Afectación ocular como primera y única manifestación del síndrome de Bardet-Biedl: presentación de un caso / Ocular impairment as the first and only manifestation of Bardet–Biedl syndrome: A case report

El síndrome de Bardet-Biedl (SBB) es una ciliopatía que se asocia principalmente a distrofia retiniana, disfunción renal, polidactilia posaxial, obesidad, déficit cognitivo e hipogonadismo. Los síntomas vinculados a la distrofia retiniana no suelen aparecer hasta la primera década de vida, por lo que la detección tiende a retrasarse. La afectación ocular puede ser la forma inicial de manifestación de este síndrome, incluso puede ser la única, por lo que se debería tener en cuenta en el diagnóstico diferencial de una ambliopía en un niño que no mejora a pesar del correcto cumplimiento del tratamiento. Se presenta un caso de baja agudeza visual (AV) en una paciente pediátrica como manifestación inicial que lleva al diagnóstico del SBB y que es, además, el único síntoma que exhibe hasta la fecha, a pesar de tratarse de una enfermedad multisistémica.(AU)

Bardet–Biedl syndrome is a ciliopathy mainly associated with retinal dystrophy, renal dysfunction, post-axial polydactyly, obesity, cognitive deficit and hypogonadism. The symptoms associated with retinal dystrophy do not usually appear until the first decade of life, so the diagnosis is usually delayed. Ocular involvement may be the initial form of manifestation of this syndrome, it may even be the only one, so it should be taken into account in the differential diagnosis of amblyopia in a child who does not improve despite correct compliance with treatment. A case of low visual acuity in a pediatric patient is presented as an initial manifestation that leads to the diagnosis of Bardet–Biedl syndrome, and which is also the only symptom that the patient presents to date, despite being a multisystem disease.(AU)

One-Year Outcomes of Oral Treatment With Alga Capsules Containing Low Levels of 9-cis-ß-Carotene in RDH5-Related Fundus Albipunctatus.

PURPOSE: This study aimed to clarify the effect of 1-year oral treatment with 9-cis-ß-carotene-rich alga Dunaliella bardawil (Dunaliella supplementation) using full-field electroretinography (ERG) in patients with RDH5-related fundus albipunctatus (FAP). DESIGN: Prospective, interventional case series. PARTICIPANTS: The study included 12 patients (23 eyes) with RDH5-related FAP. METHODS: Twelve patients (23 eyes) with RDH5-related FAP received Dunaliella supplementation (total daily dose of ß-carotene was 74.0 mg, comprising 28.4 mg 9-cis-ß-carotene and 45.6 mg all-trans-ß-carotene at a ratio of 1:1.6) for 1 year and underwent ophthalmic examinations, including full-field ERG at baseline, 3 months, and 1 year after the initial treatment. MAIN OUTCOME MEASURES: The main outcome was changes in the amplitudes of responses of full-field ERG before and after treatment. A linear mixed-effects model was used to evaluate the adjusted mean difference between the amplitude of each response pretreatment and posttreatment. RESULTS: Prolonged dark adaptation (DA) responses at 3 months revealed a significant impairment in the b-wave of DA 0.01 (adjusted mean difference, -34.7, 95% CI, -66.8 to -2.73, P = .041) and a-wave of DA 3.0 (-29.0, 95% CI, -50.6 to -7.41, P = .013) and DA 10.0 (-40.4, 95% CI, -67.8 to -13.0, P = .007), which were also observed at 1 year. Additionally, prolonged DA and light adaptation (LA) responses revealed statistically significant impairment at 1 year in the b-wave of DA 3.0 (-43.8, 95% CI, -82.9 to -4.78, P = .035), DA 10.0 (-59.7, 95% CI, -101.8 to -17.61, P = .009), LA 3.0 (-7.31, 95% CI, -13.6 to -1.04, P = .029), and LA 3.0 flicker (-7.53, 95% CI, -12.7 to -2.34, P = .007). CONCLUSIONS: Our study results suggest that Dunaliella supplementation comprising low levels of 9-cis-ß-carotene compared with those reported in a previous study (1:1 ratio) adversely affects ERG amplitudes in patients with RDH5-related FAP.

Retinopathy and optic atrophy in a case of COQ2-related primary coenzyme Q10 deficiency.

PURPOSE: To describe a case of primary coenzyme Q10 deficiency in a child manifesting as early-onset renal failure, retinal dystrophy, and optic atrophy leading to progressive vision loss. METHODS: Clinical presentation and workup including visual fields, electroretinogram, and optical coherence tomography are presented. Genetic testing was performed. RESULTS: An eight-year-old female with nephropathy requiring renal transplantation subsequently developed progressive cone-rod dystrophy and optic atrophy. The patient had negative results on a targeted next-generation sequencing retinal dystrophy panel but whole-exome sequencing revealed two variants in COQ2 (likely biallelic), consistent with a diagnosis of primary coenzyme Q10 deficiency. CONCLUSIONS: Primary coenzyme Q10 deficiency is a rare disorder with variable systemic and ocular findings; there is also genetic heterogeneity. Genetic testing aids in the diagnosis of this condition, and variants in the COQ2 and PDSS1 genes appear to have the strongest association with ocular manifestations. Oral supplementation of coenzyme Q10 may slow progression of disease. This case highlights the utility of whole-exome sequencing in the diagnosis of a rare syndromic form of ocular disease and reports a novel phenotypic association for this condition.

Large Benefit from Simple Things: High-Dose Vitamin A Improves RBP4-Related Retinal Dystrophy.

Inherited retinal diseases (IRD) are a group of heterogeneous disorders, most of which lead to blindness with limited therapeutic options. Pathogenic variants in RBP4, coding for a major blood carrier of retinol, retinol-binding protein 4, are responsible for a peculiar form of IRD. The aim of this study was to investigate if retinal function of an RBP4-related IRD patient can be improved by retinol administration. Our patient presented a peculiar white-dot retinopathy, reminiscent of vitamin A deficient retinopathy. Using a customized next generation sequencing (NGS) IRD panel we discovered a novel loss-of-function homozygous pathogenic variant in RBP4: c.255G >A, p.(Trp85*). Western blotting revealed the absence of RBP4 protein in the patient's serum. Blood retinol levels were undetectable. The patient was put on a high-dose oral retinol regimen (50,000 UI twice a week). Subjective symptoms and retinal function markedly and sustainably improved at 5-months and 1-year follow-up. Here we show that this novel IRD case can be treated by oral retinol administration.

[Reparative mechanisms in retina and hypothalamus contributing to rhodopsin recovery in rabbit eyes with retinal dystrophy]. / Issledovanie reparativnykh mekhanizmov v setchatke i gipotalamuse, obespechivaiushchikh vosstanovlenie rodopsina v usloviiakh distrofii setchatki u krolikov.

PURPOSE: To study the molecular reparatory mechanisms of the retina and hypothalamus in the context of experimental dystrophy of receptor apparatus in rabbit retina. MATERIAL AND METHODS: Retinal dystrophy was induced in rabbit eyes by injecting monoiodacetic acid (MIA) intravenously. Indirect ELISA test was used to evaluate the levels of rhodopsin, heat shock protein 70 kDa (HSP70) in the retina, and serotonin-modulating anticonsolidation protein (SMAP) - that directly correlates with serotonin level - in the hypothalamus. RESULTS: The 1st series of studies showed that 12 days after the administration of MIA, rhodopsin in the retina was down-regulated by 27% (p<0.001), and heat shock protein 70 kDa (HSP70) was up-regulated by 47% (p<0.001), whereas in the hypothalamus up-regulation of SMAP by 22% (p<0.01) was observed. In the 2nd series, on the 22nd day after MIA administration, significant down-regulation (by 9.5 times) of HSP70 (p<0.001) was noticed in control rabbits, though intravitreal administration of SMAP on the 15th day after MIA administration led to sharp (23 times) up-regulation of HSP70 (p<0.001) in the retina 7 days later. In the 3rd series, 7 days after intravitreal administration of inactivated SMAP, the animals getting injections of MIA had noticeable down-regulation of rhodopsin (p<0.01) in the retina. In the 4th series, 7 days after intravitreal administration of polyclonal antibodies to SMAP in the rabbits that has had MIA injections, up-regulation of rhodopsin (p<0.01) and HSP70 (p<0.01) in the retina compared with levels in the control animals (MIA and non-immune γ-globulins) was observed. CONCLUSION: The results indicate the influence of the hypothalamic serotonergic system on HSP70 level in the receptor cells of the retina. The results of the 4th series of studies also give evidence for possible feedback from the retinal cells onto hypothalamus.

A pilot investigation of audiovisual processing and multisensory integration in patients with inherited retinal dystrophies.

BACKGROUND: In this study, we examined audiovisual (AV) processing in normal and visually impaired individuals who exhibit partial loss of vision due to inherited retinal dystrophies (IRDs). METHODS: Two groups were analyzed for this pilot study: Group 1 was composed of IRD participants: two with autosomal dominant retinitis pigmentosa (RP), two with autosomal recessive cone-rod dystrophy (CORD), and two with the related complex disorder, Bardet-Biedl syndrome (BBS); Group 2 was composed of 15 non-IRD participants (controls). Audiovisual looming and receding stimuli (conveying perceptual motion) were used to assess the cortical processing and integration of unimodal (A or V) and multimodal (AV) sensory cues. Electroencephalography (EEG) was used to simultaneously resolve the temporal and spatial characteristics of AV processing and assess differences in neural responses between groups. Measurement of AV integration was accomplished via quantification of the EEG's spectral power and event-related brain potentials (ERPs). RESULTS: Results show that IRD individuals exhibit reduced AV integration for concurrent audio and visual (AV) stimuli but increased brain activity during the unimodal A (but not V) presentation. This was corroborated in behavioral responses, where IRD patients showed slower and less accurate judgments of AV and V stimuli but more accurate responses in the A-alone condition. CONCLUSIONS: Collectively, our findings imply a neural compensation from auditory sensory brain areas due to visual deprivation.

Advanced diagnostic genetic testing in inherited retinal disease: experience from a single tertiary referral centre in the UK National Health Service.

In 2013, as part of our genetic investigation of patients with inherited retinal disease, we utilized multigene panel testing of 105 genes known to cause retinal disease in our patient cohorts. This test was performed in a UK National Health Service (NHS) accredited laboratory. The results of all multigene panel tests requested between 1.4.13 and 31.8.14 were retrospectively reviewed. All patients had been previously seen at Moorfields Eye Hospital, London, UK and diagnosed with an inherited retinal dystrophy after clinical examination and detailed retinal imaging. The results were categorized into three groups: (i) Testing helped establish a certain molecular diagnosis in 45 out of 115 (39%). Variants in USH2A (n = 6) and RP1 (n = 4) were most common. (ii) Definitive conclusions could not be drawn from molecular testing alone in 13 out of 115 (11%) as either insufficient pathogenic variants were discovered or those identified were not consistent with the phenotype. (iii) Testing did not identify any pathogenic variants responsible for the phenotype in 57 out of 115 (50%). Multigene panel testing performed in an NHS setting has enabled a molecular diagnosis to be confidently made in 40% of cases. Novel variants accounted for 38% of all identified variants. Detailed retinal phenotyping helped the interpretation of specific variants. Additional care needs to be taken when assessing polymorphisms in genes that have been infrequently associated with disease, as historical techniques were not as rigorous as contemporary ones. Future iterations of sequencing are likely to offer higher sensitivity, testing a broader range of genes, more rapidly and at a reduced cost.

Effectiveness and safety of nutritional supplements in the treatment of hereditary retinal dystrophies: a systematic review.

The hereditary retinal dystrophies (HRDs) are a group of genetically determined disorders that result in loss of the visual function. There is a lack of standard pharmacological treatments or widely accepted nutritional recommendations. The objective of this review is to summarise the scientific evidence on the effectiveness and safety of nutritional supplements for the treatment of HRDs. We conducted a scientific literature search on Medline and PreMedline, EMBASE, SCI-EXPANDED, SSCI, and The Cochrane Library up to August 2014. Experimental, quasi-experimental and controlled observational studies were selected. Eight studies were ultimately included, seven on retinitis pigmentosa (RP) and one on Best disease. Vitamin A, vitamin E, docosahexaenoic acid (DHA), lutein and ß-carotene were assessed. A 15 000 IU daily dose of vitamin A was reported to have shown a small protective effect on the progression of RP, as was the use of the carotenoids lutein and ß-carotene. Different DHA doses has no effect on RP or Best disease. No supplement showed severe adverse effects in the selected studies although strong evidence of toxicity exists for high doses of vitamin A and ß-carotene in certain populations. The selected studies concluded that there may be a small beneficial effect of vitamin A, lutein and ß-carotene on the progression of RP. The limited evidence available indicates some well-designed additional studies on combined supplements strategies may achieve more robust conclusions. Moreover, the scarcity of evidence available on the treatment of HRD other than RP with nutritional supplements supports the need for further research efforts.

Eye Findings on Vigabatrin and Taurine Treatment in Two Patients with Succinic Semialdehyde Dehydrogenase Deficiency.

We describe for the first time two patients with succinic semialdehyde dehydrogenase (SSADH) deficiency, who were found to have abnormal electroretinogram (ERG) examinations at baseline, or 6 months after vigabatrin treatment was started. This was somewhat reversible with L-taurine treatment, or minimally progressive. The mechanism of injury to the retina may be induced by elevations of γ-aminobutyric acid causing peripheral photoreceptor and ganglion cell damage, and this can be exacerbated by the use of vigabatrin. The use of taurine supplementation in tandem with vigabatrin may allow reversal of retinopathy and mitigate or slow down further deterioration. Further prospective clinical trials are required to evaluate this further. We recommend starting L-taurine therapy together with vigabatrin if a trial of vigabatrin is commenced in a patient with SSADH deficiency. Close monitoring of visual fields or ERG is also recommended at baseline and during vigabatrin therapy.

Improvement in Visual Function in Patients with Inherited Diseases of the Retina Following Acupuncture Treatment.

BACKGROUND: The aim of this pilot study was to examine the short-term effect on visual function of acupuncture treatment in a cohort of patients with inherited diseases of the retina. PATIENTS AND METHODS: A prospective pilot study was performed on 14 patients (10 ♀, 4 ♂; mean age: 43.43 y (± 19.72 y)), with the clinically and electrophysiologically confirmed diagnosis of inherited disease of the retina. Acupuncture treatment consisted of needle application to the body and ears and was performed following a standardized protocol. The treatment was scheduled for 10 half-hour sessions over five weeks. Visual function was measured before acupuncture, between acupuncture treatments and after the end of treatment. Objective measurements included best corrected visual acuity (ETDRS charts), contrast vision (CSV-1000, Vector Vision) and Goldmann perimetry (isopters 3IIIe; Haag-Streit). Subjective evaluation was based on evaluation questionnaires. To exclude the effect of variability on the psychophysical tests, a non-acupuncture control group (Nr: 8; 5 ♀, 3 ♂; mean age: 38.56 y (± 9.08 y)) was taken for comparison. RESULTS: All patients with inherited diseases of the retina showed general improvement in objective visual functions, with post-/pre- acupuncture improvement in: visual acuity (p = 0.031, left eyes), contrast vision (p = 0.015 and p = 0.041; both eyes) and widening of the temporal radius of the visual field (0.013; left eyes). Subjectively, all patients reported better daytime, color and contrast vision, better visual focus and less visual tiredness. In addition, some general symptoms, such as longer sleep-onset time, feeling cold, and migraine/headache attacks were significantly reduced. CONCLUSIONS: The acupuncture protocol improved visual function in our patients with inherited diseases of the retina and was well tolerated. Nevertheless, the long-term effect of this complementary therapy remains to be evaluated.

Bilateral retinal hemorrhages following finger pressure against the soft palate (الترفيع) in recessive CRB1-related retinopathy.

PURPOSE: To report two siblings with CRB1-related retinopathy who developed retinal hemorrhages following village traditional treatment of upward finger pressure against the soft palate ([Formula: see text]). METHODS: A retrospective case series. RESULTS: Two sisters were clinically diagnosed and genetically confirmed to have recessive CRB1-related retinal dystrophy. The family did not accept the condition as non-treatable and took both sisters for a traditional village therapy, consisting of several sessions of intense upward index finger pressure by the healer against the soft palate for each child. When examined following this therapy, both sisters had bilateral pre-retinal hemorrhages which were not present before the intervention and resolved without sequelae over the next several months. CONCLUSIONS: The traditional village therapy may have compromised retinal venous outflow and/or provoked a Valsalva phenomenon, leading to the bilateral retinal hemorrhages. The fact that this occurred bilaterally and in both sisters supports the concept of relative vessel wall incompetence as part of CRB1-related retinopathy.

Red light of the visual spectrum attenuates cell death in culture and retinal ganglion cell death in situ.

PURPOSE: To ascertain whether red light, known to enhance mitochondrial function, can blunt chemical insults to cell cultures and ischaemic insults to the rat retina. METHODS: Raised intraocular pressure (IOP, 140 mmHg, 60 min) or ischaemia was delivered in complete darkness or in the presence of low intensity red light (16.5 watts/m(2) , 3000 lux, 625-635 nm) to one eye of each rat. Animals were killed at specific times after ischemia and retinas analysis for ganglion cell numbers, the localization of specific antigens or for changes in defined RNAs. RGC-5 cell cultures were also exposed to various chemical insults in the presence or absence of red light. Significant differences were determined by t-test and anova. RESULTS: Elevation of IOP causes changes in the localization of glial fibrillary acid protein (GFAP), calretinin, calbindin, choline acetyltransferase, ganglion cell numbers and an elevation (GFAP, vimentin, HO-1 and mTORC1) or reduction (Thy-1 and Brn3a) of mRNAs in the rat retina. These negative effects to the rat retina caused by ischaemia are reduced by red light. Moreover, chemical insults to cell cultures are blunted by red light. CONCLUSIONS: Low, non-toxic levels of red light focussed on the retina for a short period of time are sufficient to attenuate an insult of raised IOP to the rat retina. Since mitochondrial dysfunctions are thought to play a major role in ganglion cell death in glaucoma, we propose the potential use of red light therapy for the treatment of the disease.

Sphingolipid profile alters in retinal dystrophic P23H-1 rats and systemic FTY720 can delay retinal degeneration.

Retinal degeneration (RD) affects millions of people and is a major cause of ocular impairment and blindness. With a wide range of mutations and conditions leading to degeneration, targeting downstream processes is necessary for developing effective treatments. Ceramide and sphingosine-1-phosphate, a pair of bioactive sphingolipids, are involved in apoptosis and its prevention, respectively. Apoptotic cell death is a potential driver of RD, and in order to understand the mechanism of degeneration and potential treatments, we studied rhodopsin mutant RD model, P23H-1 rats. Investigating this genetic model of human RD allows us to investigate the association of sphingolipid metabolites with the degeneration of the retina in P23H-1 rats and the effects of a specific modulator of sphingolipid metabolism, FTY720. We found that P23H-1 rat retinas had altered sphingolipid profiles that, when treated with FTY720, were rebalanced closer to normal levels. FTY720-treated rats also showed protection from RD compared with their vehicle-treated littermates. Based on these data, we conclude that sphingolipid dysregulation plays a secondary role in retinal cell death, which may be common to many forms of RDs, and that the U.S. Food and Drug Administration-approved drug FTY720 or related compounds that modulate sphingolipid metabolism could potentially delay the cell death.

Optogenetics, visual prosthesis and electrostimulation for retinal dystrophies.

PURPOSE OF REVIEW: Outer retinal degenerations such as retinitis pigmentosa can cause profound vision loss. Various treatment strategies are being pursued to potentially restore functional vision in these patients. RECENT FINDINGS: Advances in retinal prostheses have restored some vision in patients previously blind from retinitis pigmentosa. Optogenetics is another area that shows promise for restoration of vision. Transcorneal electrostimulation shows some efficacy to treat these patients as well. SUMMARY: We review recent advances in optogenetics, visual prosthesis and electrostimulation to treat outer retinal degenerations.

[New methods of the treatment of retinal dystrophies]. / Nové moznosti lécby vrozených chorob sítnice.

There is a brief review of actual treatment possibilities of retinal dystrophies in this article. Vitaminotherapy, electrostimulation and gene therapy are used in beginning stages of disorders. The efficiency of neuroprotective substances that are applied intravitreally using encapsulated cell technology is examined, as well as influence of systemic immunotherapy. In advanced stages of retinal diseases that are connected with loss of photoreceptors are used electronic retinal prostheses. Effectivity of treatment with stem cells, transplantation of cells and tissues and optogenetic therapy are evaluated. Key words: new therapeutic methods, retinal dystrophy.

[Modern tactics of the dystrophic retina disease treatment of patients of the elder age group].

One of the problems of elderly and senile patients is the reduction of visual acuity. Primarily this is due to AREDS as the most frequent cause of loss of visual acuity in people over 60 years. Therefore, the search for ways to protect and maintain visual function of elderly and senile patients is an important task both for ophthalmology and geriatrics.