Clinical and genetic investigation of a large Tunisian family with complete achromatopsia: identification of a new nonsense mutation in GNAT2 gene.

Complete achromatopsia is a rare autosomal recessive disease associated with CNGA3, CNGB3, GNAT2 and PDE6C mutations. This retinal disorder is characterized by complete loss of color discrimination due to the absence or alteration of the cones function. The purpose of the present study was the clinical and the genetic characterization of achromatopsia in a large consanguineous Tunisian family. Ophthalmic evaluation included a full clinical examination, color vision testing and electroretinography. Linkage analysis using microsatellite markers flanking CNGA3, CNGB3, GNAT2 and PDE6C genes was performed. Mutations were screened by direct sequencing. A total of 12 individuals were diagnosed with congenital complete achromatopsia. They are members of six nuclear consanguineous families belonging to the same large consanguineous family. Linkage analysis revealed linkage to GNAT2. Mutational screening of GNAT2 revealed three intronic variations c.119-69G>C, c.161+66A>T and c.875-31G>C that co-segregated with a novel mutation p.R313X. An identical GNAT2 haplotype segregating with this mutation was identified, indicating a founder mutation. All patients were homozygous for the p.R313X mutation. This is the first report of the clinical and genetic investigation of complete achromatopsia in North Africa and the largest family with recessive achromatopsia involving GNAT2; thus, providing a unique opportunity for genotype-phenotype correlation for this extremely rare condition.

Autofluorescence Findings Of A Novel Maculopathy In Patient With Spinocerebellar Ataxia Type 1 And Of A Cone - Rod Type Retinal Dysfunction In Three Generation Family With Spinocerebellar Ataxia Type 7

Purpose: To report a novel maculopathy in a patient with SCA1. To describe autofluorescence findings in family with SCA7 and associated cone-rod retinal dysfunction.Methods: 4 affected patients from two families were assessed to investigate a progressive loss of visual acuity (VA). Examinations included fundus photography, autofluorescence (AF) fundus fluorescein angiogragraphy (FFA) and optical coherence tomography. Electroretinogram (full-field) was performed in 2 affected patients. All patients had color vision testing using Ishihara pseudoisochromatic plates. Molecular analysis was performed in family 2.Results: The patient with known diagnosis of SCA1 had a visual acuity of 20/200 bilaterally and dyschromatopsia. He had saccadic pursuit. Fundus examination showed mild retinal pigment epithelium (RPE) changes at the macula. OCT showed bilateral macular serous detachment, which was not obvious at the FFA and explained his VA. AF imaging showed a central hyperfluorescence. The 45 year old proband from family 2 had a visual acuity of 200/20 and dyschromatopsia. ERG testing showed cone type dysfunction of photoreceptors. Her daughter affected at a younger age had the same ERGs findings. Fundus examination showed mild RPE changes in proband, normal findings in her daughter. AF imaging of both patients showed a ring of high density AF around the fovea. The ring was also obvious on near infrared AF. Later onset of gait imbalance led to the diagnosis of SCA7Conclusions: Within the group of spinocerebellar ataxias, only the type 7 is associated with retinal dysfunction. We present the first report of maculopathy associated with SCA1 causing severe vision loss. The ring of high density AF in SCA7 confirmed an early retinal photoreceptor dysfunction in patient with normal fundus.

Remaining rod activity mediates visual behavior in adult Rpe65-/- mice.

Purpose: C57/Bl6, Cpfl1-/- (Cone photoreceptors function loss 1; pure rod function), Gnat1alpha-/- (rod alpha-transducin; pure cone function) and Rpe65-/-;Rho-/- double knock-out mice were studied in order to distinguish the respective contributions of the different photoreceptor (PR) systems that enable light perception and mediate a visual reflex in adult Rpe65-/- mice using a simple behavioural procedure. Methods: Visual function was estimated using a rotating automatized optomotor drum covered with vertical black and white stripes at spatial frequencies of 0.025 to 0.5 cycles per degree (cpd) in both photopic and scotopic conditions. To evaluate the contribution as well as the light intensity threshold of each PR system, we tested the mouse strains with different luminances. Results: Stripe rotation elicits head movements in wild-type (WT) animals in photopic and scotopic conditions depending on the spatial frequency, whereas Cpfl1-/- mice show a reduced activity in the photopic condition and Gnat1alpha-/- mice an almost absent response in the scotopic condition. Interestingly, a robust visual response is obtained with Rpe65-/- knockout mice at 0.075 cpd and 0.1 cpd in the photopic condition. The residual rod function in the Rpe65-/- animals was demonstrated by testing Rpe65-/-;Rho-/- mice that present no response in photopic conditions. Conclusions: The optomotor test is a simple method to estimate the visual function, and to evaluate the respective contributions of rod and cone systems. Using this test, we demonstrate that in Rpe65-/- mice, devoid of functional cones and of detectable 11-cis-retinal protein, rods mimic in part the cone function by mediating vision in photopic conditions.

Spectrum of digoxin-induced ocular toxicity: a case report and literature review.

BACKGROUND: Digoxin intoxication results in predominantly digestive, cardiac and neurological symptoms. This case is outstanding in that the intoxication occurred in a nonagenarian and induced severe, extensively documented visual symptoms as well as dysphagia and proprioceptive illusions. Moreover, it went undiagnosed for a whole month despite close medical follow-up, illustrating the difficulty in recognizing drug-induced effects in a polymorbid patient. CASE PRESENTATION: Digoxin 0.25 mg qd for atrial fibrillation was prescribed to a 91-year-old woman with an estimated creatinine clearance of 18 ml/min. Over the following 2-3 weeks she developed nausea, vomiting and dysphagia, snowy and blurry vision, photopsia, dyschromatopsia, aggravated pre-existing formed visual hallucinations and proprioceptive illusions. She saw her family doctor twice and visited the eye clinic once until, 1 month after starting digoxin, she was admitted to the emergency room. Intoxication was confirmed by a serum digoxin level of 5.7 ng/ml (reference range 0.8-2 ng/ml). After stopping digoxin, general symptoms resolved in a few days, but visual complaints persisted. Examination by the ophthalmologist revealed decreased visual acuity in both eyes, 4/10 in the right eye (OD) and 5/10 in the left eye (OS), decreased color vision as demonstrated by a score of 1/13 in both eyes (OU) on Ishihara pseudoisochromatic plates, OS cataract, and dry age-related macular degeneration (ARMD). Computerized static perimetry showed non-specific diffuse alterations suggestive of either bilateral retinopathy or optic neuropathy. Full-field electroretinography (ERG) disclosed moderate diffuse rod and cone dysfunction and multifocal ERG revealed central loss of function OU. Visual symptoms progressively improved over the next 2 months, but multifocal ERG did not. The patient was finally discharged home after a 5 week hospital stay. CONCLUSION: This case is a reminder of a complication of digoxin treatment to be considered by any treating physician. If digoxin is prescribed in a vulnerable patient, close monitoring is mandatory. In general, when facing a new health problem in a polymorbid patient, it is crucial to elicit a complete history, with all recent drug changes and detailed complaints, and to include a drug adverse reaction in the differential diagnosis.

Complex rearrangements in patients with duplications of MECP2 can occur by fork stalling and template switching

Duplication at the Xq28 band including the MECP2 gene is one of the most common genomic rearrangements identified in neurodevelopmentally delayed males. Such duplications are non-recurrent and can be generated by a non-homologous end joining (NHEJ) mechanism. We investigated the potential mechanisms for MECP2 duplication and examined whether genomic architectural features may play a role in their origin using a custom designed 4-Mb tiling-path oligonucleotide array CGH assay. Each of the 30 patients analyzed showed a unique duplication varying in size from similar to 250 kb to similar to 2.6 Mb. Interestingly, in 77% of these non-recurrent duplications, the distal breakpoints grouped within a 215 kb genomic interval, located 47 kb telomeric to the MECP2 gene. The genomic architecture of this region contains both direct and inverted low-copy repeat (LCR) sequences; this same region undergoes polymorphic structural variation in the general population. Array CGH revealed complex rearrangements in eight patients; in six patients the duplication contained an embedded triplicated segment, and in the other two, stretches of non-duplicated sequences occurred within the duplicated region. Breakpoint junction sequencing was achieved in four duplications and identified an inversion in one patient, demonstrating further complexity. We propose that the presence of LCRs in the vicinity of the MECP2 gene may generate an unstable DNA structure that can induce DNA strand lesions, such as a collapsed fork, and facilitate a Fork Stalling and Template Switching event producing the complex rearrangements involving MECP2.

Methylmercury localization in Danio rerio retina after trophic and subchronic exposure: A basis for neurotoxicology

Methylmercury is a known neurotoxic organometal which affects visual functions and few studies concerns to wild fish are available. The autometallography mercury distribution in the retina of Danio rerio was mapped using light and electron microscopy. Abundant mercury deposits were found in the photoreceptor layer (outer and inner segments of the photoreceptors) and in the inner and outer nuclear layers. Occasionally, the presence of mercury deposits in plexiform layers was observed and very rarely in the ganglion cell layer. Also the occurrence of mercury deposits in cells from the disc region was observed, but not in the nerve fiber layer. An interesting difference was found between mercury accumulation in the central and peripheral regions of the retina. These results demonstrate that mercury after trophic exposure to Danio rerio is able to cross the blood-retina barrier and accumulate in the cells of the retina even under subchronic exposure. (C) 2010 Elsevier Inc. All rights reserved.

Detecção de cor e forma por Callithrix jacchus em cativeiro

Callithrix jacchus studies involving differences between the sexes regarding the performance on tasks food still offers room for the investigation of some factors, among them there is the differences in color vision, which can directly influence the detection of visual clues on food items. This study aimed to analyze the performance of C. jacchus in tasks involving detection of food items. Some factors were analyzed such as the differences in performance between the sexes and behavioral categories present during the task. There were no differences in performance between the animals in carrying out the task, for all situations presented, examining the behavioral categories observed. The fact of the task to be very simple might have influenced the results, and it was not possible to observe differences in performance. Males and females showed the same performance in all analyzed situations. The sex differences were not found possibly due to the influence of external factors, such as the structure of the experimental apparatus. The animals are more efficient in carrying out the task during the morning, in comparison to the afternoon. The light may have been one of the factors that influenced these results. Due to the influence of other factors that probably contributed to these results, we believe that different results can be found in future work

Papel de sinais cromáticos na identificação de parceiros sexuais em sagüi comum (callithrix jacchus)

The literature concerning color vision shows a trichromatic advantage in detecting ripe fruits and young leaves, but there are contradictory results. There is also the suggestion of this type of vision being adapted to perceive socio-sexual signals. Indeed, Old World primates utilize the skin color of conspecifics as a factor of attraction. But in New World primates there is no record of a coloration signal in the body that can be utilized by other group members. The present study aims to: 1- test whether there is a relation between coloration of body regions and ovulatory cycle in female Callithrix jacchus; 2- Determine if this species uses visual signals to choose mates that are sexually receptive. We collected feces from six females during one month to quantify progesterone concentration by EIA. Body region coloration was measured using a portable spectrometer and modeled to obtain the quantum catch of each photoreceptor, the opponency channels and chromatic distance between the points in units of JND. We recorded the behavior of six males exposed to three pairs of females with a cycling and a non-cycling female in each pair using a transparent plexiglass apparatus. The color of different body regions presented a correlation between progesterone concentration and the yellow-blue and red-green visual axes, with the genitalia as the region showing the highest correlation. The visual axis more apt to see the color variations was the yellow-blue in dichromats, and in trichromats were the red-green to face, yellow-blue to abdomen and both chromatic axes to genitalia. There was no difference in the signal detectability between trichromats and dichromats, but the perception pattern differed between the phenotypes, with a better signal detection by the dichromat phenotype 562 and the trichromat phenotype 543/562. During the behavioral experiments males presented longer gaze duration in periods of experimental manipulation and gaze duration was always longer towards cycling females compared to non-cycling females. Male locomotion during experimental manipulation was greater than in the control only during the periovulatory period of the female, indicating greater excitement. The behavior of cycling females was more active than the behavior of the non-cycling ones regarding locomotion and touching of the plexiglass division of the apparatus. Male gaze duration to cycling females increased with decreasing progesterone concentration, but none of the coloration parameters was correlated to the mate preference exhibited. This coloration signal can transmit information to animals of the group about fertility of female. Different from the intense red of the genitalia swellings of Old World primates, marmoset female genitalia became more bluish-green in the fertile period. Males chose fertile females and were able to visually identify the periovulatory period of females. Choice is related to progesterone concentration, but our results do not show relation between coloration and mate preference. Maybe some behavioral measure is associated with the choice

A influência do status social no forrageio de itens camuflados e avermelhados em sagüis (Callithrix jacchus) cativos

Seeing colors can be advantageous, because they are an important signal for providing information about the environment, such as the location of food. However, not every animals sees these chromatic signals in the same way. In primates, the group of Plathyrrhini has polymorphic sex-linked vision with males always dichromats and dichromats or trichromats females. Studies indicate that trichromats during foraging would benefit by seeing better than dichromats ripe fruits against the green foliage background. On the other hand, dichromats appear to distinguish camouflaged insects better than trichromats. The marmoset (Callihtrix jacchus) is a neotropical primate species that have color vision polymorphism. This species establishes family groups with highly reproductive bias, with breeding females often having preferential access to food. This work aims to study whether the social context influences the foraging ability of camouflaged and red items in groups of C. jacchus. Four groups of captive marmosets were presented to four food tasks, involving difficult, easy, reddish and camouflaged food targets. Foods were presented in a concentrated and dispersed manner, to check whether there was monopolization of the resources by the dominant subjects and if this would affect the ability of individuals to find the food targets. Success was measured by latency to food acquisition and number of targets consumed. Males and females differed in their foraging success for camouflaged and reddish items, although this difference has not appeared in all situations and experimental conditions. In general males were more successful for detecting camouflaged items while females succeeded more in identifying reddish items. There were no differences in foraging success between individuals of different social status, however, there were differences in the success of consumption of food items for different situations when food was concentrate compared with dispersed food. Taken as a role, there was a greater difficulty in detecting food items when they were presented in concentrated arrangement, which is supposed to be related to a higher difficulty to approach and stay near the food. Although it appears that there was no direct competition seems to have group's indirect influence on the detection of food items and foraging success of individuals, affecting mainly those items more difficult to detect

Detecção de predadores por dicromatas e tricromatas humanos e a sua implicação na evolução da visão de cores em primatas

Among placental mammals, primates are the only ones to present trichromatic color vision. However, the distribution of trichromacy among primates is not homogeneous: Old World primates shows an uniform trichromacy (with all individuals being trichromats) and New World primates exhibit a color vision polymorphism (with dichromatic males and dichromatic or trichromatic females). Visual ecology studies have investigated which selective pressures may have been responsible for the evolution of trichromacy in primates, diverging from the dichromat standard found in other mammals. Cues associated with foraging and the socio-reproductive status were analyzed, indicating a trichromatic advantage for the rapid detection of visually conspicuous objects against a green background. However, dichromats are characterized by an efficient capture of cryptic and camouflaged stimuli. These advantages regarding phenotype may be responsible for the maintenance of the visual polymorphism in New World primates and for the high incidence of color blindness in humans (standing around 8% in Caucasian men). An important factor that has not yet been experimentally taken into account is the predation risk and its effect on the evolution of trichromacy in primates. To answer this question, we prepared and edited pictures of animals with different coats: oncillas (Leopardus spp.), puma (Puma concolor) and ferret (Galictis cuja). The specimens were taxidermized and the photographs were taken in three different vegetation scenarios (dense forest, cerrado and grassland). The images of the predators were manipulated so that they fit into two categories of stimulus size (small or large). After color calibration and photo editing, these were presented to 40 humans (20 dichromats and 20 trichromats) by a computer program, which presented a set of four photos at a time (one picture containing the taxidermized animal amid the background vegetation and three depicting only the background vegetation) and recorded the response latency and success rate of the subjects. The results show a trichromatic advantage in detecting potential predators. The predator detection was influenced by the background, the predator species, the dimension of the stimulus and the observer s visual phenotype. As humans have a high rate of dyschromatopsias, when compared to wild Catarrhini or human tribal populations, it is possible that the increased rate of dichromats is a result of reduced pressure for rapid predator detection. Since our species came to live in more cohesive groups and resistant to attack by predators, with the advent of agriculture and the formation of villages, it is possible that the lower risk of predation has reduced the selection in favor of trichromats

Sinalização cromática da condição reprodutiva de fêmeas de segui comum (Callithrix jacchus)

As social animals, primates use different sensory modalities (acoustic, chemical, tactile and visual) to convey information about social and sexual status to conspecifics. Among these modalities, visual signals are widely used, especially color signals, since primates are the mammalian group that displays the greatest variety of colors in their skin and fur. Studies with Old World primate species suggest that hormonal variations are related to variations in the colors of individual faces and genitals. Therefore, chromatic cues can be used by conspecifics to identify the reproductive condition of an individual. To date, studies with the same approach are unknown for New World species. However, behavioral and physiological studies suggest that different New World primate species seem to perceive reproductive conditions such as the timing of female conception and gestation. Thus, in this study, our aim was to: i) identify whether there are chromatic cues on the skin of female common marmosets, (Callithrix jacchus) that indicate their reproductive condition; ii) define whether this chromatic variation can be perceived by all visual phenotypes known in this species; iii) identify if these chromatic cues can be perceived under different light intensity levels (dim, intermediate and high). For this, we selected 13 female common marmosets in four distinct reproductive conditions: pregnant female preceding parturition, postpartum mothers, noncycling and cycling females. The coloration of the skin in genital and thigh areas in females was measured using a spectrophotometer. Using mathematical models of visual perception, we calculated the values of quantum catch for each photoreceptor type known in this species, the visual opponency channels and color contrast between those body spots. Our results indicate the occurance of chromatic variations in the genital area during the weeks that precede and follow parturition, forming a U-pattern of variation perceptible to males and females in natural conditions of low and high luminosity. Furthermore, we observed distinct color patterns in the genital skin of pregnant and cycling females that indicate their reproductive conditions. Finally, we present evidence of color contrast in noncycling females that is higher than that of pregnant ones. This study suggests that there is a chromatic xii variation in the genital skin of females that can be perceived by conspecifics and that may be related to hormonal changes typical of pregnancy and the ovarian cycle

Um teste computadorizado para a avaliação de visão de cores em crianças e sujeitos não-verbais baseado no teste de discriminação de cores de Mollon-Reffin

O presente estudo visou garantir condições favoráveis para a avaliação de discriminação de cores em crianças, por meio de uma adaptação no modo Trivector do teste de discriminação de cores de Mollon-Reffin. Como a tarefa original, de indicar a abertura do C de Landolt, se mostrou pouco intuitiva para crianças pequenas, o alvo foi mudado para uma área colorida aproximadamente quadrada e a resposta requerida passou a ser tocar no alvo. O modo de teste Trivector mede os limiares de discriminação de cor ao longo de três linhas de confusão características das três formas variantes de visão de cor humana: protan-, deutan- e tritan-. O Experimento I avaliou a concordância entre o teste original e a versão adaptada, com 29 sujeitos adultos com visão de cor normal. A comparação dos limiares obtidos com as duas versões, por meio do método de avaliação de concordância de Bland-Altman, mostrou boa concordância entre as versões. No Experimento II, o teste adaptado foi aplicado em 25 crianças de 2 a 7 anos, usando técnicas de treino operante para estabelecer e manter o desempenho dos sujeitos. Os limiares diminuíram progressivamente acompanhando o aumento na idade. Os limiares protan- e deutan- foram consistentemente menores que os limiares tritan-, um padrão que já havia sido observado com adultos no teste original. Os resultados demonstram que, feitas as adaptações necessárias, o teste é adequado para a avaliação da discriminação de cor em crianças pequenas e pode ser uma ferramenta útil para a identificação das variações da visão de cor durante o desenvolvimento, bem como para a aplicação em outras populações humanas e, inclusive, outros primatas. (CNPq, FINEP).

Comparação de dois procedimentos computadorizados para avaliação de discriminação de cores em Cebus sp

A visão de cores consiste na discriminação de objetos com base em sua composição espectral, auxiliando na interação organismo-ambiente. Dentre os primatas, estima-se que a dicromacia seja uma característica compartilhada pela maioria das espécies platirrinas, sendo esta condição polimórfica e ligada ao sexo. O objetivo deste estudo foi comparar os resultados produzidos por equipamentos e softwares distintos para avaliar a tri/dicromacia em dois machos e duas fêmeas da espécie Cebus sp. Foram utilizados dois programas computadorizados: um envolvendo uma versão adaptada do Cambridge Colour Test e outro desenvolvido para o uso em sistema computacional padrão. Nos Experimentos 1 e 2 foi possível averiguar a condição tricromata de uma participante e dicromata dos participantes restantes. No Experimento 3, uma participante fêmea e um macho apresentaram desempenho dicromata compatível com o registrado nos experimentos anteriores. Neste mesmo experimento, uma participante fêmea apresentou desempenho tricromata compatível com o registrado nos experimentos anteriores. Concluiu-se com este estudo que condições favoráveis para a avaliação de visão de cores em primatas platirrinos podem ser edificadas envolvendo equipamento e software de baixo custo financeiro e de fácil programação. Entretanto, devido ao pequeno número de sessões realizadas com o equipamento de baixo custo, sugere-se a replicação do Experimento 3 e a realização de novas sessões com maior número de participantes e envolvendo novos arranjos de estímulos. Acredita-se que se novos dados corroborarem os produzidos aqui, este procedimento e equipamento poderá ser utilizado para avaliação de outras espécies platirrinas onde dados comportamentais são escassos.

Seletividade espacial de cor do potencial cortical provocado visual pseudoaleatório

A seletividade espacial para cor tem sido investigada usando métodos eletrofisiológicos invasivos e não invasivos, e métodos psicofísicos. Em eletrofisiologia cortical visual não invasiva este tópico foi investigado usando métodos convencionais de estimulação periódica e extração de respostas por promediação simples. Novos métodos de estimulação (apresentação pseudo-aleatória) e extração de respostas corticais não invasivas (correlação cruzada) foram desenvolvidos e ainda não foram usados para investigar a seletividade espacial de cor de respostas corticais. Este trabalho objetivou introduzir esse novo método de eletrofisiologia pseudoaleatória para estudar a seletividade espacial de cor. Foram avaliados 14 tricromatas e 16 discromatópsicos com acuidade visual normal ou corrigida. Os voluntários foram avaliados pelo anomaloscópio HMC e teste de figuras de Ishihara para caracterizar a visão de cores quanto à presença de tricromacia. Foram usadas redes senoidais, 8º de ângulo visual, vermelho-verde para 8 frequências espaciais entre 0,2 a 10 cpg. O estímulo foi temporalmente modulado por uma sequência-m binária em um modo de apresentação de padrão reverso. O sistema VERIS foi usado para extrair o primeiro e o segundo slice do kernel de segunda ordem (K2.1 e K2.2, respectivamente). Após a modelagem da resposta às frequências espaciais com função de diferença de gaussianas, extraiu-se a frequência espacial ótima e banda de frequências com amplitudes acima de ¾ da amplitude máxima da função para servirem como indicadores da seletividade espacial da função. Também foi estimada a acuidade visual cromática pelo ajuste de uma função linear aos dados de amplitude a partir da frequência espacial do pico de amplitude até a mais alta frequência espacial testada. Em tricromatas, foi encontrada respostas cromáticas no K2.1 e no K2.2 que apresentaram seletividade espacial diferentes. Os componentes negativos do K2.1 e do K2.2 apresentaram sintonia passa-banda e o componente positivo do K2.1 apresentou sintonia passa-baixa. A acuidade visual estimada de todos os componentes estudados foi próxima àquelas encontradas por Mullen (1985) e Kelly (1983). Diferentes componentes celulares podem estar contribuindo para a geração do VECP pseudoaleatório. Este novo método se candidata a ser uma importante ferramenta para a avaliação não invasiva da visão de cores em humanos.

Division of labor between M and P visual pathways: different visual pathways minimize joint entropy differently

Visual perception and action are strongly linked with parallel processing channels connecting the retina, the lateral geniculate nucleus, and the input layers of the primary visual cortex. Achromatic vision is provided by at least two of such channels formed by the M and P neurons. These cell pathways are similarly organized in primates having different lifestyles, including species that are diurnal, nocturnal, and which exhibit a variety of color vision phenotypes. We describe the M and P cell properties by 3D Gábor functions and their 3D Fourier transform. The M and P cells occupy different loci in the Gábor information diagram or Fourier Space. This separation allows the M and P pathways to transmit visual signals with distinct 6D joint entropy for space, spatial frequency, time, and temporal frequency. By combining the M and P impacts on the cortical neurons beyond V1 input layers, the cortical pathways are able to process aspects of visual stimuli with a better precision than it would be possible using the M or P pathway alone. This performance fulfils the requirements of different behavioral tasks.