Congenital stationary night blindness: an update and review of the disease spectrum in Saudi Arabia.

Congenital stationary night blindness (CSNB) is a group of rare, mainly stationary disorders of the retina, resulting from dysfunction of several specific and essential visual processing mechanisms. The inheritance is often recessive and as such, CSNB may be more common among populations with a high degree of consanguinity. Here, we present a topic update and a review of the clinical and molecular genetic spectrum of CSNB in Saudi Arabia. Since a major review article on CSNB in 2015, which described 17 genes underlying CSNB, an additional four genes have been incriminated in autosomal recessive CSNB: RIMS2, GNB3, GUCY2D and ABCA4. These have been associated with syndromic cone-rod synaptic disease, ON bipolar cell dysfunction with reduced cone sensitivity, CSNB with dysfunction of the phototransduction (Riggs type) and CSNB with cone-rod dystrophy, respectively. In Saudi Arabia, a total of 24 patients with CSNB were identified, using a combination of literature search and retrospective study of previously unpublished cases. Recessive mutations in TRPM1 and CABP4 accounted for the majority of cases (5 and 13 for each gene, respectively). These genes were associated with complete (cCSNB) and incomplete (icCSNB), respectively, and were associated with high myopia in the former and hyperopia in the latter. Four novel mutations were identified. For the first time, we describe the fundus albipunctatus in two patients from Saudi Arabia, caused by recessive mutation in RDH5 and RPE65, where the former in addition featured findings compatible with cone dystrophy. No cases were identified with any dominantly inherited CSNB.

Genetic mapping of autosomal recessive microspherophakia to chromosome 14q24.3 in a consanguineous Pakistani family and screening of exon 36 of LTBP2 gene.

Latent transforming growth factor beta binding protein 2 (LTBP2) plays a critical role in the development of connective tissue structure and function. Mutations in gene encoding LTBP2 are known to cause syndromic and a non-syndromic microspherophakia. Here, we present a 'first' report of genetic linkage of microspherophakia (MSP) to LTBP2 locus in a large consanguineous Pakistani family with four affected individuals in three loops. Using polymorphic microsatellite markers, haplotypes and linkage analysis, the diseased phenotype in MSP001 family was mapped to the LTBP2 gene. A maximum two point Logarithm of the odds (LOD) score of 4.16 was obtained with marker D14S284 at θ =0. Mutational analysis of exon 36 of LTBP2 using Sanger's sequencing did not reveal any previously reported mutations. Further analysis of the remaining exons are required to identify the causative variant.

Clinical characteristics of congenital lamellar cataract and myopia in a Chinese family.

To investigate the clinical characteristics and the genetic defect in a Chinese family with congenital lamellar cataract with myopia. Three generations of a single family were recruited in the present study. A detailed family history and clinical data were recorded. A total of 100 unrelated ethnically matched controls without family history of congenital cataracts and myopia were also recruited. Genomic DNA was extracted from peripheral blood leukocytes. The sequencing of candidate genes was performed to screen out the disease-causing mutation. The effects of amino acid changes on the structure of proteins were predicted by bioinformatics analysis. Affected individuals presented lamellar lens opacities and myopia. Direct sequencing revealed a heterozygous c. 34 C>T variation in the αA-crystallin protein (CRYAA) gene, which resulted in the replacement of a highly conserved arginine by cystine at codon 12 (p.R12C). This mutation co-segregated with all affected individuals and was not observed in unaffected members or the 100 normal controls. Bioinformatic analysis showed that a highly conserved region was located around Arg12, an increase in local hydrophobicity was shown around the substitution site and the secondary structure of the mutant CRYAA protein has been changed. This is the case of a congenital lamellar cataract phenotype with myopia associated with the mutation of Arg12Cys (p.R12C) in CRYAA. Our finding confirms the high rate of mutations at this dinucleotide. In addition, these results demonstrate a myopia susceptibility locus in this region, which might also be associated with the mutation in CRYAA.

Cochlear Implantation Outcomes in Children with Agenesis of the Corpus Callosum: A Retrospective Study and A Review of the Literature.

OBJECTIVES: The aim of the present study was to analyze the outcomes of cochlear implantation (CI) in patients with agenesis of the corpus callosum (CCA). A literature review and a retrospective analysis of our cochlear implant database were performed. MATERIALS AND METHODS: To the best of our knowledge, in the English literature, there was only one case reported with CCA who had undergone CI surgery. This case had Donnai-Barrow syndrome. In the Cukurova University School of Medicine Department of Otorhinolaryngology database, 5 of the 1317 patients who underwent CI surgery who had CCA were selected. The patients' demographic characteristics, operative findings, surgical outcomes, and additional disabilities were investigated. The patients' preoperative and postoperative Listening Progress Profile (LiP) and Meaningful Auditory Integration Scale (MAIS) tests were done to analyze the auditory performances. RESULTS: The participants of the study were 5 (0.38%) individuals (2 male and 3 female patients; ages 5.5, 7.5, 8, 9, and 12 years). Two of the patients had total agenesis, and the other three had partial agenesis of the CCA. In the histories of the patients, one patient had parental consanguinity, and one had febrile convulsion. No patient had an additional disability. None had experienced device failure. No patients were non-users or limited users of cochlear implants. Postoperative LiP and MAIS test scores were improved for all patients nearly as the patients without any deformity. They showed normal auditory performance in the analysis in their postoperative 48 months of follow-up. CONCLUSION: Patients who had CCA are good candidates for CI surgery.

Variante genética del síndrome de Stickler / Genetic variant of Stickler's syndrome

Casos clínicos: Se remiten para estudio tres pacientes miopes de una misma familia por presentar vítreo degradado de manera severa, membranas ecuatoriales, hiperplasia del epitelio pigmentario de la retina, envainamiento vascular y esclerosis de predominio periférico. Se solicita estudio genético que confirma el diagnóstico de síndrome de Stickler con una variante en la mutación del gen COL2A1. Discusión: El síndrome de Stickler se debe sospechar en familias que presenten un fenotipo característico con sinéresis vítrea y las referidas alteraciones en la retina, pudiendo existir en ocasiones variantes genéticas que no expresan en su totalidad el fenotipo clásico (AU)

Cases reports: Three myopic components of a same family came for study because presented severely degraded vitreous, equatorial membranes, retinal pigment epithelium hyperplasia, vascular sheathed and sclerosis of peripheral predominance. A genetic study confirmed the diagnosis of Stickler syndrome with a variant in the mutation of the COL2A1 gene. Discussion: Stickler's syndrome should be suspected in families with a characteristic phenotype with vitreous syneresis and alterations in the retina, but there may be genetic variants that do not express the classic phenotype (AU)

[Peripheral refraction and retinal contour in congenital and acquired high myopia]. / Perifericheskaia refraktsiia i kontur setchatki pri vrozhdennoi i priobretennoi miopii vysokoi stepeni.

AIM: to perform a comparative study of peripheral refraction and retinal contour in patients with congenital versus acquired high myopia. MATERIAL AND METHODS: A total of 30 patients (60 eyes) with high myopia aged 8 to 18 years (11.2±0.32 years on average) were examined. The patients were divided into 2 groups. Group 1 consisted of 21 patients (42 eyes) with acquired myopia of -6.0 to -10.25 diopters (-7.55±0.17 diopters on average), group 2 - of 9 patients (18 eyes) with congenital myopia of -8.75 to -28.75 diopters (-16.39±1.24 diopters on average). Using the Grand Seiko WR-5100K binocular open-field autoref/keratometer (Japan), relative peripheral refraction was assessed with account to relative peripheral eye length measured by the IOL Master partial coherent interferometer ('Carl Zeiss', Germany) at 15° and 30° nasally and temporally from the foveal center along the horizontal meridian. RESULTS: In acquired myopia, relative peripheral refraction and relative peripheral eye length readings evidenced the formation of peripheral hyperopic defocus in all examined zones. Congenital high myopia cases were notable for myopic defocus at 15° of the nasal retina (N15 zone): -0.67±0.33 diopters against the eye length change of -0.33±0.13 mm. CONCLUSION: The research helped identify retinal contour changes characteristic of congenital myopia and indicative of posterior pole irregularity.

OCT in a Myelinated Retinal Nerve Fiber Syndrome with Reduced Vision.

PURPOSE: The prognosis of success with vision therapy in refractive "amblyopia" associated with the syndrome of myelinated nerve fibers (MRNF), optic disc hypoplasia, and myopia is reported to be poorer than that of anisomyopic amblyopia without these features. The reason for the poorer prognosis has not been well understood. The purpose of this study was to perform spectral domain (SD) ocular coherence tomography (OCT) to determine if there is a structural etiology that may explain the poorer prognosis. CASE REPORTS: Case 1 was a 12-year-old male patient with anisometropic "amblyopia" in the right eye, MRNF denser superiorly, a hypoplastic disc, and a myopic fundus with a flat intact macula. The OCT demonstrated an attenuated photoreceptor integrity line (PIL) in the macula. Case 2 was a 10-year-old male patient with a constant left esotropia, MRNF denser superiorly, a hypoplastic disc, and a myopic fundus with a flat intact macula. The OCT demonstrated an absent PIL. Case 3 was a 58-year-old female patient with a history of diabetic retinopathy OU, long-standing reduced vision in the right eye, MRNF denser superiorly, optic nerve hypoplasia, and a myopic fundus with an intact macula. The OCT demonstrated an absent PIL in the macula. CONCLUSIONS: This case series identifies three patients with the syndrome of MRNF, optic nerve hypoplasia, and anisomyopia in one eye with reduced vision and reports OCT findings using SD-OCT systems. All three patients demonstrated an absence or attenuation of the photoreceptor integrity line (PIL) in the macula in the affected eye. To our knowledge, there is no known association between this syndrome and abnormality of the PIL reported in the literature. Patients with this syndrome may have a guarded prognosis in the success of vision therapy.

[Correlation between biomechanical properties of the corneoscleral tunic and stereometric parameters of the optic nerve head in congenital and acquired myopia].

The correlation between biomechanical properties of the corneoscleral tunic and stereometric parameters of the optic nerve head in children and adolescents with congenital and acquired myopia has been studied comparatively. The results showed that in children with high myopia, congenital or acquired, the corneoscleral parameters (scleral echodensity at the equator and the posterior pole, corneoscleral hysteresis, cornea resistance factor, and ocular rigidity coefficient) are lower than those in emmetropes. Moreover, the corneoscleral biomechanical characteristics affect the optic nerve head parameters. This fact has to be taken into account when examining adults with high myopia for the purpose of early diagnostics of glaucoma.

[Morphometric and functional features of macula in patients with high congenital myopia].

Combined use of OCT and ERG allowed us to study correlation of functional changes and morphological retinal features in patients with congenital myopia with or without myopic maculopathy. The study revealed the following features of retinal contour in macula region in congenital myopia compared to emmetropia: increase of neuroepithelial thickness in fovea centre, trend to decrease of its thickness in perifoveolar zone, significant (1,7-fold) reduction of neuroepithelial thickness difference between central and pericentral zones and subsequently change of retinal profile. Revealed data should be considered in retinal thickness evaluation of adults with high myopia and in assessment of normal postnatal macula development in children with high myopia. Combination of ophthalmoscopy, OCT and m-ERG may help in early diagnosis and monitoring of progressing macula changes.

Retinal horizontal cells reduced in a rat model of congenital stationary night blindness.

This work was conducted to determine whether congenital stationary night blindness (CSNB), which is caused by a Cacna1f mutation, could affect development of second-order neurons in the retina, such as horizontal cells (HCs). The CSNB rats and age-matched wild type rats were sacrificed at postnatal days (PND) 15, 30 and 60. Morphometric analyses of HCs, which were labeled by a primary antibody to calbindin D-28K, were performed at the light microscopic level on retinal cross sections and whole mount retinas. Calbindin D-28K was measured by western blotting in retinal samples. We found that the average number and density of HCs, Calbindin level and thickness of OPL were all decreased significantly in CSNB group compared to control group. These results indicated that second-order retinal neurons, such as horizontal cells, are affected by retinal degeneration. The relationship between the absence of HCs and the gene defect of CSNB requires further research.

Stickler syndrome in Pierre-Robin sequence prenatal ultrasonographic diagnosis and postnatal therapy: two cases report.

The Pierre-Robin Syndrome (PRS) is a rare congenital abnormality, with an approximately 1/30,000 estimated rate, characterized by the presence of the combination of mandibular hypoplasia (micrognathia or small jaw), glossoptosis (retrusion of the tongue into the pharyngeal airway) and, often, a posterior cleft of the secondary palate. It may be an isolated occurrence or part of a more complex syndrome and it is associated with long-term respiratory, nutritional, and developmental difficulties. Stickler syndrome (SS) is a rare autosomal dominant connective tissue disorder estimated to affect approximately 1/7500 newborns. It is diagnosed clinically and, at present, there is no consensus on a minimal clinical diagnostic criterion. The most frequent diagnosis in patients with syndromic Pierre Robin sequence is Stickler syndrome, which may be complicated by congenital high myopia and substantial risk of retinal detachment. However, cases of Stickler syndrome with probable visual complications are rarely identified among this group of patients by members of the cleft team. The patient had an acute unilateral hydrops, with a monolateral keratoconus. The ocular abnormalities included: severe myopia, abnormalities of the vitreous, and high risk of retinal detachment (with subsequent blindness). We report two extremely rare cases of prenatal diagnosis of PRS and SS, prematurely identified by prenatal ultrasonography and successively managed by oculists ophthalmogists.

Congenital axial high myopia detected by prenatal ultrasound.

High-resolution prenatal ultrasound can allow for early detection and monitoring of many fetal anomalies, including those involving the globe and orbit. The authors present a case of congenital axial high myopia that was diagnosed at 33 gestational weeks and monitored by prenatal ultrasonography. Some systemic abnormalities that can be associated with congenital high myopia are reviewed. High ammetropias, anisometropia, and either axial myopia or axial hyperopia can be detected in utero and give this early detection a greater chance of treating and reversing the devastating effects of amblyopia.

[Retinal bioelectrical activity in children with congenital myopia].

Congenital myopia is a particular form of short sight that forms in the intrauterine development of a fetus and that is generally characterized by high myopia, a longer anteroposterior axis (APA) of the eye, and its fundal changes. The authors have studied the functional state of the central and peripheral retinal segments in children with congenital myopia by electric retinography (ERG). They examined 23 patients (46 eyes) aged 6 to 16 years, who had moderate and high congenital myopia, the diagnosis in whom had been established in their early life, with various ophthalmoscopic manifestations: without macular changes, with the hyperpigmented macula, an undifferentiated macular region, and acquired chorioretinal dystrophy. Visometry, refractometry, ophthalmoscopy, ultrasound biometry (APA measurement), and mixed, local, and multifocal ERG were performed. Four patients were diagnosed as having congenital persistent nocturnal blindness of the Schubert-Bornstein type. Varying bioelectrical activity changes in the retinal macular region were revealed in congenital myopia both in the absence of ophthalmoscopic changes and with the changes in the fundus of the eye as macular hyperpigmentation, undifferentiated macular region, and central chorioretinal dystrophy. There was a moderate and high inverse correlation between the parameters of bioelectrical activity (the amplitude of b wave of the maximum ERG, that of b wave of local ERG and the retinal density of a P1 component in all rings) on the one hand, and the spherical equivalent of refraction and the length of ADA, on the other.

A canine model of inherited myopia: familial aggregation of refractive error in labrador retrievers.

PURPOSE: To determine whether the distribution of naturally occurring myopia in Labrador Retrievers has a genetic component. METHODS: Pedigree records of a large canine family were analyzed. Pure Labrador Retrievers, 1 to 8 years of age, free of ocular disease, and available for testing were studied. Refractive error was measured by cycloplegic retinoscopy in both eyes. The family included mating loops, and so an expectation maximization (EM) algorithm (multivar program, MORGAN software; University of Washington, Seattle) was used to calculate log likelihoods of refractive error with environmental and additive genetic models. The fixed effects of coat color, sex, and litter size were also tested. RESULTS: In our sample of 116 dogs from this one family, the average spherical equivalent refraction (SER) was -0.41 D (range, -5.38 to +1.65 D, mean of both eyes, n = 116): 31% were myopic (SER or= +1.00 D). The significance of fixed and genetic effects was tested by comparing the full model (including genetic and all fixed effects) to models with one effect removed. Litter size and additive genetic effects were significant (P = 0.0013 and P = 0.000093, respectively), whereas sex and coat color were not. The overall variance in SER was accounted for approximately equally by additive genetic variance and residual/environmental variance. Narrow sense heritability of SER was 0.506. CONCLUSIONS: The distribution of refractive error within this family of Labrador Retrievers had a significant genetic component, but was also influenced by other factors (litter size, and undefined residual/environmental effects). The dog represents a unique model for the study of naturally occurring, heritable, high-prevalence, low-degree myopia.

Long-term endothelial cell loss after traumatic dislocation and repositioning of Artisan phakic IOL.

PURPOSE: To evaluate long-term endothelial cell loss after traumatic dislocation and repositioning of an Artisan phakic intraocular lens (PIOL). METHODS: Traumatic PIOL dislocation occurred in the patient's left eye 4 months after uneventful implantation for unilateral congenital myopia. Using the Konan semi-automated analysis method, endothelial cell density was measured preoperatively, before Artisan repositioning, and 1, 2, and 4 years after primary implantation. RESULTS: Endothelial cell density was 2770 cells/mm2 preoperatively and 2634 cells/mm2 before Artisan repositioning. After successful repositioning, endothelial cell density progressively decreased--1, 2, and 4 years from primary implantation, endothelial cell density was 2582, 2524, and 2538 cells/mm2, respectively, corresponding to losses of 6.8%, 8.9%, and 8.4%, respectively. CONCLUSIONS: Progressive and long-term endothelial loss after traumatic dislocation and repositioning of the Artisan PIOL may be comparable to that reported after uneventful implantation.

[High myopia and retinal ultrastructure of albino guinea-pigs].

OBJECTIVE: To explore the relationship between melanin synthesis and the congenital high myopia of albino guinea-pigs. METHODS: Twelve albino guinea-pigs and 12 pigmented guinea-pigs of 220~250 grams (aged 5~6 weeks) were chosen at random. The eyes were examined with retinoscopy, A-scan ultrasonography and vernier caliper. The retinal structures were examined with light and electronic microscope. RESULTS: The diopter was -19.17 D in albino guinea-pigs and +0.63 D in pigmented guinea-pigs on average. Compared with the pigmented guinea-pigs, the axial dimensions of the albino guinea-pigs were elongated. There was significant difference between the albino guinea-pigs and the pigmented guinea-pigs. The retinal thickness, pigment granules and membrane disc of the outer segment of the visual cells decreased in the albino guinea-pigs, and the membrane disc space became narrow. The normal retinal thickness, plenty of pigment granules , membrane disc and wide membrane disc space could be observed in the pigmented guinea-pigs. CONCLUSION: Albino guinea-pigs have high myopia, and pigmented guinea pigs have light hyperopia. There are structural differences in the retina between albino guinea-pigs and pigmented guinea-pigs. The abnormity of albino guinea-pigs provides optical foundation for its high myopia.

Visual complications of Stickler syndrome in paediatric patients with Robin sequence.

BACKGROUND: The most frequent diagnosis in patients with syndromic Pierre Robin sequence is Stickler syndrome, which may be complicated by congenital high myopia and substantial risk of retinal detachment. However, cases of Stickler syndrome with probable visual complications are rarely identified among this group of patients by members of the cleft team. This study was designed to determine the prevalence of Stickler syndrome among the author's group of patients with Robin sequence, and to investigate the visual outcome among paediatric patients with Robin sequence and Stickler syndrome. MATERIAL AND METHODS: Eight children (six male and two female) with Stickler syndrome and Robin sequence were referred to be followed up every 6 months in the Ophthalmologic Department because of high myopia at less than 10 years of age. Three patients came from the author's study group and five were referred by other cleft surgeons. They were examined with repeat ophthalmic and indirect fundus examinations including cycloplegic refraction, and slit lamp biomicroscope examinations. Laser photocoagulation (2 cases) treatment for retinal degeneration or operation (3 cases) for retinal detachment was performed once evidence of significant ophthalmologic finding was noted. RESULTS: Of the 91 cases of newborns with isolated cleft palate treated by the first author, eight patients had Robin sequence, and among these, three had Stickler syndrome. The prevalence of Stickler syndrome among this subgroup of patients was 37.5% (3/8). Among these three patients and the additional five referred by other cleft surgeons, the average spherical equivalents of the first cycloplegic refraction for the 16 eyes was -12.39+/-2.72 diopter (D) (range -8.75 to -18.5D). Of the eight patients, five did not need any therapy, two children had retinal degeneration in the left eye and retinal detachment in the right eye while one child had retinal detachment in the right eye only. Laser photocoagulation was performed in the two left eyes with retinal degeneration and was successful. Surgery was performed on the three eyes with retinal detachment, one was successful while two failed and the patients developed total blindness at ages four and six respectively. Out of these three children with retinal complications, only one child remained free of visual deterioration in both eyes during the follow-up period. CONCLUSION: Early identification of Stickler syndrome in children with Robin sequence by cleft surgeons is necessary to insure early referral to an ophthalmologist for detection of myopia, monitoring for retinal detachment, and prevention of visual complications.

Molecular genetic analysis of a consanguineous south Indian family with congenital glaucoma: relevance of genetic testing and counseling.

The genetic background of congenital glaucoma in a consanguineous south Indian family was examined by homozygosity analyses. Significant evidence for the homozygosity of alleles was detected for markers D2S177 and D2S1346 that are tightly linked to the CYP1B1 gene, and further involvement of this gene was confirmed by the co-segregation of a novel truncating mutation (Q110X) in exon 2 with the disease in all affected members. Newborn genetic screening and carrier identification were also performed in the family. The role of consanguinity and the risk of autosomal recessive disease were discussed and genetic counseling was given.