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The Journal of Clinical Investigation May 2017Duane retraction syndrome (DRS) is the most common form of congenital paralytic strabismus in humans and can result from α2-chimaerin (CHN1) missense mutations. We...
Duane retraction syndrome (DRS) is the most common form of congenital paralytic strabismus in humans and can result from α2-chimaerin (CHN1) missense mutations. We report a knockin α2-chimaerin mouse (Chn1KI/KI) that models DRS. Whole embryo imaging of Chn1KI/KI mice revealed stalled abducens nerve growth and selective trochlear and first cervical spinal nerve guidance abnormalities. Stalled abducens nerve bundles did not reach the orbit, resulting in secondary aberrant misinnervation of the lateral rectus muscle by the oculomotor nerve. By contrast, Chn1KO/KO mice did not have DRS, and embryos displayed abducens nerve wandering distinct from the Chn1KI/KI phenotype. Murine embryos lacking EPH receptor A4 (Epha4KO/KO), which is upstream of α2-chimaerin in corticospinal neurons, exhibited similar abducens wandering that paralleled previously reported gait alterations in Chn1KO/KO and Epha4KO/KO adult mice. Findings from Chn1KI/KI Epha4KO/KO mice demonstrated that mutant α2-chimaerin and EphA4 have different genetic interactions in distinct motor neuron pools: abducens neurons use bidirectional ephrin signaling via mutant α2-chimaerin to direct growth, while cervical spinal neurons use only ephrin forward signaling, and trochlear neurons do not use ephrin signaling. These findings reveal a role for ephrin bidirectional signaling upstream of mutant α2-chimaerin in DRS, which may contribute to the selective vulnerability of abducens motor neurons in this disorder.
Topics: Animals; Cerebral Cortex; Chimerin 1; Duane Retraction Syndrome; Embryo, Mammalian; Humans; Mice; Mice, Knockout; Motor Neurons; Receptor, EphA4; Signal Transduction; Spinal Cord
PubMed: 28346224
DOI: 10.1172/JCI88502 -
Indian Journal of Ophthalmology Feb 2017High-resolution magnetic resonance imaging (MRI) of intracranial parts of sixth nerve and seventh nerve and the extraocular muscles (EOMs) in orbit to correlate the...
PURPOSE
High-resolution magnetic resonance imaging (MRI) of intracranial parts of sixth nerve and seventh nerve and the extraocular muscles (EOMs) in orbit to correlate the clinical characteristics in patients with two special forms of strabismus in congenital cranial dysinnervation disorders which are Duane's retraction syndrome (DRS) and Mobius syndrome.
MATERIALS AND METHODS
Morphological analysis by 3T MRI of orbit (using surface coils) and brain (using 32 channel head coil) was performed on 6 patients with clinical DRS (1 bilateral), 2 cases with Mobius syndrome, and 1 case with congenital sixth nerve palsy. These were compared with findings in five controls.
RESULTS
We observed absence/hypoplasia of sixth nerve in five out of seven eyes with DRS (71.42%), anomalous course in one eye, sixth and seventh nerve absence/hypoplasia in affected eyes with Mobius syndrome and bilateral absence/hypoplasia of the sixth nerve in congenital sixth nerve palsy. For EOMs we calculated maximum diameter, area, and circumference of muscles using Osirix software, and noticed significant hypoplasia of lateral rectus in comparison to controls (P < 0.001).
CONCLUSIONS
MRI gives useful information regarding confirmation of clinical diagnosis and its neurological anomalies in complex cases and helps to plan tailor made surgical management.
Topics: Abducens Nerve; Abducens Nerve Diseases; Abnormalities, Multiple; Duane Retraction Syndrome; Humans; Imaging, Three-Dimensional; Magnetic Resonance Imaging; Mobius Syndrome; Oculomotor Muscles; Orbit; Pilot Projects
PubMed: 28345573
DOI: 10.4103/ijo.IJO_1013_15 -
Neurology India 2017
Topics: Adolescent; Cysticercosis; Duane Retraction Syndrome; Humans; Magnetic Resonance Imaging; Male; Orbit
PubMed: 28084290
DOI: 10.4103/0028-3886.198232 -
Zhongguo Dang Dai Er Ke Za Zhi =... Nov 2016Alagille syndrome (ALGS) is an autosomal dominant disorder which is mainly caused by JAG1 gene mutation and can affect multiple systems including the liver, heart, eyes,...
Alagille syndrome (ALGS) is an autosomal dominant disorder which is mainly caused by JAG1 gene mutation and can affect multiple systems including the liver, heart, eyes, skeleton and face. This paper reports the clinical and genetic features of an ALGS patient. A 2-year-and-9-month-old boy was referred to the hospital with the complaint of abnormal liver function and heart murmur discovered over two years. Jaundice of the skin and sclera was not observed. The child had a prominent forehead, left esotropia, depressed nasal bridge and micromandible. The two lungs were clear on auscultation, but a systolic cardiac murmur of grade 2/6 could be heard between the 2nd and 3rd intercostal space at the left sternal border. Neither abdominal distension nor enlarged liver or spleen was discovered. X-ray radiography uncovered butterfly malformation of the 6th and 8th thoracic vertebrae. Serum biochemistry analysis revealed elevation of total bile acids, bilirubin and transaminases. Based on the clinical characteristics and the consultation opinion of the ophthalmologist, the child was diagnosed to have ALGS with Duane retraction syndrome. DNA direct sequencing detected a novel JAG1 mutation c.2419delG(p.Glu807AsnfsX819) in the child. Symptomatic and supportive therapy was performed thereafter and clinical follow-up was conducted until he was 4 years and 2 months. In the follow-up visits, his general condition remained stable, but the facial malformations, left esotropia, cardiac murmur and abnormal liver function persistend. The long-term outcome needed to be observed.
Topics: Alagille Syndrome; Child, Preschool; Humans; Jagged-1 Protein; Male; Mutation
PubMed: 27817779
DOI: 10.7499/j.issn.1008-8830.2016.11.015 -
Middle East African Journal of... 2016Duane's retraction syndrome (DRS) is characterized by limitations in horizontal eye movements, globe retraction, and palpebral fissure narrowing on attempted adduction....
Duane's retraction syndrome (DRS) is characterized by limitations in horizontal eye movements, globe retraction, and palpebral fissure narrowing on attempted adduction. This disorder is caused by a disturbance in innervation originating in the brain stem and represents <1% of all cases of strabismus. It is postulated that this syndrome is due to an insult during the early weeks (8-10 weeks) of pregnancy and is 10-20 times more frequently associated with other systemic congenital anomalies. This case report of bilateral DRS included bilateral iris-retinal coloboma and congenital heart disease, sensory hearing loss, and inguinal hernia.
Topics: Child; Coloboma; Duane Retraction Syndrome; Female; Hearing Loss, Sensorineural; Heart Defects, Congenital; Hernia, Inguinal; Humans; Iris; Retina
PubMed: 27555711
DOI: 10.4103/0974-9233.186119 -
Journal of AAPOS : the Official... Aug 2016To identify cases of synergistic divergence whose characteristics suggest that this entity is a form of Duane syndrome.
PURPOSE
To identify cases of synergistic divergence whose characteristics suggest that this entity is a form of Duane syndrome.
METHODS
The records of all patients with a Duane syndrome diagnosis, including standardized eye position photographs, from the E-Consultation program of Cybersight, Orbis International were analyzed.
RESULTS
A total of 350 Duane syndrome cases were identified. Of these, 19 (5%) had features consistent with synergistic divergence, or type 4 Duane syndrome. Of the 19, 16 (84%) were male, 15 (79%) had palpebral fissure narrowing, all had anomalous head posture, and 18 (95%) were exotropic. Only 9 (47%) patients were reported to have undergone surgery.
CONCLUSIONS
Synergistic divergence is a rare entity with features similar to those of Duane syndrome. We suggest that this entity be classified as type 4 Duane syndrome, because it has unique findings and an innervation pattern that differs from the other 3 recognized types.
Topics: Duane Retraction Syndrome; Exotropia; Eyelids; Female; Head; Humans; Male; Posture
PubMed: 27381527
DOI: 10.1016/j.jaapos.2016.05.012 -
PloS One 2016We have previously reported that the presence of the abducens nerve was variable in patients with type 3 Duane's retraction syndrome (DRS), being present in 2 of 5 eyes...
BACKGROUND
We have previously reported that the presence of the abducens nerve was variable in patients with type 3 Duane's retraction syndrome (DRS), being present in 2 of 5 eyes (40%) and absent in 3 (60%) on magnetic resonance imaging (MRI). The previous study included only 5 eyes with unilateral DRS type 3.
OBJECTIVES
To supplement existing scarce pathologic information by evaluating the presence of the abducens nerve using high resolution thin-section MRI system in a larger number of patients with DRS type 3, thus to provide further insight into the pathogenesis of DRS.
DATA EXTRACTION
A retrospective review of medical records on ophthalmologic examination and high resolution thin-section MRI at the brainstem level and orbit was performed. A total of 31 patients who showed the typical signs of DRS type 3, including abduction and adduction deficit, globe retraction, narrowing of fissure on adduction and upshoot and/or downshoot, were included. The abducens nerve and any other extraocular muscle abnormalities discovered by MRI were noted.
RESULTS
DRS was unilateral in 26 patients (84%) and bilateral in 5 patients (16%). Two out of 5 bilateral patients had DRS type 3 in the right eye and DRS type 1 in the left eye. Of the 34 affected orbits with DRS type 3 in 31 patients, the abducens nerve was absent or hypoplastic in 31 eyes (91%) and present in 3 eyes (9%). Patients with a present abducens nerve showed more limitation in adduction compared to patients with an absent abducens nerve (P = 0.030).
CONCLUSIONS
The abducens nerve is absent or hypoplastic in 91% of DRS type 3. Patients with a present abducens nerve showed more prominent limitation of adduction. As DRS type 3 partly share the same pathophysiology with type 1 and 2 DRS, the classification of DRS may have to be revised according to MRI findings.
Topics: Abducens Nerve; Adolescent; Adult; Aged; Child; Child, Preschool; Duane Retraction Syndrome; Female; Humans; Infant; Magnetic Resonance Imaging; Male; Middle Aged
PubMed: 27352171
DOI: 10.1371/journal.pone.0150670 -
American Journal of Human Genetics Jun 2016Duane 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...
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.
Topics: Animals; Duane Retraction Syndrome; Embryo, Mammalian; Female; Hearing Loss; Humans; Labyrinth Diseases; MafB Transcription Factor; Male; Mice; Mice, Knockout; Oculomotor Muscles; Pedigree
PubMed: 27181683
DOI: 10.1016/j.ajhg.2016.03.023 -
European Journal of Medical Genetics Feb 2016Okihiro syndrome, Duane-radial ray syndrome or acro-reno-ocular syndrome (OMIM #607323) are alternative denominations describing an extremely variable condition,...
Okihiro syndrome, Duane-radial ray syndrome or acro-reno-ocular syndrome (OMIM #607323) are alternative denominations describing an extremely variable condition, characterized by several radial defects of the upper limbs associated with Duane anomaly. It is a rare autosomal dominant disorder determined by variants in the SALL4 gene which encodes a transcription factor with eight zinc finger motifs. Here we report a novel heterozygous frameshift variant, c.410dupG, present in a Brazilian family. The five affected individuals exhibit a broad spectrum of phenotypes, ranging from the severe one presented by the index case (grossly shortened and deformed forearm, markedly hypoplastic and appendicular thumb, malformed right foot and ear malformation), to the less conspicuous condition presented by his near relatives (usually only triphalangeal or hypoplastic thumbs, sometimes associated with ulnar deviation); Duane's anomaly, however, was not observed in any of the affected family members. The c.410dupG variant is predicted to result in the translation of a truncated protein with 180 amino acid residues, lacking seven of the eight zinc finger motifs, with the same size of the predicted products of the already reported c.496dupC variant, described in two unrelated cases. However, the phenotypes observed in the three families (the one here reported and other two with c.496dupC variant) are very different. The analysis of cases so far published does not permit to establish a clear or direct genotype-phenotype correlation, but the three more severe foot malformation cases are due to variants predicted to encode truncated proteins lacking seven ZFMs. This might indicate a possible correlation between foot malformation and reduced size of the protein, suggesting that the nonsense-mediated-decay mechanism might not be so effective as to eliminate all SALL4 variants harboring premature termination codons.
Topics: Brazil; DNA Mutational Analysis; Duane Retraction Syndrome; Female; Frameshift Mutation; Humans; Male; Pedigree; Penetrance; Transcription Factors
PubMed: 26791099
DOI: 10.1016/j.ejmg.2015.12.015 -
Journal of AAPOS : the Official... Dec 2015
Topics: Child, Preschool; Duane Retraction Syndrome; Exotropia; Fibrosis; Head; Humans; Male; Oculomotor Muscles; Ophthalmologic Surgical Procedures; Posture
PubMed: 26691035
DOI: 10.1016/j.jaapos.2015.05.023