Asymptomatic retinal dysfunction in alpha-methylacyl-CoA racemase deficiency.

Purpose: Alpha-methylacyl-CoA racemase (AMACR) deficiency is a peroxisomal disorder due to biallelic mutations in AMACR. At least 13 genetically confirmed patients have been reported to date. Seven had obvious pigmentary retinopathy; however, for the other six, no retinal phenotype was mentioned. The purpose of this report is to document subtle retinal findings in an additional affected family. Methods: Retrospective case series (three affected siblings and their unaffected parents). Results: Three Arab siblings (16, 19, and 22 years old) with prior juvenile cholelithiasis had been diagnosed with AMACR deficiency based on biochemical analysis, whole exome sequencing, and confirmatory segregation analysis (AMACR NM_001167595.1: c.877T>C; p.C293R). For all three, there were no visual complaints, but retinal multimodal imaging and electroretinography suggested subtle retinal dysfunction. Conclusions: Retinal dysfunction is a parameter that should be measured in patients with known or suspected AMACR deficiency even in the absence of visual symptoms. This may be helpful with clinical diagnosis and monitoring response to dietary interventions.

The morbid genome of ciliopathies: an update.

PURPOSE: Ciliopathies are highly heterogeneous clinical disorders of the primary cilium. We aim to characterize a large cohort of ciliopathies phenotypically and molecularly. METHODS: Detailed phenotypic and genomic analysis of patients with ciliopathies, and functional characterization of novel candidate genes. RESULTS: In this study, we describe 125 families with ciliopathies and show that deleterious variants in previously reported genes, including cryptic splicing variants, account for 87% of cases. Additionally, we further support a number of previously reported candidate genes (BBIP1, MAPKBP1, PDE6D, and WDPCP), and propose nine novel candidate genes (CCDC67, CCDC96, CCDC172, CEP295, FAM166B, LRRC34, TMEM17, TTC6, and TTC23), three of which (LRRC34, TTC6, and TTC23) are supported by functional assays that we performed on available patient-derived fibroblasts. From a phenotypic perspective, we expand the phenomenon of allelism that characterizes ciliopathies by describing novel associations including WDR19-related Stargardt disease and SCLT1- and CEP164-related Bardet-Biedl syndrome. CONCLUSION: In this cohort of phenotypically and molecularly characterized ciliopathies, we draw important lessons that inform the clinical management and the diagnostics of this class of disorders as well as their basic biology.

A novel c.980C>G variant in OAT results in identifiable gyrate atrophy phenotype associated with retinal detachment in a young female.

Background: Gyrate atrophy of the choroid and retina (GA) is a rare autosomal recessive disorder characterized by nyctalopia, myopia, sharply demarcated expanding peripheral chorioretinal atrophic lesions, early cataract, progressive visual loss and hyperornithinemia. Only three cases of GA associated with rhegmatogenous retinal detachments (RRD) have been reported. The genotype-phenotype correlation of RRD in GA is limited by lack of genetic information in the previously reported cases. Here we report two young sisters with a characteristic GA phenotype associated with a novel variant in the ornithine aminotransferase gene (OAT), in whom one developed unilateral RRD at the age of 9 years.Materials and Methods: Retrospective report of two cases including genetic analysis and multimodal retinal imaging.Results: A 9-year-old Saudi girl presented with a funnel-shaped RRD, extensive proliferative vitreoretinopathy, peripheral choroidal detachment and neovascular glaucoma in her right eye. Fundus examination of her left eye showed an attached retina with sharply-demarcated peripheral chorioretinal atrophic patches suggestive of GA. Whole exome sequencing confirmed GA by revealing a homozygous c.980 C > G (p. Pro327Arg) variant in exon 8 of OAT. The RRD was inoperable. The chorioretinal lesions in the left eye enlarged slowly over 3 years of follow up. Examination of the proband's older sister revealed a similar but more advanced GA phenotype in both eyes.Conclusions: A characteristic GA phenotype associated with a novel variant in OAT is reported. This variant might be associated with childhood-onset RRD in the proband.

Recognizable Patterns of Submacular Fibrosis in Enhanced S-Cone Syndrome.

PURPOSE: To highlight recognizable patterns of subretinal fibrosis in enhanced S-cone syndrome (ESCS). DESIGN: Retrospective case series. PARTICIPANTS: Forty-seven patients with subretinal fibrosis identified from 101 patients with clinically diagnosed ESCS, confirmed by full-field electroretinography (35/47), genetic testing (34/47), or both. METHODS: Multimodal retinal imaging, electroretinography, and genetic analysis. MAIN OUTCOME MEASURES: Patterns of subretinal fibrosis with angiographic, OCT, and genetic correlations. RESULTS: Eighty-five eyes of 47 patients (24 male patients; 36 unrelated consanguineous families) had subretinal fibrosis. Mean age at presentation was 14 years. Best-corrected visual acuity ranged from 20/20 to hand movements. All 34 genetically tested patients were homozygous for pathogenic NR2E3 variants. Subretinal fibrosis was always in the macular area, although it extended beyond in some patients. Six recurrent patterns of submacular fibrosis were noted: central unifocal nodular, circumferential unifocal nodular, multifocal nodular, arcuate, helicoid, and thick geographic. Some patients showed a combination of patterns. Previous misdiagnosis as inflammatory disease was common. Fibrosis was fairly symmetrical in a given patient but not always present or identical in other affected individuals with a given homozygous mutation from the same or other families. CONCLUSIONS: These recognizable patterns of submacular fibrosis are part of the ESCS phenotypic spectrum and strongly suggest the disease. In addition to facilitating diagnosis, recognition of these patterns can spare patients unnecessary workup for an inflammatory cause.

Association of the Recurrent Rare Variant c.415T>C p.Phe139Leu in CLN5 With a Recessively Inherited Macular Dystrophy.

Importance: Homozygous variants in the neuronal ceroid lipofuscinosis type 5 (CLN5) gene are associated with neuronal ceroid lipofuscinosis, a progressive neurologic disorder that leads to ataxia, seizures, and early death. The association between a homozygous variant in this gene and a macular dystrophy is described here. Objective: To describe an autosomal recessive macular dystrophy associated with a recurrent variant in CLN5. Design, Setting, and Participants: This cohort study took place at a national referral center and had a follow-up duration ranging between 1 and 5 years. All patients who were identified to carry a specific homozygous missense variant in CLN5, among more than 2000 patients who were diagnosed with or suspected to have retinal dystrophies, who did not carry this variant, were included. Data were collected between June 2014 and September 2020. Exposures: All patients who were sampled for DNA analysis due to molecularly unconfirmed retinal dystrophy and who were subsequently identified to carry the homozygous missense variant c.415T>C (p.Phe139Leu) in CLN5 were included, while patients who did not carry the variant were excluded. Main Outcomes and Measures: Retinal phenotype associated with this specific homozygous missense variant in CLN5. Results: Seven affected patients (mean [SD] age, 43 [18] years; age range, 33-52 years; 5 male) carried the homozygous missense in CLN5. All patients were diagnosed as having a macular dystrophy. Four patients had mild electroretinographic alterations. All patients had hypoautofluorescent maculas with retinal thinning (central subfield thickness, 80 µm). Visual acuity ranged between 2/200 and 20/100. Neurologic symptoms were mild (dizziness) in 5 patients and absent in 2 patients. Neuroimaging demonstrated cerebellar atrophy and white matter lesions, respectively, in 2 patients. Conclusions and Relevance: These results suggest that CLN5, similar to CLN7, may be associated with isolated macular dystrophy as well as neuronal ceroid lipofuscinosis. The variant c.415T>C p.Phe139Leu does not seem to be associated with any prominent neurologic disease at least until the fourth to sixth decades of life. These findings may imply a specific role of CLN5 in macular neurons. Additional study is suggested, such as molecular screening for this variant in cohorts of patients with undiagnosed macular dystrophies and biological studies of its molecular effects.

Incidence, Risk Factors and Surgical Outcomes of Cataract among Patients with Vogt-Koyanagi-Harada Disease.

Purpose: To investigate risk factors and surgical outcomes of cataract in Vogt-Koyanagi-Harada (VKH) disease.Methods: Review of 187 patients (374 eyes).Results: At presentation, cataract was diagnosed in 56 (14.9%) eyes all had chronic recurrent VKH. During follow-up, cataract developed in additional 51 (13.6%) eyes. Fifteen (13.6%) of these had initial-onset acute VKH with anterior segment (AS) inflammation and 36 (19.4%) had chronic recurrent VKH. No patient with initial-onset acute VKH without AS inflammation developed cataract. Risk factors for cataract development during follow-up included female gender, keratic precipitates, anterior chamber reaction ≥2+, chronic recurrent VKH, posterior synechiae, iris nodules, glaucoma, glaucoma surgery, choroidal neovascular membrane, "sunset glow fundus" and chorioretinal atrophy. Thirty-two eyes underwent cataract extraction. Fourteen (43.8%) eyes achieved ≥20/40. Posterior segment complications of chronic recurrent VKH accounted for <20/40 outcome.Conclusions: Poor outcome after surgery is secondary to posterior segment complications of chronic recurrent VKH.

Incidence and Natural History of Retinochoroidal Neovascularization in Enhanced S-Cone Syndrome.

OBJECTIVE: We examined the incidence and natural history of macular retinochoroidal neovascularization (RCN) in enhanced S-cone syndrome (ESCS). DESIGN: Retrospective case series. METHODS: This single-center study included 14 of 93 patients with ESCS who had signs of active or inactive RCN in ≥1 eye. We conducted multimodal retinal imaging, full-field electroretinography, and molecular genetic analysis of NR2E3 gene. Our main outcome measures included the cumulative incidence of RCN in ESCS, type of RCN, and mode of evolution of RCN. RESULTS: Fourteen (15.1%) of 93 patients with ESCS had RCN in ≥1 eye at 2 to 27 years of age. All 22 RCNs (21 eyes of 14 patients) were macular. Twelve of the RCNs were active with exudates/hemorrhages. Of these, 5 appeared de novo in a subretinal location, with photographic evidence of no pre-existing lesions. The latter were compatible with type 3 neovascularization or retinal angiomatous proliferation and subsequently evolved into unifocal fibrotic nodules. The remaining active lesions all had some degree of pre-existing fibrosis and remained stable. Ten inactive fibrotic nodules, identical to end-stage de novo lesions, were found and were presumed to represent healed RCNs. CONCLUSIONS: RCN, a treatable condition, may occur as early as 2 years of age and may be much more common in patients with ESCS than previously estimated. It may be the primary cause of the unifocal submacular fibrosis that is commonly observed in this condition. Additional research is needed to establish the pathogenesis of RCN in patients with ESCS and its optimal management.

Electronegative Electroretinograms in the United Arab Emirates.

PURPOSE: An electronegative electroretinogram (ERG), defined as having a b:a wave ratio ≤1 in the scotopic flash ERG response, indicates relative inner retinal dysfunction. Causes vary depending upon the study population. In the Arabian Gulf, where inherited retinal disease is relatively prevalent, common diagnoses associated with electronegative ERGs have not been described. In this study, we report the frequency and causes of electronegative ERGs in a cohort of Emirati patients with inherited retinal disease. METHODS: A retrospective review was performed of all full-field ERGs done for Emirati patients in the Ocular Genetics Service of Cleveland Clinic Abu Dhabi from January 2017 to December 2019. Those who had an electronegative ERG in at least one eye were included in the study. RESULTS: Out of 137 patients, 9 probands (6.6%) had an electronegative ERG. The mean age at presentation was 24 years (range 5-48 years), and five patients (55.6%) were male. The final clinical diagnoses were congenital stationary night blindness (CSNB) (two TRPM1-related and one Oguchi disease), X-linked retinoschisis (XLRS) (one genetically confirmed and two not genetically tested), cone-rod dystrophy (one CRX-related and one not genetically tested), and enhanced S-cone syndrome (ESCS) (one NRL-related). The one patient who did not have bilateral electronegative ERGs was a male with XLRS whose fellow eye had an unrecordable ERG. CONCLUSIONS: In this series of Emirati patients, an electronegative ERG was most commonly associated with the inherited retinal diseases recessive CSNB and XLRS. An electronegative ERG was noted in a case of NRL-related ESCS.

Adult Orbital Lesions in Saudi Arabia: A Multi-centered Demographic Study with Clinicopathological Correlation.

The demographics, clinical features, and histopathological classification of orbital space-occupying lesions in adults have not been widely described in our part of the world except for the pediatric population. In this retrospective study, we collected 110 consecutive adult patients (18 years and older) with orbital lesions (excluding lacrimal gland lesions) that were diagnosed histopathologically in two tertiary eye centers in Riyadh, Saudi Arabia (January 2000 to July 2017). Patients with thyroid-related orbitopathy, infectious, and inflammatory/pseudo-inflammatory lesions were excluded. We had 60 males (54.5%) and 50 females (45.5%). The mean age at presentation was 51.4 years (range 19-99). Proptosis was the most common clinical presentation (mean duration 15.4 months). The orbital lesions in order of increasing prevalence were: lymphoproliferative lesions in 26.4%; vascular in 21.8%; secondary tumors in 14.6%; neurogenic in 13.6%; structural in 10.0%; soft tissue tumors 8.2%; then metastatic tumors (2.7%) and others (extramedullary leukemia, fibrous dysplasia, and histiocytic lesion: Rosai-Dorfman disease): one case each. Gender distribution was varied in lymphoproliferative disorders compared to vascular lesions. Cavernous hemangioma was the most common vascular lesion (83.3%) and schwannoma was the most common neurogenic tumor (60%). Secondary lesions extended to the orbit mostly from eyelids in nine out of 16 or conjunctiva in four out of 16 cases. A favorable outcome was observed in about 80% of patients who underwent excisional biopsy. The rest encountered local recurrence of the tumors, growing of residual lesions, and recurrence with further invasion to nearby structures. We concluded having a similar demographic pattern of orbital lesions in adults as has been universally reported. We have fewer secondary tumors. We have summarized the pathological profile of adult orbital lesions according to patients' age, gender, symptoms, and location of the lesion as a baseline guide for proper diagnosis of any orbital mass prior to surgical management planning and for future prognostic studies.

A novel variant in DOCK6 gene associated with Adams-Oliver syndrome type 2.

BACKGROUND: Adams-Oliver syndrome (AOS) is a rare, inherited multi-systemic malformation syndrome characterized by a combination of aplasia cutis congenita and transverse terminal limb defects along with variable involvement of the central nervous system, eyes, and cardiovascular system. AOS can be inherited as both autosomal-dominant and recessive traits. Pathogenic variants in the DOCK6, ARHGAP31, EOGT, RBPJ, DLL4, and NOTCH1 genes have been associated with AOS. PURPOSE: To report a novel homozygous variant in the DOCK6 gene associated with Adams-Oliver syndrome type 2. MATERIALS AND METHODS: Case report. RESULTS: We report a case of a 4-month-old male who presented with microcephaly, global developmental delay, truncal hypotonia, and limb reduction defects. Ophthalmic examination revealed bilateral nystagmus and retinal detachment with mild cataractous changes in addition to retrolental plaque in the left eye. Next generation sequencing analysis identified a novel homozygous frameshift likely pathogenic variant (c.1269_1285dup (p.Arg429Glnfs*32)) in the DOCK6 gene. The constellation of the clinical findings and the genetic mutation were consistent with a diagnosis of AOS type 2. CONCLUSION: The discovery of this new likely pathogenic variant enriches the genotypic spectrum of DOCK6 gene and contributes to genetic diagnosis and counseling of families with AOS. Neurologic and ocular findings appear to be consistent with AOS type 2 for which multidisciplinary clinical evaluation is crucial.

Orbital solitary fibrous tumors: a multi-centered histopathological and immunohistochemical analysis with radiological description.

BACKGROUND: Solitary fibrous tumors (SFT), formerly called hemangiopericytoma, are rare tumors derived from mesenchymal cells originally described in the pleura, but these tumors may affect extraserosal tissues including the lacrimal gland and orbit. OBJECTIVE: Conduct a multi-centered clinical, radiological and histopathological analysis of 17 orbital SFT cases. DESIGN: A retrospective case series. SETTING: Three eye centers in two countries. PATIENTS AND METHODS: The data collected from the charts of 17 adult patients presenting with tissue diagnosis of orbital hemangiopericytoma or SFT from January 2003 to December 2018 included demographics, clinical imaging and histopathological information including immunohistochemical (IHC) characteristics. MAIN OUTCOME MEASURES: The demographic characteristics, clinical presentation, and histopathological patterns or variants of SFT were analyzed. SAMPLE SIZE: 17 adult patients. RESULTS: Mean age was 45 years (range 23-80 years). Male to female ratio was 3:1. The right eye was affected in 12 (70.5%) patients. Commonest presentation was proptosis in 13/17 (76% of patients). Other symptoms were impaired motility (29%) and ptosis (11%). Lesions mostly affected the medial orbit (35%), then orbital apex in 11%. The histopathological classic pattern-less variant was the commonest. One case with aggressive behavior, multiple recurrences and atypical features was encountered. Immunohistochemical (IHC) markers used included CD34 expression in all cases, Bcl-2 expression in 10/11, CD99 in 9/9 and Vimentin in 4/4. STAT6 was used in 2 cases. CONCLUSIONS: SFTs are rare tumors affecting the orbit in both genders equally in their mid-forties, but showed male predominance in our analysis with a predominant classic histopathological pattern. Tissue diagnosis is essential and requires IHC studies for confirmation. LIMITATIONS: Sample size is relatively small owing to the rarity of this tumor in the orbit. CONFLICT OF INTEREST: None.

Exploiting the Autozygome to Support Previously Published Mendelian Gene-Disease Associations: An Update.

There is a growing interest in standardizing gene-disease associations for the purpose of facilitating the proper classification of variants in the context of Mendelian diseases. One key line of evidence is the independent observation of pathogenic variants in unrelated individuals with similar phenotypes. Here, we expand on our previous effort to exploit the power of autozygosity to produce homozygous pathogenic variants that are otherwise very difficult to encounter in the homozygous state due to their rarity. The identification of such variants in genes with only tentative associations to Mendelian diseases can add to the existing evidence when observed in the context of compatible phenotypes. In this study, we report 20 homozygous variants in 18 genes (ADAMTS18, ARNT2, ASTN1, C3, DMBX1, DUT, GABRB3, GM2A, KIF12, LOXL3, NUP160, PTRHD1, RAP1GDS1, RHOBTB2, SIGMAR1, SPAST, TENM3, and WASHC5) that satisfy the ACMG classification for pathogenic/likely pathogenic if the involved genes had confirmed rather than tentative links to diseases. These variants were selected because they were truncating, founder with compelling segregation or supported by robust functional assays as with the DUT variant that we present its validation using yeast model. Our findings support the previously reported disease associations for these genes and represent a step toward their confirmation.

Acute dacryocystitis complicated by orbital cellulitis and loss of vision: A case report and review of the literature.

INTRODUCTION: Acute dacryocystitis usually presents as a pre-septal cellulitis since the lacrimal sac lies anterior to the orbital septum. Orbital cellulitis secondary to acute dacryocystitis is very rare due to a variety of anatomic barriers to the orbit but can occur and result in abscess formation with risk of visual compromise. PRESENTATION OF CASE: We describe a case of otherwise healthy adult who presented with complete visual loss following orbital cellulitis and abscess formation secondary to acute dacryocystitis. The clinical, radiological, intraoperative and postoperative findings are discussed. DISCUSSION: Typically, orbital cellulitis responds well to systemic antibiotic and surgical drainage without permanent visual loss. There are 7 cases reported in the literature of acute dacryocystitis complicated by permanent visual loss. CONCLUSION: Patients with acute dacryocystitis need to be carefully monitored for signs of orbital cellulitis. Prompt recognition and appropriate treatment of this condition are essential.