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Igor Kozak,1,2 Ganeshwaran H Mochida,3,4 Doris DM Lin,5 Syed M Ali,2,6 Thomas M Bosley7 1Department of Ophthalmology and Vision Science, University of Arizona, Tucson, AZ, USA; 2Research Department, Moorfields Eye Hospital Center, Abu Dhabi, United Arab Emirates; 3Division of Genetics and Genomics, Department of Pediatrics, Boston Children’s Hospital, Boston, MA, USA; 4Allen Discovery Center for Human Brain Evolution, Boston, MA, USA; 5Division of Neuroradiology, Russel H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD, USA; 6Department of Ophthalmology, Kanad Hospital, Al Ain, United Arab Emirates; 7Wilmer Eye Institute, Johns Hopkins University, Baltimore, MD, USACorrespondence: Igor Kozak, Department of Ophthalmology and Vision Science, University of Arizona, Tucson, AZ, USA, Tel +1-520-626-2010, Email ikozak@arizona.eduAbstract: Hemorrhagic Destruction of the Brain, Subependymal Calcification, and Congenital Cataracts (HDBSCC) is a rare syndrome caused by biallelic mutations in the JAM3 gene with significant intrafamilial variability in clinical presentation and brain imaging phenotypes. The clinical presentation of HDBSCC includes severe recurrent hemorrhages involving the brain parenchyma and the ventricles beginning in utero and continuing in infancy together with dense central cataracts present at birth. This comprehensive review documents reported cases on this unique condition and describes its genetic, neuroradiologic and ophthalmic features. It should be included in the differential diagnosis of children with congenital cataracts and neurodevelopmental abnormalities. Unique clinical, imaging findings and genetic testing can help the diagnosis.Keywords: hemorrhagic destruction of the brain, subependymal calcification, and congenital cataracts, junctional adhesion molecule 3 gene, neuroradiology, imaging, eye

Purpose: To describe clinical and ocular abnormalities in a case of Developmental Delay with Gastrointestinal, Cardiovascular, Genitourinary, and Skeletal Abnormalities (DEGCAGS syndrome)., Methods: A clinical report., Case Description: An infant born to a consanguineous Middle Eastern family who was delivered by cesarean section because of in utero growth restriction, premature labor, and breech presentation. Post-partum medical problems included hypotension, generalized hypotonia, bradycardia, apnea requiring resuscitation and positive pressure ventilation, facial dysmorphia, skeletal malformations, and disorders of the gastrointestinal, immune, urinary, respiratory, cardiac, and visual systems. The family reported that a previous child had severe hypotonia at birth and was given the diagnosis of hypoxic ischemic encephalopathy; that child remains on a ventilator in a chronic care facility. Our patient was found to be homozygous for a novel pathogenic missense variant in theZNF699 zinc finger gene on chromosome 19p13 causing a syndrome known as Developmental Delay with Gastrointestinal, Cardiovascular, Genitourinary, and Skeletal Abnormalities (DEGCAGS syndrome). We review this variable syndrome, including abnormalities of the visual system not described previously., Conclusions: We describe the 15th child to be presumably identified with the DEGCAGS syndrome and the first individual with homozygous missense variants in the ZNF699 gene who had complete clinical examination and detailed retinal imaging., (© 2023 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.)

Competing Interests: The authors report no conflicts of interest.

Background: En face optical coherence tomography (OCT) uses the data acquired during OCT of the optic disc, which typically is used to determine measurements of the peripapillary retinal nerve fiber layer (ppRNFL), to generate a coronal composite fundus image rather than a cross-sectional image. En face OCT has been reported to identify retinal changes related to papilledema in idiopathic intracranial hypertension (IIH) but has not been evaluated for monitoring papilledema. This study aimed to assess the reliability and validity of en face OCT for monitoring papilledema., Methods: Using the Pearson correlation coefficient (R), these measurements were compared with ppRNFL thickness as well as average diameter and estimated area. Four fellowship-trained neuro-ophthalmologists were asked to qualitatively rank en face images by the area of optic disc edema while masked from all other clinical data. Rankings were compared with ppRNFL thickness as a gold standard and with en face OCT characteristics using the Pearson correlation coefficient (R)., Results: Experts were able to correctly identify an increase in average ppRNFL thickness >10 µm with a mean (SD) of 91% (±7%) accuracy. A ranking error among experts corresponded to a mean (standard error) change in the ppRNFL thickness of 6 (±6) µm. The mean Pearson correlation coefficient by the area of disc edema among experts was 0.92 (±0.13)., Conclusions: Multiple objective parameters of en face OCT of optic disc edema have an excellent correlation with ppRNFL thickness. These results suggest that en face OCT is a valid clinical tool for monitoring papilledema in IIH., Competing Interests: The authors report no conflicts of interest., (Copyright © 2020 by North American Neuro-Ophthalmology Society.)

Oculomotor synkinesis is the involuntary movement of the eyes or eyelids with a voluntary attempt at a different movement. The chemokine receptor CXCR4 and its ligand CXCL12 regulate oculomotor nerve development; mice with loss of either molecule have oculomotor synkinesis. In a consanguineous family with congenital ptosis and elevation of the ptotic eyelid with ipsilateral abduction, we identified a co-segregating homozygous missense variant (c.772G>A) in ACKR3, which encodes an atypical chemokine receptor that binds CXCL12 and functions as a scavenger receptor, regulating levels of CXCL12 available for CXCR4 signaling. The mutant protein (p.V258M) is expressed and traffics to the cell surface but has a lower binding affinity for CXCL12. Mice with loss of Ackr3 have variable phenotypes that include misrouting of the oculomotor and abducens nerves. All embryos show oculomotor nerve misrouting, ranging from complete misprojection in the midbrain, to aberrant peripheral branching, to a thin nerve, which aberrantly innervates the lateral rectus (as seen in Duane syndrome). The abducens nerve phenotype ranges from complete absence, to aberrant projections within the orbit, to a normal trajectory. Loss of ACKR3 in the midbrain leads to downregulation of CXCR4 protein, consistent with reports that excess CXCL12 causes ligand-induced degradation of CXCR4. Correspondingly, excess CXCL12 applied to ex vivo oculomotor slices causes axon misrouting, similar to inhibition of CXCR4. Thus, ACKR3, through its regulation of CXCL12 levels, is an important regulator of axon guidance in the oculomotor system; complete loss causes oculomotor synkinesis in mice, while reduced function causes oculomotor synkinesis in humans., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Purpose: To report novel retinal findings in Kearns-Sayre syndrome and correlate degree of retinopathy with other clinical findings., Methods: Observational case series of patients from Saudi Arabia with retinal and neuroophthalmologic examinations, medical chart review, and mitochondrial genetic evaluation., Results: The three unrelated patients had progressive external ophthalmoplegia and pigmentary retinopathy bilaterally. Muscle biopsy in two of the cases revealed mitochondrial myopathy. All three had abnormal findings on neuroimaging and modestly reduced visual acuity in both eyes with a variable pigmentary retinopathy. One of the patients had bilateral subretinal fibrosis with a full-thickness macular hole in the right eye. All three patients had single, large-scale mitochondrial DNA (mtDNA) deletions (5.0-7.6 kb in size) with blood mtDNA heteroplasmy levels ranging from below 20% to 57%. Severity of pigmentary retinopathy did not correlate with severity of progressive external ophthalmoplegia, but did correspond grossly with electroretinographic abnormalities, just as the degree of ocular motility restriction and ptosis in each patient correlated with the size of their extraocular muscles on neuroimaging. In addition, the size of the single, large-scale mtDNA deletion and level of mtDNA heteroplasmy corresponded with degree of ocular motility restriction but not with severity of retinopathy., Conclusion: Subretinal fibrosis and macular hole are novel retinal observations which expand clinical profile in Kearns-Sayre syndrome. Genetic testing for mtDNA deletions and heteroplasmy in blood, muscle biopsy, careful ocular and retinal examination including electroretinography, and imaging are indispensable tests for this condition.

Background: To evaluate the relative frequencies of arteritic and nonarteritic anterior ischemic optic neuropathy (AION) in an Arab population and to compare and contrast these findings with known epidemiological data from Caucasian populations., Methods: A retrospective review of the medical records of all patients diagnosed with AION at the King Khaled Eye Specialist Hospital (KKESH) in Riyadh, Saudi Arabia, between 1997 and 2012., Results: Of 171 patients with AION, 4 had biopsy-proven giant-cell arteritis (GCA). The relative frequencies of arteritic anterior ischemic optic neuropathy (AAION) and nonarteritic anterior ischemic optic neuropathy (NAION) in this Arab cohort were 2.3% and 97.7%, respectively., Conclusions: The relative frequencies of arteritic anterior ischemic optic neuropathy and nonarteritic anterior ischemic optic neuropathy differ between Arab and North American clinic-based populations, with giant-cell arteritis-related ischemia being much less frequent in Saudi Arabia.

Peripheral nerve sheath tumors (PNSTs) are known to occur in the orbit and comprise 4% of all orbital tumors, but have not been well studied in contemporary literature. Ninety specimens involving the eye and ocular adnexa (1979-2015) from 67 patients were studied. The mean age was 32.5years. Locations included orbit (58.9%), eyelid (60.0%), and other ocular adnexa. Most specimens were neurofibromas (70.0%), followed by schwannomas (11.1%), neuromas (11.1%), granular cell tumors (n=4), nerve sheath myxomas (n=2), and malignant PNST (n=1). Fifty-six (88.9%) neurofibroma cases were neurofibromatosis 1 associated. Among neurofibromas, 31.7% were localized, 38.1% were plexiform, 25.4% were diffuse, and 4.8% were diffuse and plexiform. These tumors involved skin (31.7%), soft tissue (11.1%), skeletal muscle (22.2%), peripheral nerve (63.0%), lacrimal gland (20.6%), and choroid (n=1). Other histologic findings included pseudo-Meissner corpuscles (27%), Schwann cell nodules (4.8%), prominent myxoid component (7.9%), melanin-like pigment (3.2%), and inflammation (14.3%). Available immunostains included S100 (+ in 15/15 cases), EMA (+ in 2/4 cases), CD34 (+ in 4/4 cases), and Ki-67 (<1% in 4/4 cases). Among 10 schwannomas, 8 were conventional and 2 were plexiform. Observed features included capsule (n=5), hyalinized vessels (n=5), Verocay bodies (n=7), and Antoni B pattern (n=5). Immunostaining included S100+ in 4 of 4 cases, and collagen IV+ and Ki-67 <1% in 3 of 3 cases. Neurofibromas are the most common PNST involving the eye and ocular adnexa, and the majority are associated with neurofibromatosis 1. Plexiform and diffuse patterns and the presence of pseudo-Meissner corpuscles are relatively frequent in this area., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Motor, sensory, and integrative activities of the brain are coordinated by a series of midline-bridging neuronal commissures whose development is tightly regulated. Here we report a new human syndrome in which these commissures are widely disrupted, thus causing clinical manifestations of horizontal gaze palsy, scoliosis, and intellectual disability. Affected individuals were found to possess biallelic loss-of-function mutations in the gene encoding the axon-guidance receptor 'deleted in colorectal carcinoma' (DCC), which has been implicated in congenital mirror movements when it is mutated in the heterozygous state but whose biallelic loss-of-function human phenotype has not been reported. Structural MRI and diffusion tractography demonstrated broad disorganization of white-matter tracts throughout the human central nervous system (CNS), including loss of all commissural tracts at multiple levels of the neuraxis. Combined with data from animal models, these findings show that DCC is a master regulator of midline crossing and development of white-matter projections throughout the human CNS.

Purpose: To assess the importance of monogenic mutations and chromosomal copy number variants (CNVs) in the occurrence of nonsyndromic bilateral Duane retraction syndrome (bilateral nsDRS)., Methods: The medical records of 12 patients with bilateral nsDRS were reviewed. Genes associated with DRS and associated congenital cranial dysinnervation disorders (SALL4, CHN1, HOXA1, TUBB3, and KIF21A) were sequenced in the standard fashion in each patient. Array comparative genomic hybridization (array CGH) was performed using Affymetrix Cytogenetics Whole-Genome 2.7M array, and the results were analyzed using Affymetrix Chromosome Analysis Suite v1.2. CNVs were assessed as unlikely to be pathologic if they were also present in the Database of Genomic Variants (DGV) or our local database of array CGH results in 150 normal individuals of Middle Eastern ethnicity., Results: No patient had a sequence mutation in SALL4, CHN1, HOXA1, TUBB3, or KIF21A. These 12 patients each had 36-42 chromosomal deletions and/or duplications (mean with standard deviation, 26.25 ± 6.77), but all of these CNVs were present either in the DGV or in our local database of normal individuals of similar ethnicity and, therefore, are considered nonpathogenic., Conclusions: The results reported here suggest that bilateral nsDRS is not usually associated with mutations in these genes or with chromosomal CNVs. Current evidence suggests other factors such as epigenetic and/or teratogenic abnormalities may be a potential cause of bilateral nsDRS., (Copyright © 2016 American Association for Pediatric Ophthalmology and Strabismus. Published by Elsevier Inc. All rights reserved.)

Purpose: We describe the clinical features of a boy with bilateral Duane retraction syndrome (DRS), Duchenne muscular dystrophy (DMD), and other medical problems., Methods: The child was followed-up for five years; his chart was reviewed, including the results of a muscle biopsy and genetic testing. Multiplex ligation-dependent probe amplification (MLPA) was used to interrogate deletions/duplications in the dystrophin gene., Results: The proband had bilateral DRS with otherwise normal ocular motility; he also had developmental delay, mild mental retardation, and seizures. Clinical diagnosis of DMD included progressive proximal weakness, highly elevated creatine kinase levels, and a muscle biopsy showing significant dystrophic changes including contracted, degenerative, and regenerative fibers, and negative dystrophin immunostaining. MLPA documented duplication of exons 3 and 4 of the dystrophin gene., Conclusions: This boy is the third patient to be reported with DRS and DMD, the second with bilateral DRS and the only one with other neurologic features. Mutated dystrophin is present in extraocular muscles and in the central nervous system (CNS) in DMD, leaving open the question of whether this co-occurrence is the result of the genetic muscle abnormality, CNS effects caused by dystrophin mutations, or chance.

An 11-year-old girl with Joubert syndrome was evaluated for a dim red reflex in her left eye. Fundus examination revealed retinal telangiectasias bilaterally compatible with Coats-like pigmentary retinopathy, a phenomenon not previously reported in Joubert syndrome. Coats-like exudative retinopathy may result in permanent visual loss if left untreated. The exudative retinopathy was controlled after multiple sessions of indirect laser photocoagulation and cryotherapy, with a good visual outcome., (Copyright © 2016 American Association for Pediatric Ophthalmology and Strabismus. Published by Elsevier Inc. All rights reserved.)

Duane retraction syndrome (DRS) is a congenital eye-movement disorder defined by limited outward gaze and retraction of the eye on attempted inward gaze. Here, we report on three heterozygous loss-of-function MAFB mutations causing DRS and a dominant-negative MAFB mutation causing DRS and deafness. Using genotype-phenotype correlations in humans and Mafb-knockout mice, we propose a threshold model for variable loss of MAFB function. Postmortem studies of DRS have reported abducens nerve hypoplasia and aberrant innervation of the lateral rectus muscle by the oculomotor nerve. Our studies in mice now confirm this human DRS pathology. Moreover, we demonstrate that selectively disrupting abducens nerve development is sufficient to cause secondary innervation of the lateral rectus muscle by aberrant oculomotor nerve branches, which form at developmental decision regions close to target extraocular muscles. Thus, we present evidence that the primary cause of DRS is failure of the abducens nerve to fully innervate the lateral rectus muscle in early development., (Copyright © 2016 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Purpose: To assess the frequency and significance of optic disk cupping after methanol poisoning., Methods: We retrospectively reviewed the medical records of 50 consecutive patients with methanol poisoning, including visual acuity, pupillary reaction, and optic disk features such as the presence and degree of cupping. All patients were examined in the chronic phase after optic nerve damage., Results: Optic disk cupping ≥0.8 c/d was present in at least one eye of 22 of these 50 patients (43/100 eyes). Severity of cupping was statistically symmetric in the two eyes, and increasing severity of cupping was correlated with worse visual acuity (p=0.007) and increasing visual field loss. Degree of cupping was significantly correlated with increasing patient age but not with putaminal necrosis., Conclusions: Optic disk cupping after methanol poisoning may be more common than previously recognised. Cupping in this setting may reflect toxicity of methanol metabolites to axons and glial cells in the prelaminar, laminar and retrolaminar regions, and seems to be important as a marker for worse optic nerve damage., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Background: The etiology of many cases of childhood-onset chorea remains undetermined, although advances in genomics are revealing both new disease-associated genes and variant phenotypes associated with known genes., Methods: We report a Saudi family with a neurodegenerative course dominated by progressive chorea and dementia in whom we performed homozygosity mapping and whole exome sequencing., Results: We identified a homozygous missense mutation in GM2A within a prominent block of homozygosity. This mutation is predicted to impair protein function., Discussion: Although discovered more than two decades ago, to date, only five patients with this rare form of GM2 gangliosidosis have been reported. The phenotype of previously described GM2A patients has been typified by onset in infancy, profound hypotonia and impaired volitional movement, intractable seizures, hyperacusis, and a macular cherry red spot. Our findings expand the phenotypic spectrum of GM2A mutation-positive gangliosidosis to include generalized chorea without macular findings or hyperacusis and highlight how mutations in neurodegenerative disease genes may present in unexpected ways.

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.

Objectives: To present the visual sequelae of methanol poisoning and to emphasize the characteristics of methanol exposure in the Kingdom of Saudi Arabia (KSA)., Methods: A retrospective case series was carried out on 50 sequential patients with methanol poisoning seen at the King Khaled Eye Specialist Hospital and King Saud University Hospitals in Riyadh, KSA between 2008 and 2014. All patients were examined by a neuro-ophthalmologist at least one month after methanol intoxication., Results: All 50 patients were young or middle-aged males. All admitted to drinking unbranded alcohol within 2-3 days before profound or relatively profound, painless, bilateral visual loss. Mean visual acuity in this group was hand motions (logMAR 2.82; range 0.1 - 5.0) with some eye to eye variability within individuals. Worse visual acuity was correlated with advancing age (Pearson correlation: oculus dextrus [right eye] - 0.37, p=0.008; oculus sinister [left eye] - 0.36, p=0.011). All patients had optic atrophy bilaterally, and all tested patients had visual field defects. Tremors with or without rigidity were present in 12 patients, and 11 of 30 patients who had neuroimaging performed had evidence of putaminal necrosis., Conclusion: Methanol intoxication causes visual loss within 12-48 hours due to relatively severe, painless, bilateral optic nerve damage that may be somewhat variable between eyes, and is generally worse with advancing age. The coincidence of bilateral optic nerve damage and bilateral putaminal necrosis in a young or middle-aged male is very suspicious for methanol-induced damage.

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: 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.

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 evaluate the causes of ocular motility disturbances in a group of patients with orbitofacial neurofibromatosis (OFNF) with neurofibromas on the lid, brow, face, or in the orbit from infancy or early childhood., Methods: The medical records of patients with OFNF from one institution were retrospectively reviewed; selected patients were reexamined., Results: A total of 45 patients with unilateral OFNF and 4 with bilateral OFNF were included. Of these, 14 had no strabismus and relatively good vision, with no ductional abnormalities on either side despite large globes, sphenoid dysplasia, and neurofibromas in the orbit and/or cavernous sinus in many. The 8 patients with comitant strabismus also had no ductional abnormalities with a similar constellation of anatomic abnormalities, but these patients all had poor vision in at least one eye. The 27 patients with incomitant strabismus all had downward displacement of the globe and limited ductions., Conclusions: The pathologic anatomic changes associated with OFNF do not always cause ocular motility abnormalities: strabismus generally was not present when ocular motility was full and visual acuity was good. Comitant strabismus occurred in the setting of full ocular motility with reduced vision in at least one eye. Incomitant strabismus was always accompanied by reduced vision and a ductional abnormality in one or both eyes due to anatomic abnormalities of the orbit and skull., (Copyright © 2014 American Association for Pediatric Ophthalmology and Strabismus. Published by Elsevier Inc. All rights reserved.)

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: 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.

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.

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.

Mutations in PLA2G6 gene have variable phenotypic outcome including infantile neuroaxonal dystrophy, atypical neuroaxonal dystrophy, idiopathic neurodegeneration with brain iron accumulation and Karak syndrome. The cause of this phenotypic variation is so far unknown which impairs both genetic diagnosis and appropriate family counseling. We report detailed clinical, electrophysiological, neuroimaging, histologic, biochemical and genetic characterization of 11 patients, from 6 consanguineous families, who were followed for a period of up to 17 years. Cerebellar atrophy was constant and the earliest feature of the disease preceding brain iron accumulation, leading to the provisional diagnosis of a recessive progressive ataxia in these patients. Ultrastructural characterization of patients' muscle biopsies revealed focal accumulation of granular and membranous material possibly resulting from defective membrane homeostasis caused by disrupted PLA2G6 function. Enzyme studies in one of these muscle biopsies provided evidence for a relatively low mitochondrial content, which is compatible with the structural mitochondrial alterations seen by electron microscopy. Genetic characterization of 11 patients led to the identification of six underlying PLA2G6 gene mutations, five of which are novel. Importantly, by combining clinical and genetic data we have observed that while the phenotype of neurodegeneration associated with PLA2G6 mutations is variable in this cohort of patients belonging to the same ethnic background, it is partially influenced by the genotype, considering the age at onset and the functional disability criteria. Molecular testing for PLA2G6 mutations is, therefore, indicated in childhood-onset ataxia syndromes, if neuroimaging shows cerebellar atrophy with or without evidence of iron accumulation.

Objective: To describe the visual outcome of patients with lens subluxation (LS), including ectopia lentis (EL) due to genetic causes, who underwent surgical correction using standard selection criteria and surgical techniques in order to assess effectiveness of current LS therapy., Methods: This is a retrospective review of 17 sequential patients with LS who underwent lens aspiration between 2000 and 2012 through an anterior (limbal) or posterior (pars plana) approach at King Abdulaziz University Hospital, Riyadh, Saudi Arabia. Snellen visual acuity was converted to the logarithm of the Minimum Angle of Resolution (logMAR) equivalent for statistical analysis. All statistical comparisons were performed by t-test., Results: This series consisted of 28 eyes with causes of LS including Marfan syndrome (12 eyes), familial EL (5 eyes), homocystinuria (4 eyes), sickle cell anemia (2 eyes), and trauma (6 eyes). Mean visual acuity (VA) for the entire group increased from 20/200 before surgery to 20/70 after surgery (p>/=0.01). Post-operative VA was >/=20/60 in all eyes that did not have complicating factors such as amblyopia, retinal detachment, and/or other ocular abnormalities. Visual outcome of limbal and pars plana approaches was statistically similar (p>/=0.29). Patients with genetic causes of EL had a significantly better visual outcome than other patients (p>/=0.01); out of these, patients with Marfan syndrome had a better visual outcome than other patients with genetic abnormalities (p>/=0.02)., Conclusion: Accepted surgical criteria and techniques improved visual outcome in patients with LS. Patients with Marfan syndrome and others genetic abnormalities without ocular complications had best visual outcomes.

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.

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.)

We describe a patient who received cosmetic botulinum toxin type A injections to the brow and subsequently developed unilateral ptosis that was variable during examination and was transiently improved after the ice pack test. Ptosis gradually resolved spontaneously over approximately 3 months. This is the third patient to have variable ptosis documented after botulinum toxin type A injection to the brow and the second to have a positive ice test. The ice test is not completely specific for myasthenia gravis but may, at times, improve ptosis resulting from other defects at the neuromuscular junction. Wound botulism now is much more common because of illicit drug use, and the ice test also might be positive in this setting.

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.

More American neurologists may consider the possibility of living and working abroad as the world changes in coming years. This option may be particularly appealing to neurologists who are younger or older (and have fewer family responsibilities) and to some in mid-career. Professional life for a neurologist in America is generally secure and well-reimbursed, and the decision to move across the globe is not trivial. On the other hand, many more locales offer favorable practice opportunities as the world generally becomes wealthier, and health care in some places, like the Middle East and China, is expanding rapidly. Reasons to consider taking a job abroad include the adventure of living in a foreign culture, altruism, unique professional opportunities, a somewhat less rigorous work schedule, vacation travel in areas distant from America, a shared family experience, and occasionally financial benefit. Potential complications include physical safety in some places, cultural incompatibility, language barriers, funding American university education for children, and returning to employment in America.

Purpose: On occasion, neurofibromas in neurofibromatosis type 1 may be present on the lid, brow, or face of an infant or child, a circumstance commonly referred to as "orbitofacial neurofibromatosis" (OFNF). The present study evaluates the causes and extent of visual loss in a group of patients with OFNF., Design: Case series., Participants: Fifty-five patients with OFNF., Methods: Retrospective medical record review and reexamination of selected patients from one institution., Main Outcome Measures: Visual acuity and identification of underlying cause of reduced vision., Results: Fifty patients with unilateral OFNF (23 male, 27 female, aged 4-48 years at last visit) and 5 patients with bilateral OFNF (2 male, 3 female, aged 15-43 years) had adequate information available to assess afferent visual functioning. Nine patients (4 male, 5 female, aged 4-28 years) had optic pathway glioma (OPG) in addition to OFNF. Patients were followed as long as 27 years (mean 8.4 years). Thirty-nine patients (71% of total) had visual acuity of ≤20/60 on the side of OFNF involvement (or the side of worse OFNF involvement in patients with bilateral disease). One or more causes of amblyopia were present in 29 of these patients, 19 patients had organic disease of the eye (e.g., glaucoma or retinal detachment) or the afferent system (e.g., OPG), and 12 patients had correctable refractive errors., Conclusions: Visual loss in this OFNF cohort was common, typically profound, and usually multifactorial. Some causes of visual loss (including congenital glaucoma with buphthalmos and retinal detachment, disconjugate gaze due in part to distorted skull development causing strabismic amblyopia, and OPG) were difficult to treat adequately and tended to cause progressive, profound visual loss. Therefore, careful observation should be made during the period of visual immaturity for possible causes of amblyopia that might be treatable, such as refractive changes, occlusion of the visual axis, or congenital glaucoma. As affected individuals get older, physicians must be vigilant for the progression of optic nerve disease due to glaucoma or OPG and to the possibility that vision might be improved by refraction., (Copyright © 2012 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

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.

Purpose: Adults with facial nerve paresis (FNP) generally develop ectropion, but a recent report of children with syndromatic FNPs implies that entropion may be more common in this setting than ectropion. This study evaluates eyelid position and other periorbital changes in children with isolated, non-syndromatic FNP., Methods: Charts were reviewed of 10 sequential children who presented to a major national eye referral centre with isolated FNP of variable aetiology. Severity of FNP was assessed according to the House-Brackmann scale., Results: All 10 patients (4 males and 6 females; mean age at presentation, 4 years) had unilateral, isolated FNP. Mild lower-eyelid entropion was present in four patients, and severe lower-eyelid entropion required surgical correction in three patients. All patients had lower eyelid retraction (mean 2.3 mm) and lagophthalmos (mean 2.9 mm). None had enophthalmos, lower eyelid ectropion, or brow ptosis., Conclusion: Unlike adults, children with isolated FNP seem prone to develop entropion rather than ectropion. Entropion reported previously in five syndromic children with FNP seems more likely related to patients' age than to their congenital syndromes.

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.

Purpose: To report clinical observations and surgical management in a large series of patients with orbitofacial neurofibromatosis type 1 (OFNF)., Patients and Methods: Patients were identified and medical records reviewed for demographic data, ophthalmologic examinations, surgical interventions, and procedure outcome to create a retrospective, non-comparative case series of patients with OFNF seen at one medical centre over a 23-year period., Results: Sixty patients with OFNF (31 females and 29 males; mean age, 14 years) were followed for an average of 5.7 years. Presenting signs and symptoms included eyelid swelling in all patients, ptosis in 56 (93.3%), proptosis in 34 (56.6%), dystopia or strabismus in 30 (50%), and decreased visual acuity in 50 (83.3%). Surgical intervention included ptosis repair in 54 (90%; mean 1.6 surgical procedures), facial and orbital tumour debulking in 54 (90%; mean 2.3 surgeries), and canthoplasty in 28 (46.6%) patients. Eleven patients required enucleation or exenteration of a blind eye., Conclusion: Patients with OFNF often require multiple procedures to preserve vision, prevent additional disfigurement, and achieve cosmetic rehabilitation. Patients need regular ophthalmological monitoring given the potential for progressive visual and cosmetic consequences.

Purpose: To investigate the expression of the myocilin gene (MYOC) in the blood of primary open angle glaucoma (POAG) patients to determine if altered systemic expression is playing a role., Methods: Patients (n=47) were eligible for inclusion if they met standard clinical criteria for POAG. Control subjects (n=27) were recruited who were free from glaucoma by examination. RNA was extracted from leukocytes of patients and controls and converted to cDNA by reverse transcriptase enzyme, and quantitative PCR was used to assess expression levels of MYOC and the house keeping gene β-globulin (HBB). The ratio of MYOC expression to HBB expression for POAG patients was compared to that of controls and to clinical characteristics of POAG patients., Results: Mean gene expression values were statistically similar in POAG patients and controls for both MYOC (p≤0.55) and HBB (p≤0.48). MYOC/HBB ratios were also statistically indistinguishable between POAG patients and controls (p≤0.90). MYOC/HBB ratios were not significantly associated with age, sex, or ethnicity of patients within the POAG group. Similarly, MYOC/HBB ratios were not significantly associated with clinical parameters related to POAG severity, including maximum intraocular pressure, vertical cup-to-disk ratio, static perimetry mean deviation, or static perimetry pattern standard deviation., Conclusions: MYOC expression is not altered in the blood of POAG patients, unlike MYOC expression in trabecular meshwork (TM) cultures. These results suggests that MYOC expression is not altered systemically but rather that MYOC expression may contribute to POAG pathogenesis in specific tissues such as TM.

Purpose: To investigate the expression level of the optineurin gene (OPTN) in the blood of primary open angle glaucoma (POAG) patients to determine if altered expression is playing a role in primary open angle glaucoma systemically., Methods: Patients (n=47) were eligible for inclusion if they met standard clinical criteria for POAG, including age greater than 40 years, intraocular pressure ≥21 mmHg in at least one eye before treatment, normal-appearing anterior chamber angles bilaterally on gonioscopy, and optic nerve injury characteristic of POAG. Control subjects (n=27) were recruited who were free from glaucoma by examination. DNA from patient was sequenced to look for possible mutations in the coding region of OPTN or its promoter. RNA was extracted from leukocytes of patients and controls and converted to cDNA by reverse transcriptase enzyme, and quantitative PCR was used to assess expression levels of OPTN and the β-globulin gene. The ratio of OPTN expression to β-globulin gene expression for POAG patients was compared to that of controls and to clinical characteristics of POAG patients., Results: No mutation(s) were detected in any of the patients after sequencing the full OPTN gene and its promoter region. Mean OPTN (p≤0.35), and β-globulin (p≤0.48) gene expression values were statistically similar in POAG patients and controls. OPTN/β-globulin (p≤0.83) ratios were also indistinguishable between POAG patients and controls. OPTN/β-globulin ratios were not significantly associated with age, sex, or ethnicity of patients within the POAG group. Similarly, OPTN/β-globulin ratios were not significantly affected by ethnicity or clinical parameters related to POAG severity including maximum intraocular pressure, vertical cup-to-disk ratio, static perimetry mean deviation, or static perimetry pattern standard deviation., Conclusions: OPTN expression is not altered in the blood of POAG patients, suggesting that OPTN expression is not changed systemically and implying that other mechanisms are involved in POAG pathogenesis.