- Email: [email protected]
Bilateral Synergistic Convergence Associated with Homozygous ROB03 Mutation (p.Pro771Leu)
Bilateral Synergistic Convergence Associated with Homozygous ROB03 Mutation (p.Pro771Leu) Arif O. Khan, MD,1 Darren T. Oystreck, OC(C),1 Nada Al-Tassan, PhD,2 Latifa Al-Sharif, Bsc,2 Thomas M. Bosley, MD3 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. Ophthalmology 2008;115:2262–2265 © 2008 by the American Academy of Ophthalmology.
Synergistic convergence is a rare abnormal extraocular muscle motility pattern consisting of bilateral adduction during attempted lateral gaze in the absence of convergence spasm. It has been described previously in an adult with clinical and radiologic evidence for congenital fibrosis of the extraocular muscles type 1 (CFEOM1, On-Line Mendelian Inheritance in Man [MIM] 135700).1 In that patient, synergistic convergence was presumably infranuclear in origin, related to the aberrant orbital innervation that is part of the congenital cranial dysinnervation disorders.2 We describe the phenotype and document the genotype for a second patient with synergistic convergence. Unlike the previously reported case, our patient probably has a supranuclear etiology caused by a novel homozygous mutation in ROB03 [MIM *608630], the gene associated with horizontal gaze palsy and progressive scoliosis (HGPPS) [MIM 60731].3,4
a 3.0 Tesla Siemens Magneton Allegra scanner (Siemens Medical Systems, Erlangen, Germany), including axial 3-dimensional Fourier transform constructive interference in steady-state of the brainstem. Family members were observed but not thoroughly examined; they had no ophthalmologic or general medical symptoms. A 5-mL venous blood sample was collected from the patient for diagnostic sequencing of coding exons in the candidate genes KIF21A (MIM *608283), HOXA1 (MIM *142955), and ROB03. Sequencing was done using polymerase chain reaction on a MegaBace 1000 capillary sequencer (Global Medical Instrumentation, Ramsey, MN; exact primers and conditions available on request). Carrier testing for the apparent ROB03 mutation was performed on the proband’s parents and 4 siblings. Controls were 50 healthy Saudi individuals (100 chromosomes) who donated their DNA for polymorphism research. When a sequence variant was identified, it was tested for in one control (2 chromosomes). If the variant was not found in the one control, it was tested for in the 100 normal chromosomes.
Materials and Methods
Results
Institutional review board approval was granted for this project. The patient had complete ophthalmologic, neurologic, and orthoptic examinations. Magnetic resonance imaging of the brain was obtained on
The proband, a 9-year-old girl who was the fifth child of a first-cousin marriage, was seen because of congenital, nonprogressive, abnormal eye movements. Birth history and medical history
2262
© 2008 by the American Academy of Ophthalmology Published by Elsevier Inc.
ISSN 0161-6420/08/$–see front matter doi:10.1016/j.ophtha.2008.08.010
Khan et al 䡠 Bilateral Synergistic Convergence Associated with Homozygous ROB03 Mutation
Figure 1. Ocular versions demonstrate that during attempted side gaze, convergence is substituted for horizontal gaze. Vertical versions are normal.
were unremarkable. She did not walk until 2 years of age but seemed cognitively normal. Parents and all siblings were healthy. The family had no history of significant medical, neurologic, or ophthalmologic disease. The patient’s vision with current glasses (⫺10 diopters [D] right eye [OD], ⫺12–2.00⫻073 D left eye [OS]) measured 20/50 OD and 20/70 OS. Low-amplitude, low-frequency horizontal pendular nystagmus was present intermittently. At times she obliquely nodded her head with low amplitude and a high frequency, but this also was not consistent. She often blinked asynchronously, that is,
at times the left eye blinked without the right eye and at other times the right eye blinked without the left eye. Neither eye abducted on attempted horizontal gaze, although vertical gaze was intact. Rather, on attempted horizontal gaze to either side, both eyes adducted without pupillary miosis (Fig 1, Video 1 [available at http://aaojournal.org]). The same inappropriate adduction occurred in both eyes during duction testing. These synergistic convergence movements were not voluntary and could not be voluntarily inhibited. Convergence to a near target was appropriate, including bilateral pupillary miosis. Abduction (with
Figure 2. (A) Scout spine x-ray showing modest thoracolumbar scoliosis concave left not apparent during clothed ophthalmologic examination. Axial steady-state free precession transverse magnetic resonance imaging through the medulla (B) and pons (C) confirming hypoplasia with deep anterior and posterior midline clefts and a somewhat large fourth ventricle typical of HGPPS. T2-weighted transverse (D) and coronal (E) magnetic resonance imaging through the orbits demonstrating normal appearing extraocular muscles and myopic globes.
2263
Ophthalmology Volume 115, Number 12, December 2008 and without monocular patching of the opposite eye) could not be demonstrated by the vestibulo-ocular reflex or doll’s-head maneuver. In the primary position, she had a mild left hypertropia that increased slightly in upgaze and decreased in downgaze. Forced ductions could not be performed despite topical anesthetic because of the child’s sensitivity. She used a face turn rather than eye movements to view objects to her side. Pupillary examination was normal, and visual fields were full to confrontation. Slit-lamp examination of the anterior segment was within normal limits, and cycloplegic refraction (cyclopentolate 1%) was comparable to her current glasses. Examination of the posterior pole revealed a myopic fundus in both eyes. Scoliosis (specifically assessed because of possible HGPPS) was not apparent when she was clothed. Plain x-rays of the spine showed a previously undetected, modest scoliosis (Fig 2A). Magnetic resonance imaging revealed brainstem hypoplasia typical of HGPPS,3,4 including a deep anterior midline cleft, a small pons, small cerebellar peduncles, and intact cranial nerves (CNs) 3 and 6 bilaterally (Fig 2B, C). Globes were large, compatible with her known myopia. Extraocular muscles were normal in size bilaterally (Fig 2D, E), and the remainder of the brain was unremarkable.
Two heterozygous amino acid polymorphisms were found in genes surveyed (p.Ala209Ala [c.627 T⬎G] in KIF21A; p.Arg73His [c.218 G⬎A] in HOXA1). The silent c.627 T⬎G KIF21A variant was found in a random normal control (heterozygous state), and the p.Arg74His HOXA1 variant was found in a random normal control (homozygous state); because both variants were found in the first normal control tested, additional controls were not tested for these polymorphisms. A novel homozygous p.Pro771Leu (c.2312 C⬎T) variant was identified in ROB03 (Fig 3A, B) and was confirmed by sequencing exon 15 in both directions (ENSEMBLE reference sequence ENSG00000154134). This variant was not found in 100 random normal chromosomes and affected an amino acid that is highly conserved in several species (Fig 3C).5,6 Carrier testing for this mutation revealed that both parents were heterozygous for this mutation, 2 brothers were homozygous for the normal allele (p.Pro771), and 2 sisters were heterozygous for the mutation.
Discussion Our patient had strong, involuntary, synergistic convergence movements in both eyes on attempted lateral gaze to either
Figure 3. The sequence traces show the region of exon 15 of ROB03 where the c.2312 C⬎T (p.Pro771Leu) change is located. A normal control sequence trace (A) is homozygous for the normal allele (“C” at position 2312). The patient (B) is homozygous for the mutant allele (“T” at position 2312). Arrow points to the base substitution. C, There is evolutionary conservation of the p.Pro771Leu variant in ROB03. The comparison shows the affected site (arrow) in Homo sapiens (H. sap) with homologues from Macaca mulatta (Macaca), Mus musculus (Mus), Rattus norvegicus (Rattus), and Canis familiaris (Canis) using ClustalW.5 Identical, conserved and semi-conserved residues are shaded gray, blue, and yellow, respectively.
2264
Khan et al 䡠 Bilateral Synergistic Convergence Associated with Homozygous ROB03 Mutation side. These movements persisted on duction testing (with the contralateral eye covered), and pupillary changes were not significant. She was easily able to perform graded convergence to a near target with appropriate miosis. Neither eye abducted at all with any maneuver, but vertical gaze was intact. Our patient had no conjugate horizontal eye movements, but vertical ocular motility was normal. She had modest scoliosis, asynchronous blinking, and small amplitude horizontal pendular nystagmus. She also had brainstem hypoplasia typical of HGPPS on neuroimaging2,3 without ocular or orbital changes (i.e., no evidence for CFEOM). The diagnosis of HGPPS was confirmed by the presence of a novel homozygous ROB03 mutation not found in controls but present in heterozygote form in both parents (obligate heterozygotes) and 2 of 4 siblings. ROB03 is only known to affect decussation of neuronal tracts within the human brainstem and spinal cord during weeks 15 to 19 of development;3 therefore, synergistic convergence in our patient is likely the result of a central malfunction of the convergence and horizontal gaze mechanisms. In contrast, the only previously reported case of synergistic convergence1 occurred in the context of a congenital cranial dysinnervation disorder that looked most like CFEOM1 (infraduction OU, exotropia, and almost complete ophthalmoplegia), although genetic testing for KIF21A was not performed. Neuroimaging was also consistent with CFEOM because it confirmed hypoplastic extraocular muscles and absent ocular motor cranial nerve nuclei.1,2 Synergistic convergence in that patient was, therefore, likely peripheral in origin, related to abnormal ocular motor cranial nerve development with aberrant orbital innervation.2 Synergistic convergence, it seems, can occur with either central (HGPPS in the current patient) or peripheral (probably CFEOM1 in the previous patient) miswiring of the ocular motility system. A model of conjugate gaze proposed by Leigh and Zee7 offers a possible mechanism for synergistic convergence in the setting of HGPPS. Some element of convergence is required for conjugate eye movements to track an object if that object is not at optical infinity. In their model, upper brainstem control of convergence in the mesencephalic reticular formation and pontine control of horizontal gaze in the paramedian pontine reticular formation act together to direct conjugate gaze. Loss of one of these inputs can lead to compensatory action from the other input; that is, loss of horizontal gaze could lead to convergence during attempted horizontal gaze. This theory is supported by case reports of patients who had acquired horizontal gaze loss as the result of pontine injury and substituted convergence with miosis for the lost horizontal gaze.8,9
No previously reported patient with HGPPS has had synergistic convergence, although one did seem to use convergence voluntarily to cross-fixate at an object positioned slightly to the side of primary gaze.4 Convergence is typically intact in patients with HGPPS, although it can be poor.4 The fact that miosis did not accompany convergence during attempted horizontal gaze in our patient suggests discrete neuroanatomic localization of the 3 components of the near triad (convergence, miosis, and accommodation), a concept that has been suggested before and for which there is neuroanatomic evidence.10,11 At this point, it remains unclear why this patient with homozygous p.Pro771Leu ROB03 mutation had synergistic convergence and other patients with HGPPS did not.
References 1. Kim JH, Hwang JM. Adduction on attempted abduction: the opposite of synergistic divergence. Arch Ophthalmol 2006; 124:918 –20. 2. Gutowski NJ, Bosley TM, Engle EC. 110th ENMC International Workshop: the congenital cranial dysinnervation disorders (CCDDs). Naarden, The Netherlands, 25–27 October, 2002. Neuromuscul Disord 2003;13:573– 8. 3. Jen JC, Chan WM, Bosley TM, et al. Mutations in a human ROBO gene disrupt hindbrain axon pathway crossing and morphogenesis. Science 2004;304:1509 –13. 4. Bosley TM, Salih MA, Jen JC, et al. Neurologic features of horizontal gaze palsy and progressive scoliosis with mutations in ROB03. Neurology 2005;64:1196 –203. 5. Marchler-Bauer A, Anderson JB, Derbyshire MK, et al. CDD: a conserved domain database for interactive domain family analysis. Nucleic Acids Res 2007;35(database issue):D237– 40. 6. Chenna R, Sugawara H, Koike T, et al. Multiple sequence alignment with the Clustal series of programs. Nucleic Acids Res 2003;31:3497–500. 7. Leigh RJ, Zee DS. Vergence eye movements. In: The Neurology of Eye Movements. 2nd ed. Philadelphia, PA: F.A. Davis Co.; 1991:264 –90. Contemporary Neurology Series. vol. 35. 8. Beigi B, O’Keeffe M, Logan P, Eustace P. Convergence substitution for paralysed horizontal gaze. Br J Ophthalmol 1995;79:229 –32. 9. Kohno T, Oohira A, Hori S. Near reflex substituting for acquired horizontal gaze palsy: a case report. Jpn J Ophthalmol 2004;48:584 – 6. 10. Jampel RS, Mindel J. The nucleus for accommodation in the midbrain of the macaque. Invest Ophthalmol 1967;6:40 –50. 11. Goldstein JH, Schneekloth BB. Spasm of the near reflex: a spectrum of abnormalities. Surv Ophthalmol 1996;40:269 –78.
Footnotes and Financial Disclosures Originally received: May 6, 2008. Final revision: June 1, 2008. Accepted: August 5, 2008.
3
Manuscript no. 2008-549.
1
Division of Pediatric Ophthalmology, King Khaled Eye Specialist Hospital, Riyadh, Saudi Arabia. 2
Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
Division of Neurology, Cooper University Hospital, Camden, New Jersey. Financial Disclosure(s): The authors have no proprietary or commercial interest in any materials discussed in this article. Correspondence: Arif O. Khan, MD, Division of Pediatric Ophthalmology, King Khaled Eye Specialist Hospital, PO Box 7191, Riyadh 11462, Saudi Arabia. E-mail: [email protected].
2265
Synergistic convergence is a rare abnormal extraocular muscle motility pattern consisting of bilateral adduction during attempted lateral gaze in the absence of convergence spasm. It has been described previously in an adult with clinical and radiologic evidence for congenital fibrosis of the extraocular muscles type 1 (CFEOM1, On-Line Mendelian Inheritance in Man [MIM] 135700).1 In that patient, synergistic convergence was presumably infranuclear in origin, related to the aberrant orbital innervation that is part of the congenital cranial dysinnervation disorders.2 We describe the phenotype and document the genotype for a second patient with synergistic convergence. Unlike the previously reported case, our patient probably has a supranuclear etiology caused by a novel homozygous mutation in ROB03 [MIM *608630], the gene associated with horizontal gaze palsy and progressive scoliosis (HGPPS) [MIM 60731].3,4
a 3.0 Tesla Siemens Magneton Allegra scanner (Siemens Medical Systems, Erlangen, Germany), including axial 3-dimensional Fourier transform constructive interference in steady-state of the brainstem. Family members were observed but not thoroughly examined; they had no ophthalmologic or general medical symptoms. A 5-mL venous blood sample was collected from the patient for diagnostic sequencing of coding exons in the candidate genes KIF21A (MIM *608283), HOXA1 (MIM *142955), and ROB03. Sequencing was done using polymerase chain reaction on a MegaBace 1000 capillary sequencer (Global Medical Instrumentation, Ramsey, MN; exact primers and conditions available on request). Carrier testing for the apparent ROB03 mutation was performed on the proband’s parents and 4 siblings. Controls were 50 healthy Saudi individuals (100 chromosomes) who donated their DNA for polymorphism research. When a sequence variant was identified, it was tested for in one control (2 chromosomes). If the variant was not found in the one control, it was tested for in the 100 normal chromosomes.
Materials and Methods
Results
Institutional review board approval was granted for this project. The patient had complete ophthalmologic, neurologic, and orthoptic examinations. Magnetic resonance imaging of the brain was obtained on
The proband, a 9-year-old girl who was the fifth child of a first-cousin marriage, was seen because of congenital, nonprogressive, abnormal eye movements. Birth history and medical history
2262
© 2008 by the American Academy of Ophthalmology Published by Elsevier Inc.
ISSN 0161-6420/08/$–see front matter doi:10.1016/j.ophtha.2008.08.010
Khan et al 䡠 Bilateral Synergistic Convergence Associated with Homozygous ROB03 Mutation
Figure 1. Ocular versions demonstrate that during attempted side gaze, convergence is substituted for horizontal gaze. Vertical versions are normal.
were unremarkable. She did not walk until 2 years of age but seemed cognitively normal. Parents and all siblings were healthy. The family had no history of significant medical, neurologic, or ophthalmologic disease. The patient’s vision with current glasses (⫺10 diopters [D] right eye [OD], ⫺12–2.00⫻073 D left eye [OS]) measured 20/50 OD and 20/70 OS. Low-amplitude, low-frequency horizontal pendular nystagmus was present intermittently. At times she obliquely nodded her head with low amplitude and a high frequency, but this also was not consistent. She often blinked asynchronously, that is,
at times the left eye blinked without the right eye and at other times the right eye blinked without the left eye. Neither eye abducted on attempted horizontal gaze, although vertical gaze was intact. Rather, on attempted horizontal gaze to either side, both eyes adducted without pupillary miosis (Fig 1, Video 1 [available at http://aaojournal.org]). The same inappropriate adduction occurred in both eyes during duction testing. These synergistic convergence movements were not voluntary and could not be voluntarily inhibited. Convergence to a near target was appropriate, including bilateral pupillary miosis. Abduction (with
Figure 2. (A) Scout spine x-ray showing modest thoracolumbar scoliosis concave left not apparent during clothed ophthalmologic examination. Axial steady-state free precession transverse magnetic resonance imaging through the medulla (B) and pons (C) confirming hypoplasia with deep anterior and posterior midline clefts and a somewhat large fourth ventricle typical of HGPPS. T2-weighted transverse (D) and coronal (E) magnetic resonance imaging through the orbits demonstrating normal appearing extraocular muscles and myopic globes.
2263
Ophthalmology Volume 115, Number 12, December 2008 and without monocular patching of the opposite eye) could not be demonstrated by the vestibulo-ocular reflex or doll’s-head maneuver. In the primary position, she had a mild left hypertropia that increased slightly in upgaze and decreased in downgaze. Forced ductions could not be performed despite topical anesthetic because of the child’s sensitivity. She used a face turn rather than eye movements to view objects to her side. Pupillary examination was normal, and visual fields were full to confrontation. Slit-lamp examination of the anterior segment was within normal limits, and cycloplegic refraction (cyclopentolate 1%) was comparable to her current glasses. Examination of the posterior pole revealed a myopic fundus in both eyes. Scoliosis (specifically assessed because of possible HGPPS) was not apparent when she was clothed. Plain x-rays of the spine showed a previously undetected, modest scoliosis (Fig 2A). Magnetic resonance imaging revealed brainstem hypoplasia typical of HGPPS,3,4 including a deep anterior midline cleft, a small pons, small cerebellar peduncles, and intact cranial nerves (CNs) 3 and 6 bilaterally (Fig 2B, C). Globes were large, compatible with her known myopia. Extraocular muscles were normal in size bilaterally (Fig 2D, E), and the remainder of the brain was unremarkable.
Two heterozygous amino acid polymorphisms were found in genes surveyed (p.Ala209Ala [c.627 T⬎G] in KIF21A; p.Arg73His [c.218 G⬎A] in HOXA1). The silent c.627 T⬎G KIF21A variant was found in a random normal control (heterozygous state), and the p.Arg74His HOXA1 variant was found in a random normal control (homozygous state); because both variants were found in the first normal control tested, additional controls were not tested for these polymorphisms. A novel homozygous p.Pro771Leu (c.2312 C⬎T) variant was identified in ROB03 (Fig 3A, B) and was confirmed by sequencing exon 15 in both directions (ENSEMBLE reference sequence ENSG00000154134). This variant was not found in 100 random normal chromosomes and affected an amino acid that is highly conserved in several species (Fig 3C).5,6 Carrier testing for this mutation revealed that both parents were heterozygous for this mutation, 2 brothers were homozygous for the normal allele (p.Pro771), and 2 sisters were heterozygous for the mutation.
Discussion Our patient had strong, involuntary, synergistic convergence movements in both eyes on attempted lateral gaze to either
Figure 3. The sequence traces show the region of exon 15 of ROB03 where the c.2312 C⬎T (p.Pro771Leu) change is located. A normal control sequence trace (A) is homozygous for the normal allele (“C” at position 2312). The patient (B) is homozygous for the mutant allele (“T” at position 2312). Arrow points to the base substitution. C, There is evolutionary conservation of the p.Pro771Leu variant in ROB03. The comparison shows the affected site (arrow) in Homo sapiens (H. sap) with homologues from Macaca mulatta (Macaca), Mus musculus (Mus), Rattus norvegicus (Rattus), and Canis familiaris (Canis) using ClustalW.5 Identical, conserved and semi-conserved residues are shaded gray, blue, and yellow, respectively.
2264
Khan et al 䡠 Bilateral Synergistic Convergence Associated with Homozygous ROB03 Mutation side. These movements persisted on duction testing (with the contralateral eye covered), and pupillary changes were not significant. She was easily able to perform graded convergence to a near target with appropriate miosis. Neither eye abducted at all with any maneuver, but vertical gaze was intact. Our patient had no conjugate horizontal eye movements, but vertical ocular motility was normal. She had modest scoliosis, asynchronous blinking, and small amplitude horizontal pendular nystagmus. She also had brainstem hypoplasia typical of HGPPS on neuroimaging2,3 without ocular or orbital changes (i.e., no evidence for CFEOM). The diagnosis of HGPPS was confirmed by the presence of a novel homozygous ROB03 mutation not found in controls but present in heterozygote form in both parents (obligate heterozygotes) and 2 of 4 siblings. ROB03 is only known to affect decussation of neuronal tracts within the human brainstem and spinal cord during weeks 15 to 19 of development;3 therefore, synergistic convergence in our patient is likely the result of a central malfunction of the convergence and horizontal gaze mechanisms. In contrast, the only previously reported case of synergistic convergence1 occurred in the context of a congenital cranial dysinnervation disorder that looked most like CFEOM1 (infraduction OU, exotropia, and almost complete ophthalmoplegia), although genetic testing for KIF21A was not performed. Neuroimaging was also consistent with CFEOM because it confirmed hypoplastic extraocular muscles and absent ocular motor cranial nerve nuclei.1,2 Synergistic convergence in that patient was, therefore, likely peripheral in origin, related to abnormal ocular motor cranial nerve development with aberrant orbital innervation.2 Synergistic convergence, it seems, can occur with either central (HGPPS in the current patient) or peripheral (probably CFEOM1 in the previous patient) miswiring of the ocular motility system. A model of conjugate gaze proposed by Leigh and Zee7 offers a possible mechanism for synergistic convergence in the setting of HGPPS. Some element of convergence is required for conjugate eye movements to track an object if that object is not at optical infinity. In their model, upper brainstem control of convergence in the mesencephalic reticular formation and pontine control of horizontal gaze in the paramedian pontine reticular formation act together to direct conjugate gaze. Loss of one of these inputs can lead to compensatory action from the other input; that is, loss of horizontal gaze could lead to convergence during attempted horizontal gaze. This theory is supported by case reports of patients who had acquired horizontal gaze loss as the result of pontine injury and substituted convergence with miosis for the lost horizontal gaze.8,9
No previously reported patient with HGPPS has had synergistic convergence, although one did seem to use convergence voluntarily to cross-fixate at an object positioned slightly to the side of primary gaze.4 Convergence is typically intact in patients with HGPPS, although it can be poor.4 The fact that miosis did not accompany convergence during attempted horizontal gaze in our patient suggests discrete neuroanatomic localization of the 3 components of the near triad (convergence, miosis, and accommodation), a concept that has been suggested before and for which there is neuroanatomic evidence.10,11 At this point, it remains unclear why this patient with homozygous p.Pro771Leu ROB03 mutation had synergistic convergence and other patients with HGPPS did not.
References 1. Kim JH, Hwang JM. Adduction on attempted abduction: the opposite of synergistic divergence. Arch Ophthalmol 2006; 124:918 –20. 2. Gutowski NJ, Bosley TM, Engle EC. 110th ENMC International Workshop: the congenital cranial dysinnervation disorders (CCDDs). Naarden, The Netherlands, 25–27 October, 2002. Neuromuscul Disord 2003;13:573– 8. 3. Jen JC, Chan WM, Bosley TM, et al. Mutations in a human ROBO gene disrupt hindbrain axon pathway crossing and morphogenesis. Science 2004;304:1509 –13. 4. Bosley TM, Salih MA, Jen JC, et al. Neurologic features of horizontal gaze palsy and progressive scoliosis with mutations in ROB03. Neurology 2005;64:1196 –203. 5. Marchler-Bauer A, Anderson JB, Derbyshire MK, et al. CDD: a conserved domain database for interactive domain family analysis. Nucleic Acids Res 2007;35(database issue):D237– 40. 6. Chenna R, Sugawara H, Koike T, et al. Multiple sequence alignment with the Clustal series of programs. Nucleic Acids Res 2003;31:3497–500. 7. Leigh RJ, Zee DS. Vergence eye movements. In: The Neurology of Eye Movements. 2nd ed. Philadelphia, PA: F.A. Davis Co.; 1991:264 –90. Contemporary Neurology Series. vol. 35. 8. Beigi B, O’Keeffe M, Logan P, Eustace P. Convergence substitution for paralysed horizontal gaze. Br J Ophthalmol 1995;79:229 –32. 9. Kohno T, Oohira A, Hori S. Near reflex substituting for acquired horizontal gaze palsy: a case report. Jpn J Ophthalmol 2004;48:584 – 6. 10. Jampel RS, Mindel J. The nucleus for accommodation in the midbrain of the macaque. Invest Ophthalmol 1967;6:40 –50. 11. Goldstein JH, Schneekloth BB. Spasm of the near reflex: a spectrum of abnormalities. Surv Ophthalmol 1996;40:269 –78.
Footnotes and Financial Disclosures Originally received: May 6, 2008. Final revision: June 1, 2008. Accepted: August 5, 2008.
3
Manuscript no. 2008-549.
1
Division of Pediatric Ophthalmology, King Khaled Eye Specialist Hospital, Riyadh, Saudi Arabia. 2
Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
Division of Neurology, Cooper University Hospital, Camden, New Jersey. Financial Disclosure(s): The authors have no proprietary or commercial interest in any materials discussed in this article. Correspondence: Arif O. Khan, MD, Division of Pediatric Ophthalmology, King Khaled Eye Specialist Hospital, PO Box 7191, Riyadh 11462, Saudi Arabia. E-mail: [email protected].
2265