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Objectives: To compare the mean total antioxidant status (TAS) among 3 glaucoma types, namely: pseudoexfoliation glaucoma (PEG), primary open angle glaucoma (POAG), and primary angle closure glaucoma (PACG), and study its potential association with various clinical glaucoma-parameters.  , Methods: In this case-control study, plasma samples were obtained between September 2013 and October 2014 from 340 glaucoma patients (PEG [n=54]; POAG [n=147]; PACG [n=139]), and 351 controls of matching age, gender, ethnicity, and 5 different systemic co-morbidities from King Abdulaziz University Hospital, Riyadh, Saudi Arabia. The TAS in all samples was determined by a colorimetric-based assay.  , Results: The mean±standard deviation of TAS was significantly lower among cases: 0.77±0.32  than controls: 1.1±0.22, p less than 0.0001. Moreover, the TAS levels were significantly different across the 3 types of glaucoma: 0.86±0.24 in PEG, 0.47±0.32 in POAG, and 0.98±0.41 in PACG (all p less than 0.0001). In addition, there was a significant correlation between TAS and age at onset (Pearson correlation coefficient [R] 0.17, p less than 0.0001), cup/disc ratio (R: -0.13, p=0.004), and number of anti-glaucoma medications (R: -0.16, p=0.001).  , Conclusion: Our findings provide evidence that plasma TAS levels are decreased in patients with glaucoma, more so in POAG and PEG than PACG, supporting the hypothesis that decreased antioxidative defense and/or increased oxidative stress may have a critical role in the pathogenesis of glaucoma.

Background: To evaluate possible monogenic and chromosomal anomalies in a patient with unilateral Duane retraction syndrome and modest dysmorphism., Materials and Methods: Clinical evaluation, sequencing of candidate genes, and array comparative genomic hybridization (array CGH)., Results: The proband had unilateral Duane retraction syndrome (DRS) with low-set ears bilaterally, a high arched palate, and clinodactyly. Motor development and cognitive function were normal. Parents were first cousins, but no other family member was similarly affected. No mutations were detected in the HOXA1. KIF21A. SALL4, TUBB3, and CHN1 genes. Array CGH revealed a 16 Kb de novo deletion at chromosome 8p11.2 that encompassed a portion of only one gene, the Cholinergic Receptor, Nicotinic, Beta-3 (CHRNB3, Neuronal). This gene encodes a protein that is involved in the nicotinic acetylcholine receptor on neurons. It interacts functionally with other genes that code components of the acetylcholine receptor., Conclusions: This patient's chromosomal abnormality affected only one gene that is highly expressed in the brainstem and brain, involved in neurotransmission, and could be related to her Duane retraction syndrome.

We investigated whether the c.47T>C polymorphism (SNP rs4880) in the manganese superoxide dismutase (SOD2) gene is a risk factor for primary angle closure glaucoma (PACG) in the Saudi population. Among cases (n=139), the prevalence of various genotypes were 25.9%, 46.8% and 27.3% for T/T, C/T and C/C genotypes respectively. This trend was similar in the controls (n=403); 22.6%, 50.1% and 27.3% for T/T, C/T and C/C respectively. The differences in genotype distribution were not statistically significant (p=0.391 and 0.682 respectively). The minor allele frequency was 50.7% in cases and 52.4% in controls; this difference was not statistically significant (p=0.676). Investigating the potential association between this SOD2 polymorphism and different clinical indices, there was a statistically significant difference among different genotype groups in terms of three important clinical indices for PACG; Mean age at onset, duration of onset to and the mean LogMAR visual acuity (p=0.041, 0.018 and 0.033 respectively). The three markers are highly associated prognostic factors to diseases severity. If our results are proven in larger cohort and in various populations, then this SNP may have potentiality to be used as an indicator for PACG severity.

"Mirror movements" are an axonal guidance disorder that consists of involuntary contralateral movements that mimic unilateral intentional ones, typically involving the fingers of the hand. They can be isolated or associated with conditions such as Klippel-Feil syndrome, Kallmann syndrome, or congenital hemiplegia. Isolated congenital mirror movements are sometimes caused by autosomal dominant mutation in the genes DCC or RAD51. At least 4 previously reported cases had strabismus, 3 with Moebius syndrome and 1 with Duane retraction syndrome. We report the case of a boy with an unusual incomitant strabismus consistent with orbital dysinnervation and suggest that for some patients with congenital mirror movements the neurological miswiring extends to the orbit, causing congenital cranial dysinnervation disorder., (Copyright © 2015 American Association for Pediatric Ophthalmology and Strabismus. Published by Elsevier Inc. All rights reserved.)

Exfoliation syndrome (XFS) is the most common recognizable cause of open-angle glaucoma worldwide. To better understand the etiology of XFS, we conducted a genome-wide association study (GWAS) of 1,484 cases and 1,188 controls from Japan and followed up the most significant findings in a further 6,901 cases and 20,727 controls from 17 countries across 6 continents. We discovered a genome-wide significant association between a new locus (CACNA1A rs4926244) and increased susceptibility to XFS (odds ratio (OR) = 1.16, P = 3.36 × 10(-11)). Although we also confirmed overwhelming association at the LOXL1 locus, the key SNP marker (LOXL1 rs4886776) demonstrated allelic reversal depending on the ancestry group (Japanese: OR(A allele) = 9.87, P = 2.13 × 10(-217); non-Japanese: OR(A allele) = 0.49, P = 2.35 × 10(-31)). Our findings represent the first genetic locus outside of LOXL1 surpassing genome-wide significance for XFS and provide insight into the biology and pathogenesis of the disease.

Purpose: To study the differential expression of microRNA (miRNA) profiles between intraocular medulloepithelioma (ME) and normal control tissue (CT)., Material and Methods: Total RNA was extracted from formalin fixed paraffin embedded (FFPE) intraocular ME (n=7) and from age matched ciliary body controls (n=8). The clinical history and phenotype was recorded. MiRNA profiles were determined using the Affymetrix GeneChip miRNA Arrays analyzed using expression console 1.3 software. Validation of significantly dysregulated miRNA was confirmed by quantitative real-time PCR. The web-based DNA Intelligent Analysis (DIANA)-miRPath v2.0 was used to perform enrichment analysis of differentially expressed (DE) miRNA gene targets in Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway., Results: The pathologic evaluation revealed one benign (benign non-teratoid, n=1) and six malignant tumors (malignant teratoid, n=2; malignant non-teratoid, n = 4). A total of 88 miRNAs were upregulated and 43 miRNAs were downregulated significantly (P<0.05) in the tumor specimens. Many of these significantly dysregulated miRNAs were known to play various roles in carcinogenesis and tumor behavior. RT-PCR validated three significantly upregulated miRNAs and three significantly downregulated miRNAs namely miR-217, miR-216a, miR-216b, miR-146a, miR-509-3p and miR-211. Many DE miRNAs that were significant in ME tumors showed dysregulation in retinoblastoma, glioblastoma, and precursor, normal and reactive human cartilage. Enriched pathway analysis suggested a significant association of upregulated miRNAs with 15 pathways involved in prion disease and several types of cancer. The pathways involving significantly downregulated miRNAs included the toll-like receptor (TLR) (p<4.36E-16) and Nuclear Factor kappa B (NF-κB) signaling pathways (p<9.00E-06)., Conclusions: We report significantly dysregulated miRNAs in intraocular ME tumors, which exhibited abnormal profiles in other cancers as well such as retinoblastoma and glioblastoma. Pathway analysis of all dysregulated miRNAs shared commonalities with other cancer pathways.

Background: To evaluate possible monogenic and chromosomal anomalies in a patient with unilateral Duane retraction syndrome, modest dysmorphism, cerebral white matter abnormalities, and normal cognitive function., Materials and Methods: Performing high-resolution array comparative genomic hybridization (array CGH) and sequencing of HOXA1, KIF21A, SALL4, and CHN1 genes., Results: The proband had unilateral Duane retraction syndrome (DRS) type III on the right with low-set ears, prominent forehead, clinodactyly, and a history of frequent infections during early childhood. Motor development and cognitive function were normal. Parents were not related, and no other family member was similarly affected. MRI revealed multiple small areas of high signal on T2 weighted images in cerebral white matter oriented along white matter tracts. Sequencing of HOXA1, KIF21A, SALL4, and CHN1 did not reveal any mutation(s). Array CGH showed a 95 Kb de novo duplication on chromosome 19q13.4 encompassing four killer cell immunoglobulin-like receptor (KIR) genes. Conclusions. KIR genes have not previously been linked to a developmental syndrome, although they are known to be expressed in the human brain and brainstem and to be associated with certain infections and autoimmune diseases, including some affecting the nervous system. DRS and brain neuroimaging abnormalities may imply a central and peripheral oligodendrocyte abnormality related in some fashion to an immunomodulatory disturbance.

Purpose: Primary congenital glaucoma is a common disorder in the Middle East mainly caused by mutations in the the CYP1Bl gene. We report a family with three siblings that presented with recalcitrant childhood glaucoma, aniridia in two siblings with a novel CYP1B1 gene mutation., Materials and Methods: Review of pedigree, clinical history and clinical course of the family. Genetic testing in the affected family members., Results: Three sisters presented with clinical findings of severe congenital glaucoma and a positive family history. Clinical examination of two of sisters revealed corneal scarring, bilateral aniridia with severe glaucoma that required multiple surgical procedures to control intraocular pressure. The third sibling presented with garden-variety primary congenital glaucoma. Genetic analysis revealed a novel CYP1B1 gene mutation (g.8291 C > T; p.S485F)., Conclusion: CYP1B1 mutation related congenital glaucoma can present with an extreme form of anterior segment dysgenesis that includes recalcitrant glaucoma, corneal opacification and aniridia.

MicroRNAs (miRNAs) are small noncoding RNA molecules that regulate gene and protein expression by translational repression and/or mRNA degradation. miRNAs are implicated in the pathogenesis of various cardiovascular diseases and have become potential targets for therapeutic intervention. Their stability and presence in variety of readily accessible cell types including whole blood, serum, plasma, and other body fluids render them as potential source of a clinical biomarker. This review provides a brief overview of miRNA biogenesis and function, the diagnostic potential of circulating extracellular miRNA and their specific role in vivo in various cardiovascular settings, and their future perspective as clinical biomarkers. It is clearly evident from experimental studies that miRNAs are responsible for the regulation of several biological functions and alterations in cardiovascular diseases. Current data supports the concept of using circulating miRNAs as a biomarker in cardiovascular disease. It remains to be seen, however, whether circulating miRNAs can fulfil this role to improve risk and severity prediction.

Purpose: Some individuals are born with congenital limitation of ocular motility, often associated with ptosis and retraction of the globe. Many of these disorders are now known as the congenital cranial dysinnervation disorders (CCDDs). While several genes have been associated with CCDD phenotypes, there are still patients for whom the genetic basis has not been identified., Methods: Clinical evaluation and neuroimaging, sequencing of candidate genes, and array comparative genomic hybridization (array CGH)., Results: The patient was a four-year-old girl with mild dysmorphism; bilateral mild ptosis; substantial limitation of abduction OS with milder limitations of abduction OD, adduction OS, and vertical gaze OS; and retraction OS > OD on attempted adduction. No mutations were detected in the HOXA1, KIF21A, SALL4, TUBB3, and CHN1 genes. Array CGH revealed a 8 Kb de novo deletion on chromosome 2 (2q24.3) that encompassed a portion of only one gene, the Xin Actin-binding Repeat containing 2 (Gene Symbol XIRP2; NM&#95;001079810). This gene encodes a protein that is involved in muscle development and protecting actin filaments from depolymerization. It interacts functionally with 10 other proteins playing a similar role in muscle development., Conclusions: This patient's chromosomal abnormality affected only one gene that currently seems involved only in muscle development. All other genes currently associated with the CCDDs affect neurologic development. Genetic information from this patient implies that genes involved in development and maintenance of extraocular muscles can cause congenital ocular motility disorders as well.

Objectives: The aim of this study is to determine congenital adrenal hyperplasia (CAH) with the pattern of CYP21A2 gene-mutations in Saudi children., Methods: Between January 2011 and March 2014 at King Fahad Military Complex, Dhahran, Saudi Arabia, we thoroughly examined 11 patients with CAH and 2 asymptomatic individuals with a history of affected siblings. Additionally, we sequenced the full coding regions of the CYP21A2 gene and screened the gene for deletion(s)/duplication(s) using the multiplex ligation-dependent probe amplification (MLPA) technique., Results: Nine patients had classic CAH and presented with ambiguous genitalia and/or salt losing crisis. Two patients had the non-classic form of CAH and presented with precocious puberty. The remaining 2 subjects were asymptomatic. Screening the CYP21A2 gene, we detected p.Gln318X mutation in 4 patients, c.290 -13 C&gt;G (IVS2-13C&gt;G) in another 4, and a common deletion, involving exons 6 and 8 in 3 patients., Conclusion: Our strategy of Sanger sequencing followed by MLPA was very successful in detecting CYP21A2 mutations in all patients with CAH.

Objective: To assess the attitude and knowledge of the Saudi mothers toward newborn screening (NBS) program., Methods: A total of 425 Saudi women (only mothers who have at least one pregnancy) participated in the study from different regions in Saudi Arabia and completed the structured questionnaire which sought their views on the NBS services., Results: A majority of the participating women (91.1%) supported the NBS program and felt it was very important and useful. However, knowledge of NBS was found to be very limited and only 34.6% knew that NBS was a test to detect genetic disorders. A lack of communication and counseling to NBS clients by health authorities offering screening is implied., Conclusion: In general, there is a positive attitude towards the NBS program among Saudi women. However, they have several concerns to improve the availability of medication and formulas, genetic counseling, medical interventions, communication, education materials, and awareness.

Micro-RNAs (miRNAs) are regulators of gene expression that control various biological processes. The role of many identified miRNAs is not yet resolved. Recent evidence suggests that miRNA mutations and/or misexpression may contribute to genetic disorders. Point mutations in the seed region of MIR184 have been recently identified in Keratoconus (KC) patients with or without other corneal and lens abnormalities. We investigated mutations within MIR184 in KC patients from Saudi Arabia and examined the relative expression of miR-184 and miR-205 in human cornea. Ethnically matched KC cases (n = 134) were recruited and sequencing was performed using PCR-based Sanger sequencing and analyzed using the Sequencher 5.2 software. Expression of miR-184 and miR-205 was profiled in postmortem unaffected ocular tissues obtained from donors with no history of ocular diseases. miR-184 expression was 15-fold higher than that of miR-205 in cornea samples. No mutation(s) within the screened genomic region of MIR184 in KC cases was detected. This suggests that mutation in MIR184 is a rare cause of KC alone and may be more relevant to cases of KC associated with other ocular abnormalities. The increased expression of miR-184 versus miR-205 in normal cornea samples implies a possible role of miR184 in cornea development and/or corneal diseases.

Background: Duane retraction syndrome (DRS) is the most common of the congenital cranial dysinnervation disorders (CCDDs). CCDDs can be monogenic or chromosomal in origin. Identification of the genetic cause(s) in patients and families with DRS facilitates definitive diagnosis and provides insights into these developmental errors., Materials and Methods: This study described a young girl with DRS on the left and several additional developmental abnormalities. Clinical examination including neuroimaging, sequencing of candidate genes associated with DRS, and array comparative genomic hybridization (array CGH) were performed., Results: The proband had unilateral DRS type 3 on the left with somewhat low-set ears, mild motor delay with normal intelligence, and an asymmetric neck without a palpable right sternocleidomastoid muscle. Spine X-rays revealed a Klippel-Feil syndrome (KFS) and an MRI showed a webbed neck. She also had spina bifida at C8-T1 and a submucosal cleft palate. The parents of the proband were related with no other family member affected similarly. Sequencing of SALL4, CHN1, HOXA1, and TUBB3 did not show any mutation. Array CGH revealed de novo deletions of 21 Kb on chromosome 12q24.31 and 11 Kb on chromosome 22q13.31, each encompassing only one gene, ring finger protein 34, E3 ubiquitin protein ligase (RNF34) and peroxisome proliferator-activated receptor alpha (PPARA) respectively., Conclusions: This patient presents an unusual phenotype associated with a unique combination of two chromosomal microdeletions.

Purpose: To investigate the possible association of oxidative stress with keratoconus (KC), we estimated the changes in relative mitochondrial DNA (mtDNA) content., Methods: The study included 119 patients with KC and 208 controls matched for gender, ethnicity, and systemic disease status. We selected controls who were older than the patients since the mtDNA copy number tends to increase with age. The age mean (standard deviation) was 26.4(7.6) and 54.5(14.4) years for the patients and controls, respectively. The relative mtDNA copy number was estimated with the real-time quantitative PCR (qPCR) method using ND1 as the mtDNA gene and human globulin (HGB; also known as the cytoglobin gene, CYGB) as the reference single-copy nuclear gene., Results: The mean relative mtDNA content was significantly higher in patients with KC (1.20±0.45) than in the normal control subjects (1.04±0.36; p = 0.0004). Subjects with high mtDNA content (>1.259, i.e., greater than 75(th) percentile) were at an increased risk of the disease (odds ratio = 2.62, 95% confidence interval = 1.40 to 4.89; p =0.0025)., Conclusions: Increased mtDNA content in patients with KC may indicate mitochondrial respiratory chain defects and thus mitochondrial-abnormality involvement.

Objective: Homozygous homeobox A1 (HOXA1) mutations cause a spectrum of abnormalities in humans including bilateral profound deafness. This study evaluates the possible role of HOXA1 mutations in familial, non-syndromic sensorineural deafness., Methods: Forty-eight unrelated Middle Eastern families with either consanguinity or familial deafness were identified in a large deafness clinic, and the proband from each family was evaluated by chart review, audiogram, neuroimaging, and HOXA1 sequencing., Results: All 48 probands had normal neuro-ophthalmologic and general medical examinations except for refractive errors. All had congenital non-syndromic sensorineural hearing loss that was symmetric bilaterally and profound (>90 dBHL) in 33 individuals and varied from 40 to 90 dBHL in the remainder. Thirty-nine of these individuals had neuroimaging studies, all documenting normal internal carotid arteries and normal 6th, 7th, and 8th cranial nerves bilaterally. Of these, 27 had normal internal ear structures with the remaining 12 having mild to modest developmental abnormalities of the cochlea, semicircular canals, and/or vestibular aqueduct. No patient had homozygous HOXA1 mutations., Conclusions: None of these patients with non-syndromic deafness had HOXA1 mutations. None had major inner ear anomalies, obvious cerebrovascular defects, or recognized congenital heart disease. HOXA1 is likely not a common cause of non-syndromic deafness in this Middle Eastern population.

Background: To investigate whether the c.47T > C mutation in the manganese superoxide dismutase gene (Mn-SOD) is a risk factor for primary open angle glaucoma (POAG) in the Saudi population., Materials and Methods: A cohort of 226 unrelated POAG patients and 403 unrelated control subjects from Saudi Arabia were genotyped for a single nucleotide polymorphism (SNP; rs4880; c.47T > C) utilizing Taq-Man® assay ID: C&#95;8709053&#95;10. The association between mutant genotypes and various clinical indices important for POAG was also investigated., Results: Among cases, the prevalence of the wildtype genotype (T/T) was 22.1% (50/226), while the heterozygous mutated genotype (T/C) was 50.9% (115/226) and the homozygous mutant genotype (C/C) was 27% (61/226). There were no statistically significant differences between cases and controls in terms of the genotype distribution on both heterozygous mutant (p = 0.916) and homozygous mutant (p = 0.988) genotypes. POAG patients with the mutant genotypes had slightly higher intraocular pressure (IOP) than controls. Additionally, patients with T/C genotype had slight elevation of the cup/disc ratio than the normal group. Additionally, the age at onset of disease showed an increasing trend with severity of mutation where it increases across groups T/T, T/C, and C/C being at [48.9 (±16.3), 51.4 (±12.2), and 56.5 (±13.9)] respectively and a p value of 0.028 for the C/C genotype., Conclusions: This mutation could be associated with various clinical indices important for POAG. If similar findings were found in other populations and larger cohorts, then this SNP may be used as a marker for assessing the severity of the disease.

Purpose: Keratoconic corneas exhibit more mitochondrial DNA (mtDNA) damage than do normal corneas and thus mtDNA may represent a potential candidate for genetic susceptibility studies in keratoconus. To test this hypothesis we determined mitochondrial haplogroups in Saudi patients with keratoconus and healthy controls of same ethnicity., Methods: Mitochondrial haplogrouping was performed by polymerase chain reaction-based automated Sanger sequencing in 114 patients with keratoconus and 552 healthy controls., Results: Mitochondrial haplogroups H and R were significantly overrepresented in patients with keratoconus (28.9% vs. 8.5%, P < 0.0001 and 17.5% vs. 3.1%, P < 0.0001, respectively) as compared to healthy controls., Conclusions: Our data suggest that individuals with mitochondrial haplogroups H and R are at increased risk to develop keratoconus. In addition, the results provide further evidence for a plausible role of mtDNA in keratoconus etiology.

Purpose: We investigated whether a group of patients with keratoconus (KTCN) harbor mutations in the mitochondrial genome., Methods: We sequenced the full mitochondrial genome in a group of Saudi patients with KTCN (n = 26) and 100 ethnically matched controls who had no KTCN by examination., Results: A total of 10 KTCN patients (38.5%) had potentially pathogenic nonsynonymous mtDNA mutations. Of the nonsynonymous sequence changes detected, 4 (40%) were in Complex I, one was in the tRNA(Glutamine), one was in tRNA(Tryptophan), one was in tRNA(Asparagine), one was in tRNA(Histidine), and two were in the tRNA(Leucine2). One nonsynonymous sequence change was heteroplasmic, whereas all the remaining 9 were homoplasmic. These sequence changes were not detected in controls of similar ethnicity. Four sequence changes were novel (were not reported previously) and 5 were reported previously. Additionally, we detected 54 synonymous (does not result in an amino acid change) sequence changes with no pathologic significance., Conclusions: If our results are confirmed in a larger cohort and multiple ethnicities, then mtDNA mutation may be considered as a genetic risk factor contributing indirectly through the oxidative stress mechanism to the development and/or progression of KTCN.

Background: To evaluate total antioxidant status (TAS) in the plasma of primary angle closure glaucoma (PACG) patients and to compare it to that of the control group. Additionally, we aim to investigate the association of various PACG clinical indices with TAS level., Methods: Plasma samples were obtained from 139 PACG patients and 149 glaucoma-free controls of matching age, sex, and ethnicity. TAS in all samples was determined by spectrophotometric and enzyme-linked immunosorbent assay methods. We studied the possible association of the TAS level with various clinical indices relevant to PACG., Results: The mean (±SD) total antioxidant (TAS) value was almost similar in patients 1 (±0.22) compared to controls 0.97 (±0.43); p = 0.345. Among cases, mean TAS concentration showed a statistically significant lower pattern among subjects with glaucoma onset at the age of ≤ 50 years (p = 0.037) and female subjects (p = 0.014) as well as having a family history of glaucoma (p = 0.010). Interestingly, a statistically significant inverse correlation was detected between TAS concentration and intra ocular pressure (IOP), (R = -0.14, p = 0.037)., Conclusions: The inverse correlation of TAS level with IOP, highlights TAS potential role as a predictive-marker for PACG-severity.

Background: Wildervanck Syndrome (WS; cervico-oculo-acoustic syndrome) consists of Duane retraction syndrome (DRS), the Klippel-Feil anomaly, and congenital deafness. It is much more common in females than males and could be due to an X-linked mutation that is lethal to hemizygous males. We present the genetic evaluation of a male with WS and his family., Materials and Methods: Clinical evaluation and neuroimaging, sequencing of candidate genes, and array comparative genomic hybridization., Results: The patient had bilateral type 1 DRS, fusion of almost the entire cervical spine, and bilateral severe sensorineural hearing loss due to bilateral cochlear dysplasia; he also had congenital heart disease requiring surgery. His parents were unrelated, and he had eight unaffected siblings. The patient had no mutation found by Sanger sequencing of HOXA1, KIF21A, SALL4, and CHN1. He had a 3kB deletion in the X-chromosome at Xq26.3 that was not found in his mother, one unaffected sibling, or 56 healthy controls of matching ethnicity. This deletion encompassed only one gene, Fibroblast Growth Factor Homologous Factor 13 (FGF13), which encodes a 216-amino acid protein that acts intracellularly in neurons throughout brain development., Conclusions: Analysis of this patient's phenotype and genotype open the possibility that X-chromosome deletions may be a cause of WS with larger deletions being lethal to males and that FGF13 mutations may be a cause of WS.

Objective: The aim of this study was to assess the attitudes of Muslim parents from Saudi Arabia with a deaf child towards prenatal diagnosis (PND) and termination of pregnancy (TOP) for deafness and 29 other genetic and medical conditions., Methods: A questionnaire mainly focused on parent's attitude toward PND and TOP for 30 different hypothetical scenarios for a series of genetic, non-genetic and non-medical conditions was completed by 70 Saudi parents with a deaf child. The results were compared and scored, and parents' comments were noted., Results: The attitude for PND was favorable (81.4%) and was influenced by the severity of the condition among men. Among women, it was influenced by cultural considerations. For TOP, average acceptance rate (25.2%) was lower than for PND. Attitudes toward TOP were fairly similar for men and women, as both groups would consider TOP for Alzheimer disease, cleft lip and palate, and cystic fibrosis. In addition, women also ranked high deafness and thalassemia for consideration of TOP. Acceptance for TOP was not influenced by gender, income, education level, number of children, or partner attending clinic., Conclusion: In the Saudi society, cultural consideration influences attitudes towards PND and TOP rather than the severity of the condition., (© 2013 John Wiley & Sons, Ltd.)

Background: We review clinical, neuroimaging, and genetic information on six individuals with isolated sulfite oxidase deficiency (ISOD)., Methods: All patients were examined, and clinical records, biochemistry, neuroimaging, and sulfite oxidase gene (SUOX) sequencing were reviewed., Results: Data was available on six individuals from four nuclear families affected by ISOD. Each individual began to seize within the first week of life. neurologic development was arrested at brainstem reflexes, and severe microcephaly developed rapidly. neuroimaging within days of birth revealed hypoplasia of the cerebellum and corpus callosum and damage to the supratentorial brain looking like severe hypoxic-ischemic injury that evolved into cystic hemispheric white matter changes. Affected individuals all had elevated urinary S-sulfocysteine and normal urinary xanthine and hypoxanthine levels diagnostic of ISOD. Genetic studies confirmed SUOX mutations in four patients., Conclusions: ISOD impairs systemic sulfite metabolism, and yet this genetic disease affects only the brain with damage that is commonly confused with the clinical and radiologic features of severe hypoxic-ischemic encephalopathy., Lésions neurologiques dans le déficit isolé en sulfite oxydase.

Keratoconus is a progressive thinning and anterior protrusion of the cornea that results in steepening and distortion of the cornea, altered refractive powers, and reduced vision. Keratoconus has a complex multifactorial etiology, with environmental, behavioral, and multiple genetic components contributing to the disease pathophysiology. Using genome-wide and candidate gene approaches several genomic loci and genes have been identified that highlight the complex molecular etiology of this disease. The review focuses on current knowledge of these genetic risk factors associated with keratoconus.

Purpose: To investigate whether the g.4760C > T mutation in the catalase gene (CAT) is a risk factor for primary open angle glaucoma (POAG) in the Saudi population., Methods: A cohort of 225 unrelated POAG patients and 403 unrelated control subjects from Saudi Arabia were genotyped for a single nucleotide polymorphism (SNP; rs1001179; g.4760C > T) in the CAT gene utilizing Taq-Man® assay. The association between mutant genotypes and various clinical indices important for POAG was also investigated., Results: The distribution of different genotypes was comparable between both study groups. The genotype "C/C" was predominant among cases; 169 (75.1%) as well as among the controls; 289 (71.7%). As for the heterozygous mutated genotype "C/T", it was present in 52 (23.1%) of cases and 103 (25.6%) of controls, where the homozygous fully mutated genotype was present in only 4 (1.8%) of cases and 11 (2.7%) of the controls. The distribution of mutant allele was similar in both study groups (p = 0.218). Interestingly, there was a trend of association between the type of the mutation (homozygous versus heterozygous) and three clinical parameters important for predicting the severity of the disease. These parameters include mean age of onset, mean level of intraocular pressure (IOP) and mean months of duration of encountering glaucoma., Conclusions: There were no statistically significant differences between cases and controls in terms of the different genotype distribution. This mutation is possibly associated with various clinical indices important for POAG and thus may be used as a parameter for assessing POAG severity, at least in this population.

Background: To carefully assess the phenotype and genotype of a patient with partial mosaic trisomy 8 with particular attention to ophthalmologic features., Methods: Ophthalmologic and neuro-ophthalmologic examination; neuroimaging; conventional karyotyping; and array comparative genomic hybridization (CGH)., Results: The proband was the only affected child of a non-consanguineous family. At birth she was noted to have facial dysmorphism including telecanthus, low set ears, prominent nares, and an everted lower lip. She had an accommodative esotropia with otherwise normal globes, optic nerves, retinae, and orbits. She also had delayed motor milestones and mild mental retardation associated with agenesis of the corpus callosum. Both karyotyping and array CGH documented mosaic partial trisomy of chromosome 8 that included all of the "q" arm and part of the proximal "p" arm., Conclusions: This girl had a number of the classic features of mosaic trisomy 8, including an accommodative esotropia with none of the other ocular and orbital anomalies described in patients with mosaic trisomy 8. This report constitutes an initial effort to create a virtual database of patients with mosaic chromosome 8 in which careful phenotype-genotype correlation employing high resolution array CGH may help identify clues regarding the genetic etiology of ophthalmologic features of this syndrome.

Molecular diagnosis of human disorders is referred to as the detection of the various pathogenic mutations in DNA and/or RNA samples in order to facilitate detection, diagnosis, sub-classification, prognosis, and monitoring response to therapy. The use of molecular biology techniques to expand scientific knowledge of the natural history of diseases, identify people who are at risk for acquiring specific diseases, and diagnose human diseases at the nucleic acid level. Molecular diagnostics combines laboratory medicine with the knowledge and technology of molecular genetics and has been enormously revolutionized over the last decades, benefiting from the discoveries in the field of molecular biology. This review will discuss in details the recent advances in molecular diagnostics and how the Arabian Peninsula can benefit from those techniques knowing for a fact the high percentages of consanguineous marriages and the tribal nature of marriages which resulted in high incidence of genetic diseases.

Nuclear genetic disorders causing mitochondrial DNA (mtDNA) depletion are clinically and genetically heterogeneous, and the molecular etiology remains undiagnosed in the majority of cases. Through whole-exome sequencing, we identified recessive nonsense and splicing mutations in FBXL4 segregating in three unrelated consanguineous kindreds in which affected children present with a fatal encephalopathy, lactic acidosis, and severe mtDNA depletion in muscle. We show that FBXL4 is an F-box protein that colocalizes with mitochondria and that loss-of-function and splice mutations in this protein result in a severe respiratory chain deficiency, loss of mitochondrial membrane potential, and a disturbance of the dynamic mitochondrial network and nucleoid distribution in fibroblasts from affected individuals. Expression of the wild-type FBXL4 transcript in cell lines from two subjects fully rescued the levels of mtDNA copy number, leading to a correction of the mitochondrial biochemical deficit. Together our data demonstrate that mutations in FBXL4 are disease causing and establish FBXL4 as a mitochondrial protein with a possible role in maintaining mtDNA integrity and stability., (Copyright © 2013 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose of Review: We review the congenital and genetic diagnoses that are currently included in the congenital cranial dysinnervation disorders (CCDDs)., Recent Findings: Recent literature contains new genotypic and phenotypic descriptions of Duane retraction syndrome, Moebius syndrome, and other CCDDs. New genes which when mutated can result in CCDD have been identified, permitting a better understanding of associated phenotypes. More information is available regarding neurodevelopmental and clinical effects of various gene mutations associated with individual CCDDs. For certain CCDDs, the phenotype of a particular individual may not completely predict the genotype, and conversely, the genotype may not always predict the phenotype., Summary: The CCDD concept has focused attention on specific congenital disturbances of human ocular motility and on the fact that these disorders are typically neurogenic in origin. The past decade has seen rapid evolution within this field with the last 2 years yielding additional information about existing diagnoses, genes, and phenotypes that may result in better classification of these disorders and new genotype-phenotype correlations in the future.

Purpose: To evaluate total antioxidant status (TAS) in the plasma of primary open angle glaucoma (POAG) patients and to compare it to that of the control group. Additionally, we aim to investigate the association of various POAG clinical indices with TAS level., Materials and Methods: Plasma samples were obtained from 139 POAG patients and 148 glaucoma-free controls of matching age, sex, and ethnicity. TAS in all samples was determined by spectrophotometric and enzyme-linked immunosorbent assay methods.We studied the possible association of the TAS level with various clinical indices relevant to POAG., Results: The mean (±SD) total antioxidant (TAS) value was lower among patients: 0.47 (±0.32), than controls: 0.97 (±0.43) and this difference was statistically significant (p<0.0001). TAS concentration was not significantly associated neither with the level of intraocular pressure, nor with number of anti-glaucoma medications (p = 0.532 and 0.084 respectively). However, TAS level shows a trend towards reduction with increased severity of glaucoma presented in a reversed significant association with cup/disc ratio (p = 0.043)., Conclusions: Our findings provide evidence that TAS decreases in the plasma of POAG patients and that it may play a role in POAG pathogenesis. Association of TAS level with increased cup-to-disc ratio highlights TAS potential role as a predictive-marker for POAG-severity.

Background: To Investigate whether the g.4760C>T polymorphism in the promoter region of the catalase gene (CAT) is a risk factor for primary angle closure glaucoma (PACG) in the Saudi population., Methods: 138 unrelated PACG patients and 403 unrelated control subjects from Saudi Arabia were genotyped for a single nucleotide polymorphism (SNP; rs1001179; g.4760C>T) utilizing Taq-Man(®) assay. The association between different genotypes and various clinical indices important for PACG was also investigated., Results: The distribution of different genotypes was comparable between both study groups. The genotype "C/C" was predominant among cafses; 94 (68.1%) and controls; 289 (71.7%). Heterozygous genotype "C/T", was present in 41 (29.7%) of cases and 103 (25.6%) of controls, where the homozygous variant genotype was present in only 3 (2.2%) of cases and 11 (2.7%) of the controls. The distribution of variant allele was similar in both study groups (p= 0.568). Interestingly, there was a trend of association between the type of the variant (homozygous variant, heterozygous and wildtype genotype) and one important parameter for PACG, which is visual acuity. The visual acuity increase was; 0.62 (±0.74), 0.88 (±0.88) and 1.27 (±0.95) in patients carrying the "C/C", "C/T" and "T/T" genotypes respectively, which was statistically significant in both ANOVA and pairwise individual T tests (p = 0.022, 0.031 and 0.039) when compared to controls., Conclusions: This variant is possibly associated with visual acuity in PACG patients and thus had the potential to be used as a parameter for assessing PACG severity.

Genetic factors represent an important etiologic group in the causation of intellectual disability. We describe a Saudi Arabian family with closley related parents in which four of six children were affected by a congenital cognitive disturbance. The four individuals (aged 18, 16, 13, and 2 years when last examined) had motor and cognitive delay with seizures in early childhood, and three of the four (sparing only the youngest child) had progressive, severe cognitive decline with spasticity. Two affected children had ocular malformations, and the three older children had progressive visual loss. The youngest had normal globes with good functional vision when last examined but exhibited the oculodigital sign, which may signify a subclinical visual deficit. A potentially deleterious nucleotide change (c.1A>G; p.Met1Val) in the C12orf57 gene was homozygous in all affected individuals, heterozygous in the parents, and absent in an unaffected sibling and >350 normal individuals. This gene has no known function. This family manifests a autosomal recessive syndrome with some phenotypic variability that includes abnormal development of brain and eyes, delayed cognitive and motor milestones, seizures, and a severe cognitive and visual decline that is associated with a homozygous variant in a newly identified gene., (Copyright © 2013 Wiley Periodicals, Inc.)

Pediatric glaucomas are a group of heterogeneous diseases that can be potentially blinding. Their clinical presentation varies widely. Making the correct diagnosis in a timely manner and implementing a proper management plan are crucial in preventing visual loss. This review summarizes current concepts regarding terminology, classification, epidemiology, clinical features, medical and surgical treatment, and recent advances in basic science with an emphasis on the pathogenesis and genetics of pediatric glaucoma.

Purpose: To evaluate possible monogenic and chromosomal anomalies in a patient with bilateral Duane retraction syndrome and hearing impairment resulting in a phenotype resembling the HOXA1 spectrum disorder., Methods: Sequencing HOXA1 and performing high resolution array comparative genomic hybridization (arrayCGH)., Results: The proband had bilateral Duane retraction syndrome (DRS) with severe hearing loss bilaterally and an absent right vertebral artery, mimicking the major features of the Bosley-Salih-Alorainy variant of the HOXA1 spectrum. However, he also had developmental delay, mild mental retardation, and seizures. His parents were not related, but his father had milder sensorineural hearing loss bilaterally, and two paternal uncles and a paternal cousin had seizures. Neuroimaging revealed moderate maldevelopment of inner ear bony anatomy bilaterally. HOXA1 sequencing was normal, but arrayCGH revealed a small partial duplication of chromosome 7 encompassing only the PTPRN2 gene (protein tyrosine phosphatase, receptor type, N polypeptide 2) that was not present in his parents, an unaffected brother, or 53 normal ethnically-matched individuals., Conclusions: PTPRN2 is not yet linked to a genetic syndrome, although its expression has been identified in the adult human brain, in certain tumors, and in association with type 1 diabetes mellitus. The phenotype of this patient is strikingly similar to, but not identical to, that of the HOXA1 spectrum disorder. The findings in this patient raise the possibility that PTPRN2 may be active during early development of the human brainstem and that its overexpression may cause bilateral DRS with hearing loss as occurs in patients with homozygous HOXA1 mutations.

Background: Centronuclear myopathy (CNM) is a rare inherited neuromuscular disorder characterized by centrally placed nuclei in striated muscle. In this report, we describe the histological changes in the extraocular muscle (EOM) from a CNM patient with a mutation in Dynamic 2 (DNM2)., Materials and Methods: A 33-year-old Caucasian female presented with horizontal diplopia and left exotropia for 6 months prior to which she was asymptomatic. Her past medical history was significant for CNM, diagnosed based on a left quadriceps biopsy with onset of lower extremity weakness in her late 20s. She underwent a left medial rectus (LMR) resection and a left lateral rectus (LLR) recession. The resected muscle was analyzed using light and electron microscopy. Screening for mutations in the DNM2 gene was carried out and the detected mutation was confirmed by direct sequencing. Expression of the DNM2 protein was performed using immunohistochemistry (IHC)., Results: Pathology of the EOM revealed 17% centrally located muscle nuclei in contrast to 90% in the quadriceps, variable fiber size, normal ultrastructure of the EOM and normal distribution of DNM2 by IHC. Genetic analysis revealed a heterozygous R369W mutation in the DNM2 gene., Conclusion: The histological changes in the EOM in this CNM patient were mild, which reflected the mild alterations in function seen in this patient. The ophthalmologist seeing patients with new onset strabismus and a history of a myopathy should consider this entity in the differential diagnosis that could be confirmed by a muscle biopsy and mutational analysis.

Objective: The aim of this study is to investigate whether the severity of a particular condition alone influences parents' attitudes toward prenatal diagnosis (PND) and termination of pregnancy (TOP) or are there other factors involved?, Methods: A questionnaire that mainly focuses on parent's attitude toward PND and TOP for 30 different hypothetical scenarios for a series of genetic, non-genetic, and non-medical conditions were completed by 400 Saudi parents. Results were compared and scored and parent comments were noted. Additionally, cross tabulation of thalassemia, considered the most severe and had the most favorable PND and TOP, against the 29 other conditions were carried out to find similarities and different views toward TOP and PND., Results: We found that parents' attitudes toward PND and TOP for thalassemia are significantly associated with their attitudes in relation to all of the other conditions (p < 0.01)., Conclusion: Saudi Parents' attitudes toward TOP and PND are not always influenced by the severity of the condition., (© 2013 John Wiley & Sons, Ltd.)

TLR2 and TLR4 genetic variation has been investigated among the Saudis with the aim of gaining further insight into the evolutionary history of the Arabian Peninsula. Two polymorphisms located in the TLR2 gene (Pro631His and Arg753Gln, rs5743704 and rs5743708, respectively), and two (Asp299Gly and Thr399Ile, rs4986790 and rs4986791, respectively), located in the TLR4 gene have been genotyped in 201 unrelated individuals from Saudi Arabia. While the G allele has been fixed in the Arg753Gln (g.2477 G>A) polymorphism, Pro631His (g.2111 C>A) show remarkable frequencies, a polymorphism that until now has been reported exclusively among European populations. The two TLR4 markers analyzed showed moderate frequencies (ranging from 4% to 5%). Considering the reported protective role of these polymorphisms against malaria, the data suggest that the regional variation at these gene loci could have been shaped by both evolutionary infection pressure and bidirectional human migrations in the past. The population admixture may be due to the existence of gene flow from Sub-Saharan Africa and the Levant to the Arabian Peninsula.

Objective: To investigate the efficacy and safety of deep sclerectomy (DS) in Saudi patients with primary and secondary open-angle glaucoma (OAG)., Methods: In this retrospective cohort study, a total of 194 eyes of 152 patients with OAG were consecutively enrolled to undergo DS with Mitomycin-C (MMC) at King Abdulaziz University Hospital, Jeddah, Kingdom of Saudi Arabia between January 2002 and September 2010. Age at surgery, gender, type of glaucoma, operated eye, previous ocular surgery, type of implant, pre and final visit visual acuities, intraocular pressure (IOP), number of anti-glaucoma medications, optic nerve cup/disc ratio, and complications were recorded., Results: Cases were followed up to a mean of 60.9 (+/-49.7) months. The IOP reduced from a preoperative mean of 25.6 (+/-10.3) to final visit of 13.5 (+/-4), whereas the mean number of anti-glaucoma medication also reduced from 2.95 (+/-0.93) to 0.22 (+/-0.63), which was statistically significant (p<0.0001). Complete success was 82%, while overall success was 90.2%. Patients <50 years (p=0.003), high IOP (>/=21) at baseline (p=0.039), and being exposed to previous surgeries (p=0.047) were significant risk factors for failure, while combining cataract and converting to penetrating surgery have significantly improved the success rate (p=0.037)., Conclusion: Deep sclerectomy provides significant IOP reduction with low rate of visual threatening complications in Saudi patients with open angle glaucoma.

Objective: The aim of this research was to compare attitudes between women from different cultural and/or religious backgrounds toward prenatal diagnosis (PND) and termination of pregnancy (TOP) for 30 different conditions., Methods: A questionnaire examining parents' attitudes toward PND and TOP for 30 different conditions was completed by 100 Saudi, 222 UK-White, and 198 UK-Pakistani women. Comparison of overall attitudes with PND and TOP between groups was carried out, and a total score reflecting attitudes was obtained., Results: In general, there were positive attitudes toward PND among the three groups surveyed. The attitudes of Saudi and UK-Pakistani women toward PND were more favorable than UK-White women. Overall, acceptance of TOP was lower than for PND. For the majority of conditions, acceptance of TOP was highest in Saudi women and lowest in UK-Pakistani women., Conclusion: Attitudes toward TOP were significantly different between the three groups and may be influenced by cultural and/or religious factors. Availability of social services, genetic counseling, and rehabilitation centers may also influence attitude toward PND and TOP., (© 2012 John Wiley & Sons, Ltd.)

Objective: To devise a new and simple technique to help select normal embryos that are human leukocyte antigen (HLA) matched to their affected siblings for diseases, such as beta-thalassemia or sickle cell anemia, which are common in this part of the world., Methods: This study was conducted between March 2008 and April 2011 at the preimplantation Genetic Diagnosis Laboratory, Saad Specialist Hospital, Al-Khobar, Kingdom of Saudi Arabia. Embryos were obtained after 7 in vitro fertilization preimplantation genetic diagnosis (IVF-PGD) cycles. Single cells were biopsied, and extracted DNA was amplified by the multiple displacement amplification (MDA) technique. Amplified DNA was then tested for mutations in the beta-globin gene, and directly HLA typed using a sequence specific primer technique., Results: We report 7 families that underwent 7 PGD cycles with HLA typing and direct HLA loci-typing using an HLA conventional commercial kit. Two patients had PGD and HLA typing for class I and II, while the other 5 had class II. The PGD cycles resulted in 3 pregnancies out of 5 patients who had HLA matched and normal embryos. One family had a successful hematopoietic stem cell transplant., Conclusion: This report demonstrates the first clinical application of PGD coupled with direct HLA loci-typing of DNA amplified by MDA from a single cell.

Purpose: To investigate whether major single nucleotide polymorphisms (SNPs) in the LOXL1 gene associated with pseudoexfoliation glaucoma are associated with primary open angle glaucoma (POAG) in the Saudi Arabian population., Methods: The regions of the LOXL1 gene associated with pseudoexfoliation glaucoma, encompassing the three common SNPs, (rs1048661, rs3825942 and rs2165241), were sequenced in a Saudi Arabian dataset consisting of 96 POAG cases and 101 healthy controls., Results: The allele frequency of the G exfoliation risk allele for SNP rs1048661 in POAG cases and controls was 0.75 and 0.76 (p = 0.886), respectively and the allele frequency difference was not statistically significant (p = 0.866). There was no statistically significant difference in the genotypes between patients and controls (p = 0.261 and 0.156 for genotypes G/G and G/T respectively). As for SNP rs3825942, the frequency of the "G" allele in the POAG patients was comparable to that in the controls (p = 0.477) and there was no statistically significant difference in genotype G/G and A/G frequency in the study groups. As for SNP rs2165241, the "T" allele frequency in the POAG patients (0.46) was slightly higher than the frequency in controls (0.39), but this difference was not statistically significant (p = 0.176)., Conclusion: The Saudi Arabian POAG population, similar to all other populations studied to date, demonstrates no association with SNPs associated with pseudoexfoliation glaucoma.

Purpose: To identify differentially expressed genes and to elucidate gene interaction networks and molecular pathways possibly contributing to the development of POAG., Methods: Genome-wide expression profiling experiments were carried out using ABI high-density oligonucleotide microarrays in leukocytes from 25 POAG patients and 12 age-, ethnicity-, and sex-matched normal controls. Significantly modulated genes were defined as those with a false discovery rate (FDR) <0.01 and an absolute fold change (FC) >1.5. These genes are then mapped to relevant biologic processes and pathways., Results: We identified 563 genes that were significantly dysregulated (410 upregulated and 153 downregulated) in POAG compared with normal controls ("POAG gene signature"). These genes were significantly enriched with functions related to, among others, nucleoside, nucleotide, and nucleic acid metabolism, the mitogen-activated protein kinase kinase kinase cascade, apoptosis, protein synthesis, cell cycle, intracellular signaling cascade, and nervous system development and function. Among the most significantly altered canonical pathways in POAG were the ephrin receptor signaling, ubiquitin proteasome pathway, hypoxia signaling, neuregulin, and G-protein coupled receptor signaling. Network analysis revealed potentially critical roles of UBE2, TBP, GNAQ, SUMO1, CREB, p70S6k, IFNG, and CaMKII that are interacting with NF-κB, ubiquitin, proteasome, PI3K/AKT, IL12, and PDGF in the disease pathogenesis., Conclusions: Our study revealed blood gene signatures that clearly distinguish POAG patients and normal controls, as well as altered pathways that may shed light on POAG pathogenesis.

Aim: Detailed longitudinal evaluation of corneal and other ophthalmological features of patients with lipoid proteinosis (LP)., Methods: Ophthalmological examinations, chart review, ultrasound biomicroscopy, corneal confocal microscopic examinations with Nidek confoScan 4 and direct sequencing of the extracellular matrix protein 1 gene in individuals from three consanguineous Saudi families with LP., Results: Seven individuals affected with LP (four female and three male subjects) were evaluated together with nine unaffected parents and siblings. All affected individuals had homozygous mutations in extracellular matrix protein 1. Four patients were examined frequently (every 6 months) beginning in infancy and early childhood. Globe and vision were normal in all individuals, and moniliform blepharosis always appeared after the age of 4 years. Prominent corneal nerves were detected in all patients regardless of age and were more apparent in patients with more severe genetic mutations. Conversely, the severity of moniliform blepharosis seemed age-dependent rather than genotype-related., Conclusion: Prominent corneal nerves can be helpful in the early diagnosis of LP and should be added to the list of LP ophthalmological diagnostic features.