NEW OBSERVATIONS REGARDING THE RETINOPATHY OF GENETICALLY CONFIRMED KEARNS-SAYRE SYNDROME.

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.

Duane retraction syndrome in a patient with Duchenne muscular dystrophy.

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.

Ocular motility abnormalities in orbitofacial neurofibromatosis type 1.

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.

Neurologic injury in isolated sulfite oxidase deficiency.

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.

Xq26.3 microdeletion in a male with Wildervanck Syndrome.

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.

Variable ptosis after botulinum toxin type a injection with positive ice test mimicking ocular myasthenia gravis.

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.

A novel syndrome caused by the E410K amino acid substitution in the neuronal ß-tubulin isotype 3.

Missense mutations in TUBB3, the gene that encodes the neuronal-specific protein ß-tubulin isotype 3, can cause isolated or syndromic congenital fibrosis of the extraocular muscles, a form of complex congenital strabismus characterized by cranial nerve misguidance. One of the eight TUBB3 mutations reported to cause congenital fibrosis of the extraocular muscles, c.1228G>A results in a TUBB3 E410K amino acid substitution that directly alters a kinesin motor protein binding site. We report the detailed phenotypes of eight unrelated individuals who harbour this de novo mutation, and thus define the 'TUBB3 E410K syndrome'. Individuals harbouring this mutation were previously reported to have congenital fibrosis of the extraocular muscles, facial weakness, developmental delay and possible peripheral neuropathy. We now confirm by electrophysiology that a progressive sensorimotor polyneuropathy does indeed segregate with the mutation, and expand the TUBB3 E410K phenotype to include Kallmann syndrome (hypogonadotropic hypogonadism and anosmia), stereotyped midface hypoplasia, intellectual disabilities and, in some cases, vocal cord paralysis, tracheomalacia and cyclic vomiting. Neuroimaging reveals a thin corpus callosum and anterior commissure, and hypoplastic to absent olfactory sulci, olfactory bulbs and oculomotor and facial nerves, which support underlying abnormalities in axon guidance and maintenance. Thus, the E410K substitution defines a new genetic aetiology for Moebius syndrome, Kallmann syndrome and cyclic vomiting. Moreover, the c.1228G>A mutation was absent in DNA from ∼600 individuals who had either Kallmann syndrome or isolated or syndromic ocular and/or facial dysmotility disorders, but who did not have the combined features of the TUBB3 E410K syndrome, highlighting the specificity of this phenotype-genotype correlation. The definition of the TUBB3 E410K syndrome will allow clinicians to identify affected individuals and predict the mutation based on clinical features alone.

Partial chromosome 7 duplication with a phenotype mimicking the HOXA1 spectrum disorder.

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.

HOXB1 founder mutation in humans recapitulates the phenotype of Hoxb1-/- mice.

Members of the highly conserved homeobox (HOX) gene family encode transcription factors that confer cellular and tissue identities along the antero-posterior axis of mice and humans. We have identified a founder homozygous missense mutation in HOXB1 in two families from a conservative German American population. The resulting phenotype includes bilateral facial palsy, hearing loss, and strabismus and correlates extensively with the previously reported Hoxb1(-/-) mouse phenotype. The missense variant is predicted to result in the substitution of a cysteine for an arginine at amino acid residue 207 (Arg207Cys), which corresponds to the highly conserved Arg5 of the homeodomain. Arg5 interacts with thymine in the minor groove of DNA through hydrogen bonding and electrostatic attraction. Molecular modeling and an in vitro DNA-protein binding assay predict that the mutation would disrupt these interactions, destabilize the HOXB1:PBX1:DNA complex, and alter HOXB1 transcriptional activity.

Visual loss in orbitofacial neurofibromatosis type 1.

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.

Comitant strabismus: Perspectives, present and future.

Comitant strabismus is a common condition affecting infants, children and adults. Its impact on the affected patient may be severe resulting in visual loss, lack of binocularity, diplopia, social stigma and multiple corrective surgeries within the affected individual's lifespan. It is therefore important that this prevalent disorder should be better understood. We review the current understanding of the demographics and what is known of the etiology, risk factors and genetics of strabismus. We stress the importance of careful clinical assessment in classifying strabismus, and the common pitfalls in the measurement and pre-operative sensory work-up of the strabismic patient. The fact strabismus is comitant does not indicate it is benign: acute onset of comitant esotropia may be a presenting sign of pontine or cerebellar tumor. Lastly, we review the impact of genetics on our understanding of strabismus. While the causes of many types of congenital incomitant strabismus have been elucidated through careful observation and genetic screening, the genetics of comitant strabismus are more complex and multifactorial. Only through careful study and recruitment of large groups of affected individuals and families can we start to answer the question: why is this group of patients pre-disposed to develop strabismus. Doing so will help identify patients at risk, to spare them from the significant morbidity associated with this common disorder.

The neurology of carbonic anhydrase type II deficiency syndrome.

Carbonic anhydrase type II deficiency syndrome is an uncommon autosomal recessive disease with cardinal features including osteopetrosis, renal tubular acidosis and brain calcifications. We describe the neurological, neuro-ophthalmological and neuroradiological features of 23 individuals (10 males, 13 females; ages at final examination 2-29 years) from 10 unrelated consanguineous families with carbonic anhydrase type II deficiency syndrome due to homozygous intron 2 splice site mutation (the 'Arabic mutation'). All patients had osteopetrosis, renal tubular acidosis, developmental delay, short stature and craniofacial disproportion with large cranial vault and broad forehead. Mental retardation was present in approximately two-thirds and varied from mild to severe. General neurological examinations were unremarkable except for one patient with brisk deep tendon reflexes and two with severe mental retardation and spastic quadriparesis. Globes and retinae were normal, but optic nerve involvement was present in 23/46 eyes and was variable in severity, random in occurrence and statistically correlated with degree of optic canal narrowing. Ocular motility was full except for partial ductional limitations in two individuals. Saccadic abnormalities were present in two, while half of these patients had sensory or accommodative strabismus, and seven had congenital nystagmus. These abnormalities were most commonly associated with afferent disturbances, but a minor brainstem component to this disorder remains possible. All internal auditory canals were normal in size, and no patient had clinically significant hearing loss. Neuroimaging was performed in 18 patients and repeated over as long as 10 years. Brain calcification was generally progressive and followed a distinct distribution, involving predominantly basal ganglia and thalami and grey-white matter junction in frontal regions more than posterior regions. At least one child had no brain calcification at age 9 years, indicating that brain calcification may not always be present in carbonic anhydrase type II deficiency syndrome during childhood. Variability of brain calcification, cognitive disturbance and optic nerve involvement may imply additional genetic or epigenetic influences affecting the course of the disease. However, the overall phenotype of the disorder in this group of patients was somewhat less severe than reported previously, raising the possibility that early treatment of systemic acidosis with bicarbonate may be crucial in the outcome of this uncommon autosomal recessive problem.

Bilateral synergistic convergence associated with homozygous ROB03 mutation (p.Pro771Leu).

OBJECTIVE: To document the phenotype and determine the genotype of a child with synergistic convergence. DESIGN: Interventional case report. PARTICIPANTS: Patient and nuclear family (7 members total). METHODS: Ophthalmologic, neurologic, and radiologic examination of the proband; venous blood sampling for candidate gene testing of the proband; venous blood sampling for confirmatory testing in other family members. MAIN OUTCOME MEASURES: Clinical and radiologic observations in proband and candidate gene results. RESULTS: The proband, a 9-year-old girl, substituted convergence for horizontal gaze (synergistic convergence) since birth. She also had conjugate pendular nystagmus, asynchronous blinking, and high myopia. No family member had ophthalmologic or medical symptoms. Neuroradiologic imaging revealed hindbrain dysplasia and modest scoliosis. Sequencing of ROB03, the gene associated with horizontal gaze palsy and progressive scoliosis, revealed a novel missense mutation (p.Pro771Leu) that altered an evolutionarily conserved amino acid. Screening the family for this mutation confirmed that both parents were carriers and identified 2 sisters as carriers and 2 brothers as noncarriers. CONCLUSIONS: This is the second reported patient with synergistic convergence and the first associated with a documented pathologic genotype. Unlike the previously reported case (which occurred in the setting of the cranial dysinnervation disorder congenital fibrosis of the extraocular muscles), our patient presumably has a supranuclear cause. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Ophthalmic features of ataxia telangiectasia-like disorder.

INTRODUCTION: Ataxia telangiectasia (AT) is a recessive neurodegenerative disease due to a faulty repair mechanism for breaks in double-stranded DNA (ATM mutation). Ophthalmic features of AT include conjunctival telangiectasia, strabismus, saccadic dysfunction with head thrusts, and convergence insufficiency. Ataxia telangiectasia-like syndrome (ATLD) is a more recently recognized condition due to homozygous mutation in MRE11, a gene also involved in the cellular repair response to double-stranded DNA breaks; ophthalmic features of ATLD are not well described. The purpose of this article is to describe the ophthalmic features of ATLD. METHODS: Full ophthalmologic and orthoptic evaluations were obtained in 13 individuals: 10 previously reported ATLD patients, an additional related ATLD patient, and 3 nonaffected relatives. All individuals were from three unrelated consanguineous Saudi Arabian families harboring an MRE11 mutation (W210C). Age range was from 2 to 40 years of age. RESULTS: No affected patient had structural ocular abnormality (eg, conjunctival telangiectasia), manifest strabismus at distance, or duction limitation. All but one (the youngest) had saccadic dysfunction (without head thrusts). Most patients had abnormal convergence. Older patients had nystagmus with abnormalities in smooth pursuit and vestibular ocular reflex. All patients had cerebellar atrophy by neuroimaging and slowly progressive ataxia. The unaffected heterozygous relatives had unremarkable ophthalmic and neurologic examinations. CONCLUSIONS: Saccadic dysfunction without head thrusts and convergence abnormality are common in ATLD secondary to homozygous W210C MRE11 mutation. Older patients have nystagmus with abnormalities in smooth pursuit and vestibular ocular reflex. Eye movement control systems apparently deteriorate with time in this rare neurological disease. Ophthalmic features of AT that were not observed in any of our ATLD patients include conjunctival telangiectasia, head thrusting, and manifest strabismus at distance.

Duane retraction syndrome on the Arabian Peninsula.

PURPOSE: To describe the clinical features of patients from the Arabian Peninsula with Duane retraction syndrome (DRS). METHODS: Retrospective chart review of patients referred to the King Khaled Eye Specialist Hospital in Riyadh, Saudi Arabia from 1982 to 2003 with a diagnosis of DRS. Patients having had prior strabismus surgery were excluded. RESULTS: Of 404 DRS patients, 347 (86%) were unilateral, 57 (14%) were bilateral, and 111 (27%) had amblyopia. There were 221 (55%) females and 182 (45%) males. The Huber classification was as follows: 315 (78%) Type I, 16 (4%) Type II, and 77 (19%) Type III. Of the 57 bilateral cases, 25 (44%) were female and 32 (56%) were male. DISCUSSION: Overall, the clinical features of DRS patients referred to a Riyadh eye hospital are similar to those reported in series throughout the world. However, our referred bilateral DRS patients are more commonly male. The clinical features of bilateral DRS deserve further worldwide study.

Neurological features of congenital fibrosis of the extraocular muscles type 2 with mutations in PHOX2A.

Congenital fibrosis of the extraocular muscles type 2 (CFEOM2) is a complex strabismus syndrome that results from mutations in the homeodomain transcription factor PHOX2A. To define the clinical and neuroimaging features of patients with this autosomal recessive syndrome, we studied 15 patients with genetically defined CFEOM2. All patients underwent full neurological, neuro-ophthalmological and orthoptic assessments. Twelve patients had pupillary pharmacological testing and nine had 3.0 tesla MRI of the brain, brainstem and orbits. Patients were born with severe bilateral ptosis and exotropia with almost complete bilateral absence of adduction, elevation, depression and intorsion. Variable abduction was present prior to strabismus surgery in 14 patients, and central ocular motility reflexes (smooth pursuit, saccades, vestibulo-ocular reflex and optokinetic reflex) were intact except for convergence. Pupillary light and near reflexes were not present, but irises were anatomically normal and responded to pupillary pharmacology. Neuroimaging of brain and brainstem was remarkable for the anatomical absence of cranial nerve (CN) 3 and probably CN 4 bilaterally. Therefore, the CFEOM2 phenotype and neuroimaging are both consistent with the congenital absence of CNs 3 and 4. Additional features included presence of most central ocular motility reflexes, a central lack of pupillary responsiveness of uncertain aetiology and modest phenotypic variability that does not correlate with specific PHOX2A mutations. Clinical presentation, neuroimaging and Phox2a-/- animal models all support the concept that CFEOM2 is a primary neurogenic abnormality with secondary myopathic changes.

Presbyopia complicating pre-existing strabismus.

BACKGROUND: Presbyopia may affect pre-existing sensory adaptations or aggravate previously asymptomatic heterophoria. We describe the presentation, underlying problem and management of 11 patients with pre-existing strabismus or heterophoria who presented with new symptoms of double vision attributable to presbyopic change, an association not previously reported. METHODS: Patients with new strabismic symptoms attributable to presbyopia were recruited prospectively over a 1-year period. RESULTS: The 11 patients had had a recent decrease of accommodative amplitude that resulted in blurred vision at near with a breakdown of pre-existing heterophoria (2 patients), alteration of fixation pattern (6 patients), symptomatic alternating fixation (2 patients) or intolerance to correction owing to restrictive strabismus (1 patient). INTERPRETATION: At the onset of presbyopia, symptoms may be varied and subtle. Ophthalmologists and orthoptists should carefully determine the exact nature of the symptoms. Any pre-existing fixation pattern should then be established from the history, old photographs or suppression characteristics. Refractive or surgical management should be aimed at returning the patient to his or her long-standing sensory adaptation. Other important issues, such as incomplete correction of hypermetropia by refractive surgery and problems using bifocals with vertical restrictive strabismus, should be noted.