25dupGCAT mutation of the NDP gene in a Chinese infant with Norrie disease: A case report.

RATIONALE: Norrie disease (ND) is a rare X-linked recessive disease characterized by bilateral congenital blindness and auditory impairments. According to the previous studies, Norrin cystine knot growth factor (NDP) gene have been found to be responsible for ND. Herein, we report a case of ND with a novel mutation in NDP and elucidate the clinical and molecular characteristics of this patient. PATIENT CONCERNS: A 2-month-old Chinese male infant presented with gray-white opacification in the bilateral cornea. Vitreous opacity and retinal detachment were observed on ocular ultrasound. Furthermore, a novel de novo hemizygous mutation (c.22_25dupGCAT, p.S9Cfs∗18) in exon 2 of the NDP gene was identified by next-generation sequencing. SWISS-MODEL predicted that the c.22_25dupGCAT mutation truncated the NDP protein. DIAGNOSIS: Based on the above clinical and genetic evidence, this patient was eventually diagnosed with ND. INTERVENTIONS: Currently, no clinical therapy is available for ND. OUTCOMES: In addition to the typical ocular symptoms, no other abnormalities were observed. The patient's vital signs remained stable and normal. LESSON: A novel causative mutation of NDP was identified using next-generation sequencing. Our report expands the pathogenic mutation spectrum of NDP and facilitates genetic counseling and prenatal diagnosis. Additionally, we emphasize the importance of molecular genetic testing in the diagnosis of ND.

Da disfagia à restrição alimentar: efeitos das dificuldades de adaptação parental à filha com cegueira congênita / From dysphagia to food restriction: effects of parental adaptation to the daughter with congenital blindness / De la disfagia a la restricción alimentaria: efectos de las dificultades de adaptación de los padres a la hija con ceguera congénita

Introdução: O nascimento de um filho com deficiência pode alterar rotinas e influenciar no processo de adaptação dos pais, por se caracterizar como um acontecimento não esperado. Ainda pode produzir nos progenitores sentimentos semelhantes aos vivenciados em um processo de luto. Objetivo: Analisar a relação entre a adaptação parental à filha com cegueira congênita e disfagia, relacionadas à prematuridade extrema, e seu possível impacto no processo de adesão às orientações terapêuticas sobre a alimentação da criança. Método: Trata-se de um estudo de caso de cunho qualitativo. Foi realizada uma análise da adaptação parental à deficiência, e avaliações fonoaudiológicas da linguagem e da disfagia. Resultados: A avaliação fonoaudiológica evidenciou disfagia para líquidos finos e ausência de alterações de linguagem. A restrição alimentar tornou-se evidente a partir da dificuldade parental em aceitar e seguir as orientações quanto à consistência alimentar. A análise dos dados de adaptação parental à deficiência da filha sugere que essa dificuldade esteve relacionada à aceitação da cegueira e da disfagia. A emergência de restrição alimentar esteve relacionada às dificuldades na aceitação das orientações fonoaudiológicas por parte dos pais, considerando a disfagia para líquidos finos. Essas dificuldades encontram um correlato na análise da adaptação parental do pai e da mãe. Conclusão: Evidencia-se a importância do acompanhamento por uma equipe interdisciplinar.

Introduction: The birth of a child with a disability can change routines and influence the parents' adaptation process, as it is characterized as an unexpected event. It can still produce similar feelings in parents as those experienced in a grieving process. Objective: To analyze the relationship between parental adaptation to the daughter with congenital blindness and dysphagia, related to extreme prematurity, and its possible impact on the process of adherence to therapeutic guidelines on child nutrition. Method: This is a qualitative case study. An analysis of parental adaptation to disability as well as language therapy assessments of language and dysphagia were performed. Results: The speech therapy evaluation showed dysphagia for fine liquids and absence of language disorders. Dietary restriction became evident from the parental difficulty in accepting and following the guidelines regarding food consistency. The analysis of the parental adaptation data to the daughter's disability suggests that this difficulty was related to the acceptance of blindness and dysphagia. The emergence of food restriction was related to the difficulties in parents' acceptance of speech therapy guidelines, considering dysphagia for thin liquids. These difficulties find a correlate in the analysis of the father and mother's parental adaptation. Conclusion: The importance of monitoring by an interdisciplinary team is evident.

Introducción: El nacimiento de un niño con discapacidad puede cambiar las rutinas y estilos de vida de los padres, ya que se caracteriza por ser un evento inesperado. Todavía puede producir sentimientos similares en los padres a los que experimentaron en un proceso de duelo. Objetivo: Analizar la relación entre la adaptación de los padres a la hija con ceguera congénita y disfagia, relacionada con la prematuridad extrema, y ​​su posible impacto en el proceso de adherencia a las guías terapéuticas en nutrición infantil. Método: Este es un estudio de caso cualitativo. Se realizó un análisis de la adaptación de los padres a la discapacidad y la evaluación del habla y el lenguaje de la disfagia. Resultados: La evaluación de logopedia mostró disfagia por líquidos finos y ausencia de trastornos del lenguaje. La restricción dietética se hizo evidente por la dificultad de los padres para aceptar y seguir las pautas con respecto a la consistencia de los alimentos. El análisis de los datos de adaptación de los padres a la discapacidad de la hija sugiere que esta dificultad estaba relacionada con la aceptación de la ceguera y la disfagia. La aparición de la restricción alimentaria se relacionó con las dificultades en la aceptación por parte de los padres de las pautas de logopedia, considerando la disfagia por líquidos diluidos. Estas dificultades encuentran correlación en el análisis de la adaptación parental del padre y la madre. Conclusión: Es evidente la importancia del seguimiento por parte de un equipo interdisciplinario.

The effect of congenital blindness on resting-state functional connectivity revisited.

Lower resting-state functional connectivity (RSFC) between 'visual' and non-'visual' neural circuits has been reported as a hallmark of congenital blindness. In sighted individuals, RSFC between visual and non-visual brain regions has been shown to increase during rest with eyes closed relative to rest with eyes open. To determine the role of visual experience on the modulation of RSFC by resting state condition-as well as to evaluate the effect of resting state condition on group differences in RSFC-, we compared RSFC between visual and somatosensory/auditory regions in congenitally blind individuals (n = 9) and sighted participants (n = 9) during eyes open and eyes closed conditions. In the sighted group, we replicated the increase of RSFC between visual and non-visual areas during rest with eyes closed relative to rest with eyes open. This was not the case in the congenitally blind group, resulting in a lower RSFC between 'visual' and non-'visual' circuits relative to sighted controls only in the eyes closed condition. These results indicate that visual experience is necessary for the modulation of RSFC by resting state condition and highlight the importance of considering whether sighted controls should be tested with eyes open or closed in studies of functional brain reorganization as a consequence of blindness.

Retinoschisis and Norrie disease: a missing link.

OBJECTIVE: Retinoschisis and Norrie disease are X-linked recessive retinal disorders caused by mutations in RS1 and NDP genes respectively. Both are likely to be monogenic and no locus heterogeneity has been reported. However, there are reports showing overlapping features of Norrie disease and retinoschisis in a NDP knock-out mouse model and also the involvement of both the genes in retinoschisis patients. Yet, the exact molecular relationships between the two disorders have still not been understood. The study investigated the association between retinoschisin (RS1) and norrin (NDP) using in vitro and in silico approaches. Specific protein-protein interaction between RS1 and NDP was analyzed in human retina by co-immunoprecipitation assay and MALDI-TOF mass spectrometry. STRING database was used to explore the functional relationship. RESULT: Co-immunoprecipitation demonstrated lack of a direct interaction between RS1 and NDP and was further substantiated by mass spectrometry. However, STRING revealed a potential indirect functional association between the two proteins. Progressively, our analyses indicate that FZD4 protein interactome via PLIN2 as well as the MAP kinase signaling pathway to be a likely link bridging the functional relationship between retinoschisis and Norrie disease.

Identification of a variant in NDP associated with X-linked retinal dysplasia in the English cocker spaniel dog.

PURPOSE: Three related male English Cocker Spaniels (ECS) were reported to be congenitally blind. Examination of one of these revealed complete retinal detachment. A presumptive diagnosis of retinal dysplasia (RD) was provided and pedigree analysis was suggestive of an X-linked mode of inheritance. We sought to investigate the genetic basis of RD in this family of ECS. METHODS: Following whole genome sequencing (WGS) of the one remaining male RD-affected ECS, two distinct investigative approaches were employed: a candidate gene approach and a whole genome approach. In the candidate gene approach, COL9A2, COL9A3, NHEJ1, RS1 and NDP genes were investigated based on their known associations with RD and retinal detachment in dogs and humans. In the whole genome approach, affected WGS was compared with 814 unaffected canids to identify candidate variants, which were filtered based on appropriate segregation and predicted pathogenic effects followed by subsequent investigation of gene function. Candidate variants were tested for appropriate segregation in the ECS family and association with disease was assessed using samples from a total of 180 ECS. RESULTS: The same variant in NDP (c.653_654insC, p.Met114Hisfs*16) that was predicted to result in 15 aberrant amino acids before a premature stop in norrin protein, was identified independently by both approaches and was shown to segregate appropriately within the ECS family. Association of this variant with X-linked RD was significant (P = 0.0056). CONCLUSIONS: For the first time, we report a variant associated with canine X-linked RD. NDP variants are already known to cause X-linked RD, along with other abnormalities, in human Norrie disease. Thus, the dog may serve as a useful large animal model for research.

'Visual' cortices of congenitally blind adults are sensitive to response selection demands in a go/no-go task.

Studies of occipital cortex plasticity in blindness provide insight into how intrinsic constraints interact with experience to determine cortical specialization. We tested the cognitive nature and anatomical origins of occipital responses during non-verbal, non-spatial auditory tasks. In a go/no-go task, congenitally blind (N=23) and sighted (N=24) individuals heard rapidly occurring (<1/s) non-verbal sounds and made one of two button presses (frequent-go 50%, infrequent-go 25%) or withheld a response (no-go, 25%). Rapid and frequent button presses heighten response selection/inhibition demands on the no-go trials: In sighted and blind adults a right-lateralized prefrontal (PFC) network responded most to no-go trials, followed by infrequent-go and finally frequent-go trials. In the blind group only, a right-lateralized occipital network showed the same response profile and the laterality of occipital and PFC responses was correlated across blind individuals. A second experiment with spoken sentences and equations (N=16) found that no-go responses in occipital cortex are distinct from previously identified occipital responses to spoken language. Finally, in resting-state data (N=30 blind, N=31 blindfolded sighted), no-go responsive 'visual' cortex of blind relative to sighted participants was more synchronized with PFC and less synchronized with primary auditory and sensory-motor cortices. No-go responsive occipital cortex showed higher resting-state correlations with no-go responsive PFC than language responsive inferior frontal cortex. We conclude that in blindness, a right-lateralized occipital network responds to non-verbal executive processes, including response selection. These results suggest that connectivity with fronto-parietal executive networks is a key mechanism for plasticity in blindness.

Norrie disease with a spontaneously shrinking choroid plexus abnormality: a case report.

Background: Norrie disease is a genetic disorder of the retina characterized by impaired retinal vascular development leading to retinal detachment and blindness. Non-retinal manifestations of the disorder include intellectual disability and seizure disorders. However, to date, no association with neurological mass lesions has been described.Materials and methods: Case reporResults: Here, we report a case of a patient with Norrie disease who presented with an enhancing mass of the choroid plexus that spontaneously diminished in size. Conclusion: This report suggests watchful waiting as a reasonable clinical approach to choroid plexus lesions in patients with Norrie disease.

Novel Norrie disease gene mutations in Chinese patients with familial exudative vitreoretinopathy.

PURPOSE: This study aims to analyze the Norrie disease gene (NDP) variants in patients with familial exudative vitreoretinopathy (FEVR) and their clinical features. METHODS: Thirty-three Chinese patients (22 familial and 11 simplex) who were diagnosed as FEVR underwent detailed ocular examinations in Beijing Tongren Hospital. Peripheral venous blood was drawn from the patients and their family members for the extraction of genomic DNA. All exons of NDP gene were analyzed by direct sequencing of PCR-amplified DNA fragments. RESULTS: Four novel mutations in NDP gene were identified in four X-linked FEVR families: a C → T transversion, c. 625C → T, in exon 3, resulting in a serine-to-proline change in codon 73 (S73P); a C → G transition, c. 751C → G, in exon 3, resulting in an arginine-to-glycine change in codon 115 (R115G); a T → C transversion of nucleotide 331 at 5'UTR in exon 2 (c.331 T → C); and a C → T transversion of the nucleotide 5 in intron 1 (IVS1 + 5C → T). The mutations were not present in the control group (n = 100). CONCLUSIONS: Our results extend the spectrum of NDP gene mutations. The mutations in the non-coding region of NDP may play a crucial role in the pathogenesis of FEVR.