A novel missense variant in IDH3A causes autosomal recessive retinitis pigmentosa

Background: Inherited retinal degenerations (IRDs) encompass a wide spectrum of genetic ocular diseases characterized by considerable genetic and clinical heterogeneity.

Methods: Complete ophthalmic examination and next-generation sequencing.

Results: We describe a patient with no family history of vision loss, who at the age of 28 years developed visual impairment consistent with a severe form of retinitis pigmentosa. Genetic testing by means of whole exome sequencing identified a homozygous variant in the gene IDH3A. To date, only three papers have reported mutations in IDH3A, in families with early-onset retinal degeneration with or without the presence of macular pseudocoloboma.

Conclusion: This study highlights the importance of including this rarely-mutated gene in the molecular diagnostic set-ups for IRDs, and further delineates the phenotypic spectrum elicited by mutations in IDH3A.     

Multiple Evanescent White Dot Syndrome Following Intradermal Influenza Vaccination

Purpose: To present a case report of MEWDS following an intradermal influenza vaccination.

Methods: Review of the clinical, laboratory, photographic, and angiographic records of a patient with MEWDS.

Results: 27-year-old female that presented to our clinic with photopsias OD. These symptoms began 2 weeks following an influenza intradermal vaccination.

Fundus examination and diagnostic testing were consistent with MEWDS.

Conclusion: While rare, MEWDS can occur following influenza vaccination.     

Time Course of Subretinal Proliferation after Scleral Buckling for Rhegmatogenous Retinal Detachment Repair

Purpose: To observe course of subretinal proliferation (SRP) after scleral buckling (SB) for the rhegmatogenous retinal detachment.

Methods: Fundus photographs and serial optical coherence tomographies (OCTs) were retrospectively analyzed in 10 cases from 9 patients.

Results: Preoperative SRP locations were beneath the retina in six cases, intraretinal in one, and between the retina and retinal pigment epithelium (RPE) in one. One demonstrated SRP heterogeneity. Final SRP locations were intraretinal in two, on the RPE in seven, and beneath the retina in one. In two, the SRP invaginated into the retina while being absorbed.

Conclusions: Detached retina can be reattached following retinal break occlusion by SB, although the remaining SRP can disturb the reattachment. OCT images of SRP demonstrated various features. Before surgery, the SRPs were typically strand-like types located beneath the retina. Postoperatively, they were located on the RPE. In some cases, they invaginated into the retina.     

Electrophysiological verification of enhanced S-cone syndrome caused by a novel c.755T>C NR2E3 missense variant

Background: Nuclear hormone receptor gene, NR2E3, plays a critical role in retinogenesis and determination of the rod photoreceptor phenotype. Mutations in NR2E3 typically lead to recessive enhanced S-cone syndrome (ESCS), where affected individuals show higher sensitivity to short wavelength light and early onset rod dysfunction. Patients with ESCS present in early childhood with nyctalopia, enhanced sensitivity to blue light and display a very heterogeneic retinal phenotype with varying degrees of clumped pigmentation and occasional retinoschisis.

Purpose: To confirm the pathogenicity of a novel mutation in NR2E3 using electrophysiological studies.

Materials and Methods: Patient underwent detailed clinical evaluation and ophthalmic imaging followed by next generation sequencing analysis and electrophysiological studies.

Results: We describe a case of a young man of Greek descent with a family history of retinal degeneration. His fundal features at presentation were atypical of ESCS, with striking macular involvement in both eyes, including fibrotic subretinal material overlying the pigment epithelial detachment in one eye and schisis in the other. Genetic testing revealed a novel homozygous variant in NR2E3 gene of uncertain pathogenicity. Instead of performing further genetic analyses, electrophysiological studies showed pathognomonic changes in the S-cone response.

Conclusions: With the recent clinical endorsement of a gene therapy for RPE65 related-inherited retinal degeneration it is of paramount importance to correctly identify the pathogenic genetic mutation. In this particular syndrome, we highlight the value of electrophysiology to confirm the pathogenicity of a novel mutation in NR2E3 and aid the diagnosis of ESCS, with potential for gene therapy in the future.     

Role of OCT Angiography in the Detection of Retinal Vascular and Macular Abnormalities in Subjects with Asteroid Hyalosis

Purpose: To study the role of Optical coherence tomography (OCT) Angiography (OCTA) in detecting retinal vascular and macular abnormalities as compared to Fundus Fluorescein Angiography (FFA) in subjects with Asteroid hyalosis (AH).

Methods: In a prospective study, patients with AH underwent OCTA and FFA. AH graded as Grade 1 in 8 (optic disc, second order vessels visible), Grade 2 in 4 (optic disc, first-order vessels visible), Grade 3 in 11 (hazy view of optic disc) and Grade 4 (no view of fundus) in 2 eyes.

Results: A total of 20 patients (25 eyes) with AH were included. In comparison to FFA, OCTA was able to similarly detect Diabetic Retinopathy changes such as Neovascularization, microaneurysms, capillary dropout, and foveal avascular zone extent in vascular occlusion in all grades of AH.

Conclusion: OCTA, a noninvasive imaging tool, could detect various retinal vascular and macular abnormalities in patients with all grades of AH in comparison to FFA.     

Involutional entropion repair combining the modified Bick quick strip procedure with Quickert rotational sutures

Purpose: The purpose of the study was to determine the results of involutional entropion repair by combining the modified Bick strip procedure with Quickert rotational sutures.

Methods: A retrospective review of consecutive patients with involutional entropion who underwent repair by combined Bick and Quickert technique from January 2013 to December 2017 was performed.

Results: A total of 43 cases of involutional entropion repair were preformed in this time period. Fourteen eyelids of 12 patients had the combined procedure. There were no failures with a median follow-up of 29 months. Mean operative time, recorded in 10 patients, was 15 ± 2.2 minutes. Complications were minimal.

Conclusions: The combination of the modified Bick quick strip procedure and Quickert sutures requires minimal surgical dissection and provides excellent results for the treatment of involutional entropion.     

Adherence syndrome following inferior oblique anteropositioning – a case report

Introduction: We report a case of inferior oblique (IO) muscle adherence with fat adherence, which developed following unilateral IO anteriorization (IOAT).

Methods: A 14-year-old child with V pattern left exotropia, bilateral IO overaction, bilateral dissociated vertical deviation (DVD), and strabismic amblyopia (OS) underwent recess/resect procedure along with IOAT. He developed consecutive esotropia and drooping of upper eyelid with marked limitation of levoelevation (?4). Differential diagnoses of antielevation syndrome and adherence syndrome were considered.

On surgical exploration, forced duction test (FDT) was positive for elevation, left inferior oblique (LIO) muscle insertion was found anterior to the inferior rectus (IR) insertion along with fat adhesions which were released and IO muscle was reattached 3 mm behind and 2 mm lateral to IR insertion, along with advancement of left lateral rectus.

Results: Following resurgery, the patient had six prisms left esophoria and a hypotropia 9 prisms, with minimal limitation of levoelevation (?1). One month later, it was seen that the hypotropia had increased to 18 prism diopters and limitation of elevation was ?2.

Conclusions: Adherence syndrome is a rare and severe complication of IO weakening procedures. The initial postoperative improvement achieved in elevation and hypotropia in primary position was not maintained over subsequent follow-ups.     

Novel ocular findings in oculodentodigital dysplasia (ODDD): a case report and literature review

Background: Oculodentodigitaldysplasia (ODDD; MIM no. 164200) is a rare hereditary disorder caused by mutations in the gene GJA1.Ocular disorders included microcornea, cornea opacity and glaucoma. However, few studies described fundus findings.

Materials and methods: Ophthalmic examination included visual acuity measurement, intraocular pressure (IOP) measurements, slit-lamp biomicroscopy, B-scan ultrasonography, Ultrasound biomicroscopy (UBM), spectral-domain optical coherence tomography (SD-OCT), ERG and retcam fluorescein angiogram. In addition, blood samples were taken from this patient for mutation analyze of GJA1.

Result: The ophthalmic features of this patient were microcornea, cornea opacity, glaucoma as expected. Interestingly, the patient had a normal axial length with refractive status of emmetropia, but extremely retinal dysplasia and severe choroid thinning was noted. Flash electroretinogram (ERG) was extinguished in both eyes. This study identified a novel mutation c.91A>T in the GJA1 gene associated with fundus abnormalities. Bioinformatics and structural modeling suggested the mutation to be pathogenic.

Conclusion: Our research expanded not only the mutation spectrum, but also the clinical characteristics of ODDD. To the best of our knowledge, this is the first report on anatomical and functional chorioretinal changes in ODDD patients. These novel ocular features highlight the importance of fundus morphological and functional evaluation in ODDD.

Abbreviations: ODDD: oculodentodigital dysplasia; OCT: optical coherence tomography; ERG: electroretinogram; TACT: teller acuity card test; UBM: ultrasound biomicroscopy; MW: molecular weights; AL: axial length; Cx43: connexin 43; RPE: retinal pigment epithelium; RGCs: retinal ganglion cells; FEVR: familial exudative vitreoretinopathy; ROP: retinopathy of prematurity     

Clinical Characteristics and Prognostic Factors in Ankylosing Spondylitis Associated Uveitis

Purpose: To identify the clinical features and prognostic factors of uveitis associated with ankylosing spondylitis (AS).

Methods: This retrospective, interventional case series study reviewed the medical records of 91 AS patients with uveitis.

Results: The characteristics of AS-associated uveitis included male preponderance (70%), average onset in the fourth decade, unilateral manifestation (87.9%), and vitreous involvement or retinal vascular leakage (36.3%). All patients had acute anterior uveitis. The best corrected visual acuity in logMAR improved from 0.8 ± 0.3 to 0.1 ± 0.2. The use of biologic agents was the only significant factor in the multivariate analysis. Patients with vitreous involvement/retinal vascular leakage were more likely to use systemic/peribulbar steroids for inflammation control, and achieved equally favorable visual outcome as in those without vitreous involvement/retinal vascular leakage.

Conclusion: The clinical characteristics and profile of visual prognostic factors suggest an association between the severity of ocular inflammation and systemic disease.     

Phenotypic high myopia in X-linked retinitis pigmentosa secondary to a novel mutation in the RPGR gene

Background: Retinitis pigmentosa (RP) is a clinically and genetically heterogeneous disease causing progressive degeneration of retinal photoreceptor cells. The most severe form of this disease is X-linked RP (XLRP), in which photoreceptor degeneration begins in early childhood and complete blindness often occurs by the fourth decade of life. Two genes commonly associated with XLRP have been previously identified.

Material and methods: One Spanish family with confirmed XLRP was studied for mutations using direct sequencing. A genotype-phenotype correlation with pathologic myopia (PM) is detailed.

Results: A new pathogenic mutation in the third exon of the RP GTPase regulator (RPGR) was identified: a variant c212C>G (pSER71*). This mutation appears as a hemizygous variant in the male proband with RP, and as heterozygous variant in the females of this pedigree who invariably exhibit symmetrical PM in both eyes.

Conclusion: A complete family history allowed determination of the inheritance pattern providing genetic counseling for patients and their families. The geno-phenotypic attributes of this heterozygosity suggest a correlation between RP and PM. This novel mutation would expand the mutation spectrum of RP2 and RPGR, and help to study molecular pathogenesis of RP.     

Total Corneal Melt in Patient with Porphyria Cutanea Tarda in Presence of Another Risk Factor

Purpose: To report a case of two siblings affected by porphyria cutanea tarda (PCT) presenting with varying severity of ocular disease and evaluation of difference in the presence of risk factors.

Methods: Case report

Result: A 42-year-old Indian male diagnosed with PCT and history of daily intake of alcohol, presented with sudden decrease in vision of right eye. Examination showed perforated cornea surrounded by rim of 360-degree avascular necrotic sclera, with no evidence of infection.

Similar systemic history was present in his elder brother. He did not consume alcohol and presented with mere localized scleral thinning. Since the patient’s sibling acted as a natural control for the evaluation of alcohol as an independent risk factor, the difference in severity of disease can be explained on the basis of difference in alcohol intake.

Conclusion: In the presence of progression of the disease, other risk factors like intake of alcohol should be evaluated.     

Retinal Pigment Epithelium Detachment in Acute Vogt–Koyanagi–Harada Disease: An Unusual Finding at Presentation

Purpose: To report the cases of two patients who presented with acute Vogt–Koyanagi–Harada (VKH) disease and associated retinal pigment epithelium detachment (PED).

Methods: 2 case reports. Case 1: A 22-year-old male patient complained of acute bilateral decrease in vision. Initial best corrected visual acuity (BCVA) was 20/63, OU. There was 1+ vitreous cells, OU, exudative retinal detachment (ERD) in the right eye (RE), and a macular deep yellow lesion suggestive of PED in the left eye (LE). Case 2: A 40-year-old female patient presented with bilateral vision blurring. BCVA was 20/40 in the RE and 20/32 in the LE. There was 1+ vitreous cells OU, bilateral optic disc swelling and retinal striae.

Results: Multimodal imaging showed features of acute VKH disease with associated PED in the two patients. ERD and PED resolved under oral prednisone and cyclosporine in both cases.

Conclusion: PED may rarely occur in acute VKH disease at presentation.     

Paradoxical response to carbonic anhydrase inhibitors in patients with intraretinal cystoid spaces

Background: Intraretinal cystoid spaces (IRCS) are fluid-filled spaces seen in some retinal dystrophies and often treated with carbonic anhydrase inhibitors. The purpose of this study is to report an unexpected bilateral improvement in the IRCS after discontinuation of therapy.

Material and Methods: We identified from our records 23 patients with retinal dystrophy and IRCS who had been treated with topical and/or oral carbonic anhydrase inhibitors. All subjects had regular follow-up with OCT and previous genetic testing.

Results: We identified four (17%) patients who experienced a bilateral and symmetrical paradoxical improvement in IRCS size and visual acuity after discontinuation of carbonic anhydrase inhibitors. Two were mutations in RS1, one in CLN3 and another in NR2E3. All patients were followed for at least three years (range 39–63 months). None had systemic abnormalities.

Conclusions: Patients with IRCS may exhibit a paradoxical response after discontinuation of carbonic anhydrase inhibitors. Although the pathophysiology of these phenomena is unclear, stopping treatment may be an option in patients who cease to improve or get worse on treatment.     

Temporomandibular Disorder: An Important Cause of Temporal Headache in Patients Unlikely to Have Giant Cell Arteritis

Introduction: Temporal headache often results in an Ophthalmology referral to rule out giant cell arteritis (GCA). When clinical suspicion of GCA is low, alternative diagnoses should be considered. Temporomandibular disorder (TMD) commonly causes a temporal headache.

Materials and Methods: Patients referred with a temporal headache attending the Friday emergency ophthalmology clinic from February to July 2017 were assessed for GCA using the American College of Rheumatology (ACR) diagnostic criteria and TMD using a validated screening questionnaire.

Results: Ten symptomatic patients presented and were screened for TMD during this period. Four had mild TMD, two moderate, and three severe. The mean TMD score in patients with less than 3 ACR GCA criteria was 14.75 (SD 4.03) versus 6.8 (SD 3.06) in patients with 3 or more criteria (p = 0.0075).

Conclusion: TMD is an important cause of a temporal headache in patients unlikely to have GCA. Onward referral to dentistry for further management may be merited.     

Horizontal gaze palsy and progressive scoliosis with two novel ROBO3 gene mutations in two Jordanian families

Background: Horizontal gaze palsy and progressive scoliosis (HGPPS) is a rare autosomal recessive disorder due to mutations in ROBO3 gene. Patients have characteristic clinical and imaging findings. We report six patients from two families with this disorder with two novel mutations.

Materials and methods: One patient from a non-consanguineous family and five patients from extended consanguineous families were clinically and radiologically examined. Blood samples from the patients and their parents were obtained and all the coding exons and flanking intronic sequences of the ROBO3 gene were amplified and subjected to bidirectional DNA sequencing.

Results: All six patients had the characteristic clinical and radiological findings of HGPPS. Genetic testing showed two novel mutations including frame-shift and nonsense.

Conclusion: Two novel mutations in the ROBO3 gene were identified in two Jordanian families with six affected individuals. To our knowledge, this is the first molecular study of HGPPS in Jordan.     

The ‘over-the-top’ modified Cutler–Beard procedure for complete upper eyelid defect reconstruction

Purpose: To describe the ‘Over-the-Top’ Modified Cutler Beard Procedure (OTTMCB) for complete upper eyelid defect reconstruction

Methods: This is retrospective case note review of four patients that underwent the OTTMCB procedure. This two-stage procedure comprises the replacement of the posterior lamella with a free tarsal graft from the contralateral upper eyelid, and the anterior lamella with a lower lid skin flap over the lower eyelid margin which is divided 2–4 weeks later.

Results: The procedure was undertaken for four patients with 75–90% upper eyelid defects from tumour excision surgery. One patient had post-operative dehiscence requiring debridement and resuturing and further reconstructive surgery 18 months later to improve the cosmesis and lagophthalmos. The other three patients had good functional and cosmetic outcomes.

Conclusions: The OTTMCB procedure replaces the anterior and posterior lamellae of the upper eyelid with ‘like-for-like’ tissues. It avoids some of the drawbacks of the original and other variations of the Cutler–Beard procedure and achieves a good cosmetic outcome.     

Detailed retinal phenotype of Boucher-Neuhäuser syndrome associated with mutations in PNPLA6 mimicking choroideremia

Purpose: To confirm the pathogenic role of a novel mutation in PNPLA6 and detail the phenotype of a patient presenting with choroideremia-like chorioretinal degeneration.

Methods: A 40-year-old man with presumed choroideremia underwent a complete ophthalmic examination, full-field electroretinography (ERG), kinetic fields and two-color automated static perimetry and retinal imaging with spectral domain optical coherence tomography (SD-OCT) and near-infrared (NIR) and short wavelength (SW) fundus autofluorescence (FAF).

Results: Visual acuity was 20/200 and 20/40 for the right and left eye, respectively, with a ~ 5D myopic correction. Small cone-mediated ERG responses were detectable. The visual field by kinetic perimetry (V-4e stimulus) was limited to small (<5°) central islands separated from large peripheral islands of vision by an absolute midperipheral scotoma. There were minute islands of apparently spared retina near the foveal center separated from large peripheral islands of better appearing retina by severe pericentral and midperipheral chorioretinal atrophy. SD-OCT confirmed detectable photoreceptors near the center and in nasal midperipheral retina despite severe outer segment loss. Central photoreceptor loss was associated with disproportionately severe retinal pigment epithelium (RPE) depigmentation and choroidal atrophy. NIR- and SW-autofluorescence was widely hypoautofluorescent with the exception of residual autofluorescence along peripheral regions of relative RPE preservation. Gene screening revealed biallelic mutations (p.Arg1031GlnfsTer38/p.Arg1183Gln) in PNPLA6. Hypogonadotropic hypogonadism and cerebellar vermis hypoplasia by MRI confirmed a diagnosis of Boucher-Neuhäuser syndrome.

Conclusions: PNPLA6-associated retinal degenerations can present with predominantly retinal findings and subtle systemic abnormalities and should be considered in the differential diagnosis of diffuse chorioretinal atrophies.     

Macular degeneration as a common cause of visual loss in spinocerebellar ataxia type 1 (SCA1) patients

Background: Spinocerebellar ataxia type 1 (SCA1) caused by pathogenic CAG repeat expansion in the ATXN1 is characterized by loss of vision with little fundus abnormalities in some patients. Recently, macular degeneration has been reported to account for the visual symptoms in sporadic cases.

Materials and Methods: Five consecutive patients diagnosed as SCA1 with supporting genetical evidence were newly referred to ophthalmology department from neurology unit. They underwent ocular examination to assess visual acuity and the structural integrity of the macula using optical coherent tomography (OCT). Full-field and multifocal electroretinogram (ERG) were recorded in some patients. Genetic testing was done by a polymerase chain reaction-based method.

Results: Fundus examinations revealed normal optic disc and macula appearance. However, four out of five patients had foveal thinning by OCT. This included three patients who showed reduced visual acuity. Among the three, multifocal ERG was performed in two, which showed reduced amplitudes in the localized foveal area. Full-field ERG showed normal responses in all five patients assessed. Only one patient had normal visual function and normal macular structure.

Conclusions: Macular degeneration with subtle funduscopic alterations, sometimes mimicking occult macular dystrophy, is an important cause of visual loss in SCA1 patients, which could be reliably detected with OCT and multifocal ERGs.     

Increased microvascular disease in X-linked and autosomal recessive Alport syndrome: a case control cross sectional observational study

Background: Retinal microvascular disease reflects, in part, poor blood pressure control and systemic microvascular disease contributes to renal failure progression. This study examined the retinal microvasculature in Alport syndrome.

Materials and Methods: Retinal images from 28 males and 28 females with X-linked Alport syndrome, and 13 individuals with autosomal recessive disease were reviewed retrospectively for microvascular/ hypertensive retinopathy (Wong and Mitchell classification), and small vessel calibre (using a computerised semiautomated method and revised Knudtson formula). Data were compared with age and gender-matched individuals with normal blood pressure and renal function.

Results: Microvascular/hypertensive retinopathy was more common in males and females with X-linked Alport syndrome than age- and gender-matched controls (23, 82% and 10, 36%, p < 0.01; and 21, 75% and 13, 48%, p = 0.05, respectively), and in individuals with autosomal recessive disease compared with controls (12, 92% and 16, 43%, p < 0.01). Moderate microvascular/hypertensive changes were present in males and females with X-linked or autosomal recessive disease but not controls.

Arteriolar calibre was reduced in males with X-linked disease (142.5 ± 18.7 µm, and 150.7 ± 10.1 µm, p = 0.046) and in autosomal recessive disease (133.5 ± 11.10 µm and 149.1 ± 10.6 µm, p < 0.0001).

Microvascular/hypertensive retinopathy and arteriolar narrowing in males with X-linked disease were not different after renal transplantation and before (p NS).

Conclusions: Microvascular/hypertensive retinopathy was more common and more severe in Alport syndrome than normotensive controls. Improved BP levels may further slow the rate of renal functional decline in Alport syndrome.     

Spinocerebellar ataxia type 7 with RP1L1-negative occult macular dystrophy as retinal manifestation

Background: Spinocerebellar ataxia Type 7 (SCA7) is an autosomal dominant, progressive neurodegenerative disorder, primarily characterized by cerebellar ataxia. The disease is caused by the expansion of a CAG trinucleotide repeat within the ataxin-7 gene when its CAG repeat sequences are extended beyond 38. The degree of retinopathy can vary from pigment change in the fovea to foveal atrophy and is correlated with the number of CAG repeats. The present study describes a case of SCA7 with a retinal presentation similar to occult macular dystrophy (OMD) which is an inherited macular dystrophy characterized by presenting with a normal fundus and fluorescein angiography but with progressive central visual loss.

Materials and Methods: Report of a case.

Results: In this case, no specific abnormality was found on fundus examination, fluorescein angiography, full-field electroretinography and infrared autofluorescence. Spectral-domain optical coherence tomography showed foveal thinning, focal disruption of the ellipsoid zone, and central loss of the outer segment–retinal pigment epithelium interdigitation zone that were well matched with the multifocal electroretinography finding. Thirty-nine CAG repeats in ataxin-7 gene were identified through genetic testing.

Conclusions: SCA7 can present with a very mild form of retinal degeneration similar to the classic phenotype of RP1L1-negative OMD in case of the lower number of CAG repeats.