Mitochondrial RNA processing defect caused by a SUPV3L1 mutation in two siblings with a novel neurodegenerative syndrome.

SUPV3L1 encodes a helicase that is mainly localized in the mitochondria. It has been shown in vitro to possess both double-stranded RNA and DNA unwinding activity that is ATP-dependent. Here we report the first two patients for this gene who presented with a homozygous preliminary stop codon resulting in a C-terminal truncation of the SUPV3L1 protein. They presented with a characteristic phenotype of neurodegenerative nature with progressive spastic paraparesis, growth restriction, hypopigmentation, and predisposition to autoimmune disease. Ophthalmological examination showed severe photophobia with corneal erosions, optic atrophy, and pigmentary retinopathy, while neuroimaging showed atrophy of the optic chiasm and the pons with calcification of putamina, with intermittent and mild elevation of lactate. We show that the amino acids that are eliminated by the preliminary stop codon are highly conserved and are predicted to form an amphipathic helix. To investigate if the mutation causes mitochondrial dysfunction, we examined fibroblasts of the proband. We observed very low expression of the truncated protein, a reduction in the mature ND6 mRNA species as well as the accumulation of double-stranded RNA. Lentiviral complementation with the full-length SUPV3L1 cDNA partly restored the observed RNA phenotypes, supporting that the SUPV3L1 mutation in these patients is pathogenic and the cause of the disease.

Pathogenic STX3 variants affecting the retinal and intestinal transcripts cause an early-onset severe retinal dystrophy in microvillus inclusion disease subjects.

Biallelic STX3 variants were previously reported in five individuals with the severe congenital enteropathy, microvillus inclusion disease (MVID). Here, we provide a significant extension of the phenotypic spectrum caused by STX3 variants. We report ten individuals of diverse geographic origin with biallelic STX3 loss-of-function variants, identified through exome sequencing, single-nucleotide polymorphism array-based homozygosity mapping, and international collaboration. The evaluated individuals all presented with MVID. Eight individuals also displayed early-onset severe retinal dystrophy, i.e., syndromic-intestinal and retinal-disease. These individuals harbored STX3 variants that affected both the retinal and intestinal STX3 transcripts, whereas STX3 variants affected only the intestinal transcript in individuals with solitary MVID. That STX3 is essential for retinal photoreceptor survival was confirmed by the creation of a rod photoreceptor-specific STX3 knockout mouse model which revealed a time-dependent reduction in the number of rod photoreceptors, thinning of the outer nuclear layer, and the eventual loss of both rod and cone photoreceptors. Together, our results provide a link between STX3 loss-of-function variants and a human retinal dystrophy. Depending on the genomic site of a human loss-of-function STX3 variant, it can cause MVID, the novel intestinal-retinal syndrome reported here or, hypothetically, an isolated retinal dystrophy.

A mutation of EPT1 (SELENOI) underlies a new disorder of Kennedy pathway phospholipid biosynthesis.

Mutations in genes involved in lipid metabolism have increasingly been associated with various subtypes of hereditary spastic paraplegia, a highly heterogeneous group of neurodegenerative motor neuron disorders characterized by spastic paraparesis. Here, we report an unusual autosomal recessive neurodegenerative condition, best classified as a complicated form of hereditary spastic paraplegia, associated with mutation in the ethanolaminephosphotransferase 1 (EPT1) gene (now known as SELENOI), responsible for the final step in Kennedy pathway forming phosphatidylethanolamine from CDP-ethanolamine. Phosphatidylethanolamine is a glycerophospholipid that, together with phosphatidylcholine, constitutes more than half of the total phospholipids in eukaryotic cell membranes. We determined that the mutation defined dramatically reduces the enzymatic activity of EPT1, thereby hindering the final step in phosphatidylethanolamine synthesis. Additionally, due to central nervous system inaccessibility we undertook quantification of phosphatidylethanolamine levels and species in patient and control blood samples as an indication of liver phosphatidylethanolamine biosynthesis. Although this revealed alteration to levels of specific phosphatidylethanolamine fatty acyl species in patients, overall phosphatidylethanolamine levels were broadly unaffected indicating that in blood EPT1 inactivity may be compensated for, in part, via alternate biochemical pathways. These studies define the first human disorder arising due to defective CDP-ethanolamine biosynthesis and provide new insight into the role of Kennedy pathway components in human neurological function.

Accommodative esotropia: An outcome analysis from a tertiary center in Oman.

AIM: The aim of this study is to determine the outcome of accommodative esotropia (ET) and influencing factors in young Omani children. SUBJECTS AND METHODS: In this retrospective cohort, children diagnosed with accommodative ET who had followed up in a tertiary hospital from 2006 to 2011 were identified. Parameters studied included cycloplegic refraction and its change with time, ocular alignment, binocularity, visual acuity (VA), amblyopia, and requirement for surgery. RESULTS: A total of 51 patients were identified. Twenty-four patients were diagnosed with fully accommodative ET (FAET) and 27 with partially accommodative ET (PAET). The mean (± standard deviation [SD]) age of onset and reporting were 2.6 (±1.58) and 3.2 (±1.84) years in the two groups, respectively. The mean (SD) cycloplegic refraction at presentation was 4.50 (±1.66) in the FAET group and 3.65 (±1.67) in the PAET group. Anisometropia was present in 28% of patients. The mean follow-up period was 4.9 years. The following were detected in the final visit. A reduction in amblyopia from 43% to 6% of patients, binocularity in 75% of patients, and a mean increase of 0.64 (±1.3) D in cycloplegic refraction from the first visit (P = 0.005). The mean angle of deviation at near and distance was 29.86 (±15.21) and 17.80 (±10.14) prism diopters, respectively, in FAET patients and 30.15 (±14.83) and 29.53 (±15.53), respectively, in PAET patients. Thirty-seven percent of the PAET patients underwent surgery within 5 years from diagnosis. All participants in this cohort continued to wear glasses in the last follow-up visit. CONCLUSION: Most children with refractive accommodative ET have an excellent outcome in terms of VA and binocular vision. The PAET group was characterized by delayed reporting, the presence of anisometropia, and lower hypermetropia. Further study is required to determine the possibility of weaning glasses in FAET patients.

Macular cysts in retinal dystrophy.

PURPOSE OF REVIEW: To describe the entity of macular cysts in retinal dystrophy, differentiate it from cystoid macular edema (CME), and review the role of carbonic anhydrase inhibitors in management. RECENT FINDINGS: Macular cysts in retinal dystrophy are seen in retinopathies caused by mutations in the NR2E3 gene, juvenile X-linked retinoschisis (XLRS), and some other retinal dystrophies. These must be distinguished from CME. Optical coherence tomography can clearly demonstrate intraretinal cysts which may not be clinically detectable. Intravenous fluorescein angiography (IVFA) does not show macular hyperfluorescence (i.e. leakage). Molecular genetic testing aids in the diagnosis and elucidation of pathophysiology. Carbonic anhydrase inhibitors may promote resolution of the cysts resulting in visual improvement. SUMMARY: Non-CME macular cysts in retinal dystrophies can be differentiated from CME by a combination of clinical examination, IVFA, and molecular genetic testing to identify causative phenotype. Carbonic anhydrase inhibitors may be effective in promoting resolution.

Chronic myelogenous leukemia in a child following treatment for bilateral retinoblastoma.

A 3-year-old child was incidentally found to have chronic myelogenous leukemia (CML) during an admission for a routine ophthalmic examination under anesthesia. The child had received systemic chemotherapy and focal treatment for Groups C and D retinoblastoma in the right and left eye, respectively, when she was 7 months old. CML was treated with dasatinib, and the child attained a major molecular response. The child is now 3 years after treatment of CML, and the retinoblastoma remains inactive. CML following treatment of retinoblastoma is a rare occurrence. Long term and close monitoring of retinoblastoma patients who received systemic chemotherapy using serial blood tests is essential.

Molecular analysis of CYP1B1 in Omani patients with primary congenital glaucoma: a pilot study.

PURPOSE: To screen cytochrome P4501B1 (CYP1B1) for causative mutations in Omani patients with a clinical diagnosis of primary congenital glaucoma (PCG) METHODS: Nine PCG families were recruited for the study. All patients underwent detailed clinical examinations to confirm the diagnosis of PCG. The families of index patients were also examined. Genealogical information was obtained by pedigree analysis. The primary candidate gene, CYP1B1, was amplified from genomic DNA, sequenced, and analyzed in patients to identify the disease-causing mutations. RESULTS: Eight of the nine PCG families were consanguineous (89%). Molecular analysis of CYP1B1 showed three distinct mutations, p.G61E, p.D374N, and p.R368H, in seven of nine unrelated PCG index patients (78%). Six patients had homozygous mutations and one had a compound heterozygous mutation. Causative mutations were not identified in two families. In family 4, the index patient was found to be heterozygous for the p.E229K variant. In family 6, although affected individuals were found to be homozygous in the CYP1B1 region, no mutation could be identified. CONCLUSIONS: This study indicates that CYP1B1 could be the predominant cause of PCG in the Omani population (78%). Omani PCG patients show allelic heterogeneity. Further studies are needed to delineate the spectrum of CYP1B1mutations in Omani PCG families and to identify new or modifier genes contributing to the manifestations of PCG in this region.

Visual rehabilitation by scleral fixation of posterior chamber intraocular lenses in Omani children with aphakia.

BACKGROUND AND OBJECTIVE: To report indications and outcomes of scleral-fixated posterior chamber intraocular lenses (PC IOLs) in Omani children with aphakia. PATIENTS AND METHODS: Patients with aphakia who were younger than 16 years, unsuitable for spectacle or contact lens correction, and without capsular support underwent an anterior vitrectomy and 10-0 polypropylene inside-out scleral fixation ofa PC IOL. RESULTS: Scleral-fixated PC IOLs were implanted in 28 eyes of 24 patients. Group A comprised 10 (36%) eyes with congenital cataract and 3 (11%) eyes with ectopia lentis and group B comprised 15 (53%) eyes with traumatic cataract. The mean age at implantation was higher in group A (10.5 years) than in group B (7.3 years). Visual acuity improved in 17 of 28 (61%) eyes and remained at the preoperative levels in 11 of 28 (39%) eyes. Mean postoperative refraction was within +/- 2.0 diopters of the predicted refraction in 19 of 28 (68%) eyes. Complications included temporary intraocular pressure increase, vitreous hemorrhage, and iris capture with lens malposition. CONCLUSION: Scleral-fixated PC IOLs are beneficial for children with aphakia without posterior capsular support who are lacking other means for visual rehabilitation. Patients with traumatic cataract and lens dislocation are more likely to experience an improvement in visual acuity postoperatively than patients with congenital cataract. However, this procedure is technically more difficult than routine PC IOL implantation and potentially carries greater risks.

Normal electro-oculography in a young Omani male with genetically confirmed best disease complicated by choroidal neovascularization.

Best vitelliform macular dystrophy (VMD) is an autosomal dominant macular dystrophy caused by heterozygous mutations in the bestrophin1 gene. Patients with this condition typically have an abnormal electrooculogram. We report a case of a 16-year-old male who presented with gradual progressive vision loss in the right eye. Ophthalmic assessment included funduscopy, optical coherence tomography (OCT), fluorescein angiography, electro-oculography, electroretinography, and genetic testing. Visual acuity was 20/500 and 20/20 in the right and left eyes, respectively. Ophthalmoscopy revealed round yellow lesions in both foveae similar to what is typically seen in Best disease. A subretinal hemorrhage surrounding the right foveal lesion was also noted. OCT demonstrated an elevated neurosensory retina with a subretinal lesion in the right macula. Fluorescein angiography of the right eye confirmed the presence of choroidal neovascularization. Genetic analysis of VMD2/BEST1 sequences confirmed the diagnosis of Best disease. However, contrary to what was expected, the patient's electro-oculography was normal. The findings of this case support a small number of previous reports demonstrating cases of Best disease with normal electro-oculography. While an abnormal electro-oculography along with the typical features of Best disease confirms the diagnosis, a normal result may not exclude the diagnosis. Genetic testing is probably the most important test for establishing the diagnosis of Best disease.

Co-inheritance of the membrane frizzled-related protein ocular phenotype and glycogen storage disease type Ib.

AIM: To report co-occurrence of two rare recessive conditions, the membrane frizzled-related protein (MFRP)-related ocular phenotype and glycogen storage disease type 1b (GSD-1b), in three siblings in an Omani family. BACKGROUND: Biallelic mutations in the MFRP gene (chromosome 11q23) result in a distinct ocular phenotype characterized by retinitis pigmentosa, foveoschisis, optic nerve head drusen, and posterior microphthalmos. GSD-1b is an autosomal-recessive disorder caused by mutations in SLC37A4 gene located in the same chromosomal region. METHODS: An Omani family with three siblings diagnosed with GSD-1b presented with ocular manifestations of progressive visual impairment and diminution of night vision. All siblings underwent a standard ophthalmic and clinical genetic evaluation. Full sequencing of the MFRP and SLC37A4 genes and haplotype analysis was carried out. RESULTS: The three children (2F:1M) aged 13, 17, and 18 years were born to consanguineous parents. Their best-corrected visual acuity ranged from 20/60 to 20/15. Ophthalmic exam revealed bilateral optic disc drusen, foveoschisis, and pigmentary retinopathy, hyperopia of +12 to +15.5 diopters, and decreased axial length (15.8-16.39 mm) in all affected siblings. Full-field electroretinography showed rod-cone dysfunction. Sequence analysis revealed two novel variants in a homozygous state in the SLC37A4 and MFRP genes in all the affected patients. CONCLUSIONS: We report the MFRP-related ocular phenotype in three siblings with GSD-1b. Molecular genetic studies identified novel mutations in the MFRP and SLC37A4 genes. Co-inheritance of a haplotype harboring mutations in both loci on chromosome 11q23 resulted in co-occurrence of the MFRP-related ocular phenotype and GSD-1b. This has not been reported previously.

CRB1 heterozygotes with regional retinal dysfunction: implications for genetic testing of leber congenital amaurosis.

PURPOSE: To test human CRB1 heterozygotes for possible clinical or functional retinal changes and to evaluate whether a patient with Leber congenital amaurosis (LCA) with CRB1 mutations not consistent with previously described CRB1 phenotypes carried a modifier allele in another LCA gene. METHODS: Seven unrelated heterozygous carriers of CRB1 mutations underwent phenotyping by full eye examinations (indirect ophthalmoscopy and slit lamp biomicroscopy) and functional testing (standard full-field electroretinography [ERG] and multifocal ERG). For genotyping of the LCA patients and their parents, denaturing high-performance liquid chromatography (dHPLC) analyses were performed, followed by sequence analysis of CRB1, followed by sequence analysis of the AIPL1 and CRX genes to identify a putative modifier effect in a patient with an atypical CRB1 phenotype. RESULTS: Reduced full-field ERG b-wave amplitudes were observed with scotopic -2 dB flash (140 microV; P < 0.05), normal full-field cone ERGs, and significant regional retinal dysfunction on mfERG in five of seven carriers of CRB1 mutations. A known AIPL1 mutation (p. R302L) was identified as a potential modifier allele in a patient with LCA carrying two CRB1 mutations and with a prominent maculopathy. CONCLUSIONS: In human heterozygotes of CRB1 mutations (parents of offspring with LCA), distinctive regional retinal dysfunctions were found by multifocal ERG measurements that were consistent with the focal histologic abnormalities reported for the two CRB1 knockout mice models. This phenotypic finding may identify CRB1 carriers and point to the causal gene defect in affected LCA offspring, significantly facilitating the molecular diagnostic process. Evidence suggests a modifier allele in AIPL1 in a patient with LCA with prominent atrophic macular lesions and homozygous defects in CRB1.

Macular cystoid spaces in patients with retinal dystrophy.

BACKGROUND: Non leaking macular cystoid spaces (MCS) are seen in some retinal dystrophies. Carbonic anhydrase inhibitor (CAI) treatment may reduce the size of MSC and improve vision. METHODS: A retrospective study of patients with retinal dystrophy with MCS seen between 2009 and 2013 at two sites. Patients had ophthalmic examination, optical coherence tomography (OCT) and genetic testing. Patients with vision worse than 20/30 were treated with CAI. Post treatment visual acuity (VA), central foveal zone (CFZ) thickness, and qualitative estimation of MCS size were assessed. RESULTS: Eighteen patients, 6-47 years old, were included. IVFA was performed in 15 (83%) patients. Of the 26 eyes in 13 patients who were treated and followed, VA improved in 15 eyes (58%) of 10 patients. Ten of these 15 eyes had decreased CFZ thickness and 9/10 showed qualitative MCS improvement. Regression analysis showed that change in CFZ thickness was not significantly predictive of change in final visual acuity (p = 0.405). Five of 15 eyes with improved VA had paradoxically increased CFZ thickness and 2/5 had enlarged MCS. Three of the treated eyes (11%) in two patients had decreased VA with decreased CFZ thickness and improved MCS in 2/3 eyes. Eight eyes (31%) in six patients showed no change in VA with decreased CFZ thickness in 6/8 eyes with improved MCS. Genetic testing showed mutations of NR2E3, XLRS, CRB1, GPR98 and CNGB1. CONCLUSION: Non-leaking MCS occur in a variety of retinal dystrophies. Therapy with topical or systemic CAI has variable efficacy and may result in VA improvement with or without qualitative improvement in MCS and CFZ thickness.

New Ocular Associations in Sanjad-Sakati Syndrome: Case report from Oman.

Sanjad-Sakati syndrome (SSS; Online Mendelian Inheritance in Man [OMIM] #241410), also known as hypoparathyroidism-retardation-dysmorphism (HRD) syndrome, is an autosomal recessive disorder in which prenatal-onset extreme growth retardation, congenital hypoparathyroidism and craniofacial dysmorphism result from mutations in the tubulin-specific chaperone E (TBCE) gene on chromosome 1q42-43. We report unique ophthalmic findings in a two-year-old child with molecularly confirmed SSS, who was admitted to Sultan Qaboos University Hospital in Oman at 11 weeks old with bilateral congenital corneal clouding. The ophthalmic findings in this patient were linked to faulty microtubule assembly in the brain, abnormal intracellular membrane transport and the resulting metabolic derangement seen in patients with SSS.

Septo-optic dysplasia complex: Clinical and radiological manifestations in Omani children.

BACKGROUND: Septo-optic dysplasia (SOD), also known as de-Morsier's syndrome, is a rare disorder characterized by any combination of optic nerve hypoplasia (ONH), pituitary gland hypoplasia, and midline abnormalities of the brain including absence of septum pellucidum and corpus callosum dysgenesis. It is typically diagnosed in infancy and has a variable presentation that includes visual, neurologic, and/or hypothalamic-pituitary endocrine deficits. PURPOSE: To demonstrate the ophthalmic, endocrine, and neurologic spectrum of SOD in five Omani children and address the crucial role of high-resolution neuroimaging for its early and accurate diagnosis. MATERIALS AND METHODS: A retrospective chart review was performed in 2010 of all children in the pediatric ophthalmology database of Sultan Qaboos University Hospital (SQUH) who were diagnosed to have ONH. All relevantdemographic, ophthalmic, neurologic, endocrine, and neuro-radiological manifestations were recorded in a data collection form. All previous neuroimaging results were reviewed by a neuro-radiologist. RESULTS: Five patients (four males, one female) with the diagnosis of ONH were included in the study. They presented during the period 1998-2008. All patients were born at term, with normal birth weights to healthy mothers with insignificant antenatal history. Age at presentation ranged from three months to one year. Manifestations at presentation included severe visual impairment (5/5), neonatal hypoglycemia (3/5), seizure disorder (2/5), and failure to thrive (4/5). ONH was bilateral in 3/5 patients and unilateral in (2/5). Brain and orbit imaging revealed varying anomalies in all patients. These included absent septum pellucidum (3/5), severe corpus callosum agenesis (1/5), ectopic pituitary (5/5), falx cerebri deficiency (1/5), optic nerve hypoplasia (5/5), optic chiasmal hypoplasia (5/5), and olfactory tract hypoplasia (1/5). Endocrine deficits were detected in 4/5 patients (3 with panhypopituitarism, and 1 with growth hormone deficiency) and necessitated replacement therapy. CONCLUSION: SOD is a clinically heterogeneous disorder with a wide spectrum of ophthalmic, endocrine, and neurologic manifestations. All features might not be present in a single patient. A high consanguinity rate and lack of history of alcohol and drug use were observed in our cohort. Most affected children present first to the pediatrician with failure to thrive. Radiological confirmation of ONH necessitates high-resolution imaging and interpretation by an experienced neuro-radiologist. In our cohort, all patients with ONH had associated optic chiasmal hypoplasia. Early detection and treatment reduces disease-related morbidity, and can be life saving.

Congenital fibrosis of the extraocular muscles.

BACKGROUND: Congenital fibrosis of the extraocular muscles (CFEOM) describes a group of rare congenital eye movement disorders that result from the dysfunction of all or part of the oculomotor (CN 3) and the trochlear (CN 4) nerves, and/or the muscles these nerves innervate. AIM: To describe the clinical and neuro-radiological findings in three patients with CFEOM and review literature with respect to clinical features, genetics and management of this condition. MATERIALS AND METHODS: A retrospective chart review was performed of three Omani patients who had been diagnosed with CFEOM in our institution. All patients had undergone standardized orthoptic and ocular evaluations and magnetic resonance imaging (MRI) of the orbits and brain. RESULTS: The three patients (age range nine months - 10 years) presented a history of congenital strabismus. All patients had severe bilateral ptosis and mild to moderate visual impairment secondary to the ptosis and astigmatism. Two of three patients demonstrated a positive jaw-winking phenomenon. A moderate to large angle exotropia with varying amount of hypotropia and limitations of almost all the extra ocular muscles was noted. Patient 3 was also developmentally delayed. MRI brain and orbit showed abnormalities of the extraocular muscles in two patients and brain malformation in one patient. CONCLUSIONS: CFEOM is a rare, congenital, and non-progressive disorder with multiple extra ocular muscle restrictions. CFEOM can be associated with neuro-radiological abnormalities; its diagnosis and classification is defined by clinical characteristics and genetics. Options for treatment are limited and difficult.

Compliance of amblyopic patients with occlusion therapy: A pilot study.

BACKGROUND: Increasing evidence shows that good compliance with occlusion therapy is paramount for successful amblyopia therapy. PURPOSE: To study the degree of compliance and explore factors affecting compliance in patients undergoing occlusion therapy for amblyopia in our practice. DESIGN: Nonrandomized clinical intervention study. MATERIALS AND METHODS: A total of 31 families with a child (aged 2-12 years), undergoing unilateral amblyopia treatment at the pediatric ophthalmology clinic of Sultan Qaboos University Hospital, Oman, were recruited for this one month study. Parents were interviewed and completed a closed-ended questionnaire. Clinical data including, visual acuity, refraction, diagnosis and treatment, for each patient was collected from the hospital chart and was entered in a data collection sheet. Compliance with occlusion therapy was assessed by self-report accounts of parents and was graded into good, partial, or poor. Association between various factors and degree of compliance was studied using logistic regression modeling. RESULTS: Only 14 (45%) patients showed good compliance to occlusion therapy. 17 (55%) patients were noncompliant. Improvement in visual acuity strongly correlated with compliance to patching (P = 0.008). Other variables that were studied included, age at onset of therapy; gender; degree of amblyopia; type of amblyopia; use of glasses; and compliance with glasses. These did not emerge as significant predictors of compliance. All but one family with poor compliance stated that the main challenge in following the recommendation to patch for requisite hours was in getting their child to cooperate. Only in one instance, the family cited nonavailability of patches as the main hindrance to compliance. 10/31 (32%) families expressed a desire for more information and 18/31 (58%) parents did not understand that amblyopia meant decreased vision. CONCLUSION: Poor compliance is a barrier to successful amblyopia therapy in our practice. Improvement in visual acuity is associated with better compliance with patching. Parents find it difficult to comprehend and retain verbal explanations of various components regarding occlusion therapy for amblyopia. Future study with a larger sample of patients is recommended to investigate the factors affecting compliance with amblyopia therapy and determine predictors for poor compliance.

A Female Child with Skin Lesions and Seizures: Case report of Incontinentia Pigmenti.

Incontinentia Pigmenti (IP), (OMIM # 308300), is a rare X-linked dominant condition. It is a multisystemic disease with neuroectodermal findings involving the skin, eyes, hair, nails, teeth, and central nervous system. It is usually lethal in males; the disease has variable expression in an affected female. We report the case of a 6 month old girl who presented at Sultan Qaboos University Hospital, Oman, with neonatal seizures and hypopigemented/hyperpigmented skin lesions. She had multiple ophthalmic abnormalities and neurological manifestations which are discussed in this report.