Effect of inferior oblique myectomy on ocular torsion according to the absence of the trochlear nerve in unilateral congenital superior oblique palsy.

OBJECTIVES: To evaluate the effect of inferior oblique (IO) myectomy on ocular torsion according to the absence of the trochlear nerve in unilateral congenital superior oblique palsy (UCSOP). METHODS: We retrospectively reviewed the clinical data of patients who had been diagnosed with UCSOP and underwent ipsilateral IO myectomy (n = 43). Patients were classified into the present and absent groups according to the absence of the trochlear nerve and superior oblique hypoplasia on magnetic resonance imaging (MRI). For quantitative analysis of ocular torsion, disc-fovea angles (DFA) were collected in both eyes using fundus photographs taken within three months before surgery and one month after surgery. RESULTS: DFA of the paretic eye did not differ according to the absence of the trochlear nerve (9.4±5.6° in the present group vs. 11.0±5.4° in the absent group, p = 0.508). However, the present group had a larger DFA in the non-paretic eye than the absent group (14.1±6.7° in the present group vs. 8.0±5.0° in the absent group, p = 0.003). The change of ocular torsion after IO myectomy in the paretic eye was -5.3±3.7° in the present group and -4.8±3.5° in the absent group, respectively (p = 0.801). In the non-paretic eye, the change in DFA was -1.5±3.0° in the present group, which was larger than that in the absent group (0.7±2.6°, p = 0.047). In the multivariate analysis, the change in DFA was correlated with only the preoperative DFA (standardized ß = -0.617, p<0.001 in the paretic eye, and standardized ß = -0.517, p<0.001 in the non-paretic eye). CONCLUSIONS: In the paretic eye, there was no significant difference in the change of ocular torsion between both groups, whereas in the non-paretic eye, the present group had a larger change in DFA after IO myectomy than the absent group. However, in the multivariable analysis, the change in ocular torsion was significantly correlated with preoperative excyclotorsion but not with the presence of the trochlear nerve itself.

BRAIN AND EYE AS POTENTIAL TARGETS FOR IONIZING RADIATION IMPACT. PART IV - FETAL RADIATION-INDUCED BINOCULAR VISION DISORDERS: A PILOT STUDY. IMMUNOHISTOCHEMICAL CHANGES OF NON/IRRADIATED EYEBALL MUSCLES AFFECTED BY STRABISMUS. EVIDENCE OF A POSSIBLE MECHANISM OF THE STRABISMUS DEVELOPMENT IN PERSONS EXPOSED TO FETAL RADIATION. / GOLOVNYI MOZOK TA ORGAN ZORU IaK POTENTsIINI MIShENI DLIa VPLYVU IONIZUIuChOGO VYPROMINIuVANNIa. ChASTYNA IV - ROZLADY BINOKULIaRNOGO ZORU PLODA, SPRYChYNENI RADIATsIINYM VPLYVOM IN UTERO: PILOTNE DOSLIDZhENNIa. IMUNOGISTOKhIMIChNI ZMINY NEOPROMINENYKh M'IaZIV OChNOGO IaBLUKA PRY KOSOOKOSTI. MOZhLYVYI MEKhANIZM ROZVYTKU KOSOKOSTI V OSIB, IaKI ZAZNALY PRENATAL'NOGO OPROMINENNIa.

Strabismus is a significant cause of a decrease in the functional capabilities of the organ of vision, additionally, it leads to the deteriorating quality of life. Orbital factors and nervous system changes may play an important role in strabismus pathogenesis. There are few reports on binocular vision disorders in radiation-exposed persons.Functions of the external eyeball muscles might be disturbed based on the changed coordination process of subcortical nerve structures and due to altered metabolism. A carefully conducted research is necessary to clarify the possible pathogenesis of binocular vision disorders in radiation-exposed persons. OBJECTIVE: to assess the peculiarities of the development of strabismus and binocular vision disorders in people who were exposed to ionizing radiation in utero; to investigate the changes in distribution and appearance of myosin, dystrophin, and collagen IV between non-irradiated persons with normal binocular vision and patients with strabismus. MATERIALS AND METHODS: 583 persons, irradiated in utero because of the Chornobyl disaster were examined (at the time of examination average age was 11.3 ± 0.1 years). The control group - 808 people - Kyiv residents. Overall, 15 non-irradiated eyeball muscle samples were examined. 10 were from strabismus patients and 5 were controls. To evaluate morphological structure haematoxylin and eosin staining were used. For the detection of myosin, dystrophin, and collagen IV biotin-avidin (IMH) immunohistochemistry method was performed. Semi-quantitative grading method was used for the evaluation of immunoreactive structure appearance and local distribution. RESULTS: An increased frequency of divergent strabismus (p = 0.04190) and heterophoria (p = 0.002603) was found in the group exposed to prenatal (fetal) radiation because of the Chornobyl disaster compared to the control group. The relative risk of heterophoria was 5.08 (1.42 - 18.13). A decrease in dystrophin, myosin, and collagen IV positive structures was observed in non-irradiated strabismus-affected eyeball muscles compared to the control group. CONCLUSIONS: Detected changes indicate an increased probability in the development of strabismus in persons who had been exposed to fetal radiation. Non-irradiated strabismus-affected eyeball muscles are characterized by diminished myosin, dystrophin, and collagen IV immunohistochemical structures. Additionally, determined qualitative morphological changes in skeletal striated muscle fibers lead to the changed structural organization, indicating possible muscular dystrophy. Thereby, the presence of dystrophic processes in the eyeball muscles may play a significant role in the morphopatogenesis of strabismus. Further morphological studies are necessary to clarify the development of binocular vision disorder and the methods of their correction. These studies would be especially important to populations that were exposed to radiation.

Episcleral Apocrine Hidrocystoma Following Strabismus Surgery.

Apocrine hidrocystomas are benign cystic tumors derived from apocrine sweat glands; they are most commonly located in the skin of the head and neck regions. Ophthalmic occurrences typically appear at the lash line and canthi of the eyelid, although rare instances have been described in the conjunctiva, caruncle, and orbit. The authors illustrate an exceptional instance of a mobile episcleral cyst in a 12-year-old girl that developed about 2 years following strabismus surgery. The cyst was located anterior to the insertion of the left medial rectus and was excised in response to the patient's complaints of irritation. Histopathology of the excised specimen displayed an empty cyst lined by a double layer of cuboidal epithelium with the inner layer exhibiting apical decapitation secretion. Confirmatory immunohistochemistry demonstrated reactivity of both layers with CK7 and the outer myoepithelial layer with D2-40. Postoperative and traumatic cysts formed after interruption of the bulbar conjunctiva are usually conjunctival cysts lined by stratified squamous nonkeratinizing epithelium.

Prevalence of strabismus and its risk factors among school aged children: The Hong Kong Children Eye Study.

The study aims to determine the prevalence of strabismus and its risk factors among school children in Hong Kong. This is a cross-sectional study involving 6-8 year old children from different districts in Hong Kong. 4273 children received comprehensive ophthalmological examination, cycloplegic auto-refraction, best corrected visual acuity (BCVA), anterior segment examination, cover/uncover test, ocular motility, and fundus examination. Demographic information, pre- and post- natal background, parental smoking status, and family history of strabismus were obtained through questionnaires. Strabismus was found among 133 children (3.11%, 95% CI 2.59-3.63%), including 117 (2.74%) exotropia and 12 (0.28%) esotropia cases (exotropia-esotropia ratio: 9.75:1). There was no significant difference in prevalence across age (6-8 years) and gender. Multivariate analysis revealed associations of strabismus with myopia (≤ - 1.00D; OR 1.61; 95% CI 1.03-2.52; P = 0.037) hyperopia (≥ + 2.00D; OR 2.49; 95% CI 1.42-4.39; P = 0.002), astigmatism (≥ + 2.00D; OR 2.32; 95% CI 1.36-3.94; P = 0.002), and anisometropia (≥ 2.00D; OR 3.21; 95% CI 1.36-7.55; P = 0.008). Other risk factors for strabismus included maternal smoking during pregnancy (OR 4.21; 95% CI 1.80-9.81; P = 0.001), family history of strabismus (OR 6.36; 95% CI 2.78-14.50, P < 0.0001) and advanced maternal age at childbirth (> 35 years; OR 1.65; CI 1.09-2.49, P = 0.018). The prevalence of strabismus among children aged 6-8 years in Hong Kong is 3.11%. Refractive errors, family history of strabismus and maternal smoking history during pregnancy are risk factors. Early correction of refractive errors and avoidance of maternal smoking during pregnancy are potentially helpful in preventing strabismus.

Sacral protuberance with cleft lip and palate: Prenatal presentation of 3MC syndrome.

3MC syndromes are rare heterogeneous autosomal recessive conditions previously designated as Mingarelli, Malpuech, Michels, and Carnevale syndromes, characterized by dysmorphic facial features, facial clefts, growth restriction, and intellectual disability. 3MC is secondary to mutations in the MASP1, MASP3, COLEC11, and COLEC10 genes. The number of patients with 3MC syndrome with known mutations in the COLEC11 or MASP1 is, to date, less than 50. At the time this case presented (2015), the only gene identified in Online Mendelian Inheritance in Man to be associated with 3MC syndrome was MASP1. We present, to the best of our knowledge, the first prenatal report of 3MC syndrome, secondary to a homozygous variant in MASP1. Fetal findings included bilateral cleft lip and palate, abnormality of the sacral spine, a right echogenic pelvic kidney, and brachycephaly. 3MC syndrome should be considered as part of the differential diagnosis when fetal ultrasound detects facial clefts and spinal defects, as the risk of recurrence is significant and a molecularly confirmed diagnosis allows for alternate reproductive options.

Compartmental Strabismus.

Recent reports confirm innervational compartments of select rectus extraocular muscles as well as the superior oblique.1 Histopathological and orbital imaging studies demonstrate well defined compartmental innervation of the horizontal rectus muscles with less differentiation in the vertical rectus muscles. Acquired vertical misalignment not associated with cyclovertical muscle dysfunction has been associated with horizontal rectus muscle compartment dysfunction. Pattern and other forms of strabismus have been associated with segmental or compartmental abnormal innervation of the extraocular muscles. Taking advantage of segmental function and innervation, selective weakening and strengthening procedures have been used to treat patients with incomitant near/distance disparities, incomitant vertical and torsional strabismus, and patients with A- and V-pattern strabismus.

Strabismus in Unicoronal Craniosynostosis: Effect of Orbital Dysmorphology and Fronto-Orbital Advancement and Remodeling.

BACKGROUND: The purpose of this study was to determine what craniometric changes occur to both orbits of unicoronal craniosynostosis patients undergoing fronto-orbital advancement and remodeling, and which of these changes are associated with new onset of postoperative strabismus. METHODS: A retrospective analysis was performed of the preoperative and postoperative orbits of 24 unicoronal craniosynostosis patients and the orbits of 24 control subjects, totaling 144 orbits. Eight parameters were evaluated using multivariate logistic regression analysis. One of the parameters was modified orbital index, an indicator of severity of harlequin deformity. RESULTS: Significant differences in orbital dimensions and angles were present bilaterally in unicoronal craniosynostosis orbits when compared to controls. Fronto-orbital advancement and remodeling increased the ipsilateral unicoronal craniosynostosis orbital volume from 13,184 ± 2003 mm to 16,220 ± 2323 mm (p < 0.001). Ipsilateral horizontal cone angles were increased from 48 ± 5 degrees to 54 ± 7 degrees (p = 0.004). Ipsilateral vertical cone angles were decreased from 73 ± 8 degrees to 66 ± 10 degrees (p = 0.003). Ipsilateral modified orbital index improved from 0.83 ± 0.06 to 0.88 ± 0.06 (p = 0.003). Three of the 19 unicoronal craniosynostosis patients developed transient postoperative strabismus. Logistic regression analysis displayed a strong significant association between new-onset strabismus and a change in modified orbital index with a coefficient of 30.84 ± 14.51 (p < 0.05). CONCLUSIONS: The orbital dysmorphology in unicoronal craniosynostosis is bilateral in nature, and it is not wholly treated with conventional fronto-orbital advancement and remodeling. The severity of ipsilateral orbital dysmorphology is correlated with the incidence of postoperative strabismus following conventional fronto-orbital advancement and remodeling. Future research is needed to develop strategies to mitigate the risk of development of strabismus in this group of patients. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, III.

Ultrastructural changes of extraocular muscles in strabismus patients.

Strabismus is an ocular disorder characterized by partial or complete inability to keep eye alignment. It represents a very common ocular problem at ophthalmology clinics worldwide. The current study aimed to show the most encountered ultrastructural changes in extraocular muscles (EOMs) collected from patients with different forms of strabismus. Nine specimens of EOMs were collected from five patients during strabismus correction surgery and processed for light and electron microscopy examinations. Histologically, skeletal muscle fibers in normal EOMs appeared tight and normally arranged with clear striations. In strabismic muscles, the fibers appeared disarranged, and atrophied, swollen and disintegrated in some situations. By transmission electron microscopy, normal EOMs were formed of skeletal muscle fibers with intact basal membrane and sarcolemma, tightly aligned myofibrils with well-arranged sarcomeres, Z line and H zone, and normally distributed mitochondria. On the other hand, strabismic EOMs revealed vacuolation and degeneration of myofibrils, accumulation of lipid droplets, subsarcolemmal inclusions and clustering of mitochondria. EOMs obtained from a Down syndrome patient with V-pattern infantile esotropia showed extensive vacuolation and disintegration of myofibrils, and extra- and intracellular deposition of collagen fibers. Interestingly, some skeletal muscle cells exhibited features of autophagic cell death with a trial of engulfing process by neighboring cells. In conclusion, our study traces some characteristic ultrastructural changes in strabismic EOMs, most notably, extensive vacuolation, clustering of mitochondria, degeneration of myofibrils and autophagic changes. These changes might be emphasized as possibly secondary to strabismus.

A commonly occurring genetic variant within the NPLOC4-TSPAN10-PDE6G gene cluster is associated with the risk of strabismus.

Strabismus refers to an abnormal alignment of the eyes leading to the loss of central binocular vision. Concomitant strabismus occurs when the angle of deviation is constant in all positions of gaze and often manifests in early childhood when it is considered to be a neurodevelopmental disorder of the visual system. As such, it is inherited as a complex genetic trait, affecting 2-4% of the population. A genome-wide association study (GWAS) for self-reported strabismus (1345 cases and 65,349 controls from UK Biobank) revealed a single genome-wide significant locus on chromosome 17q25. Approximately 20 variants across the NPLOC4-TSPAN10-PDE6G gene cluster and in almost perfect linkage disequilibrium (LD) were most strongly associated (lead variant: rs75078292, OR = 1.26, p = 2.24E-08). A recessive model provided a better fit to the data than an additive model. Association with strabismus was independent of refractive error, and the degree of association with strabismus was minimally attenuated after adjustment for amblyopia. The association with strabismus was replicated in an independent cohort of clinician-diagnosed children aged 7 years old (116 cases and 5084 controls; OR = 1.85, p = 0.009). The associated variants included 2 strong candidate causal variants predicted to have functional effects: rs6420484, which substitutes tyrosine for a conserved cysteine (C177Y) in the TSPAN10 gene, and a 4-bp deletion variant, rs397693108, predicted to cause a frameshift in TSPAN10. The population-attributable risk for the locus was approximately 8.4%, indicating an important role in conferring susceptibility to strabismus.

Surgical outcomes after unilateral horizontal rectus surgery in children with infantile esotropia for the correction of A or V pattern.

PURPOSE: The management of A or V pattern deviation associated with esotropia can be challenging since the horizontal deviation changes with position of gaze. This study aimed to assess the effect of unilateral horizontal rectus surgery for the correction of horizontal deviation associated with A or V pattern in children with non-comitant infantile esotropia. METHODS: Twenty-seven children with infantile esotropia and A-V pattern, more than 10 and 15 prism diopters respectively, were included in this retrospective observational single-center study. Horizontal rectus surgery was performed on the most deviated eye under general anesthesia. The patients were divided into two groups: A pattern and V pattern. The outcome measures were change in the amount of pattern and rate of regression after surgery. The amount of pattern was characterized by the difference in esodeviation between upgaze and downgaze. RESULTS: Horizontal deviation at distance and near fixation decreased significantly (P<0.0001). Vertical gaze esotropia disparity decreased significantly (P=0.01 and P=0.0002 for A and V patterns respectively). A pattern esotropia was reported in only 2 (7%) cases after surgery compared to 9 (33%) before surgery. The number of subjects with V pattern esotropia decreased from 18 (67%) to 3 (11%) after surgery. CONCLUSIONS: The mechanisms involved in the pathophysiology of A and V patterns may not always be related to oblique muscle dysfunction. These findings suggest that unilateral horizontal rectus surgery may be an effective procedure to correct both horizontal deviation and A-V pattern in non-comitant infantile esotropia.

Epileptic ictal strabismus: a case report and review of the literature.

Ictal strabismus, sometimes associated with epileptic nystagmus, is an extremely rare epileptic phenomenon, suggestive of cortical involvement in monocular eye movement control. We describe a patient with ictal disconjugate contraversive horizontal eye deviation of cortical origin as the main clinical feature of a focal seizure. A 17-year-old, previously healthy woman had a seizure characterized by initial rightward conjugate eye deviation, followed by convergent strabismus due to adduction of the right eye towards the nose without conjugate left eye abduction (esotropia), forced leftward head deviation with impaired awareness, and subsequent evolution into a bilateral tonic-clonic seizure. Postictal and interictal neurological status were unremarkable; more specifically, neuro-ophthalmological examination revealed no nystagmus or altered eye motility. Ictal EEG showed a rhythmic theta activity over the right posterior temporal region, involving fronto-central regions when strabismus appeared. MRI showed cortical dysplasia in the right temporal lobe. Due to the low spatial resolution of scalp EEG, we could not identify with precision the symptomatogenic zone underlying ictal strabismus. However, the concomitant appearance of rhythmic theta activity over the right fronto-central region and the leftward head version with MRI perfusion sequences, showing cerebral blood flow increase in the right frontal eye field area, suggest involvement of the right frontal lobe. [Published with video sequence on www.epilepticdisorders.com].

Measurement of Medial Wall Bowing and Clinical Associations in Thyroid Eye Disease.

PURPOSE: To propose and validate a measure of medial wall bowing in thyroid eye disease (TED) and to assess the clinical correlates of bowing in TED. METHODS: In this cross-sectional cohort study, all patients affected with TED seen by a single specialist over a 2-year period were screened for study entry. Eligible participants were adults with clinical evidence of TED and either CT or MRI of the orbits. Exclusion criteria included prior history of decompression surgery and/or medical or other ophthalmic conditions that could alter the orbital anatomy. The primary outcome measure was prevalence of medial wall bowing. Secondary outcomes included the associations between medial wall bowing and exophthalmometry, diplopia, rectus muscle restriction, dysthyroid optic neuropathy (DON), strabismus, and quality of life. Medial wall bowing was defined as medial divergence of the medial wall from a straight line drawn between the anterior lacrimal crest and the middle of the optic canal and measured radiographically using axial images of the orbits. Volumetric analysis of bowing was performed on a sample of orbits with and without bowing. Volumetric and axial single slice measurements were compared. Bivariate statistics were performed. RESULTS: The final sample included 112 orbital images from 56 patients with TED. Medial wall bowing was found to be evident in 11.6% (n = 13/112) of orbits. Medial wall bowing was significantly associated with greater Hertel measurements, horizontal and vertical muscle restriction, ocular surface symptoms and Clinical Activity Score, as well as lower quality of life scores. Patients with demonstrable medial wall bowing were more likely to be affected by optic neuropathy, diplopia (Gorman score ≥ 1), strabismus, or horizontal muscle restriction. Analysis of the volume for medial wall bowing demonstrated that the height of the arc at the peak of bowing on an axial image of a 2-dimensional CT scan correlated highly with the total volume of bowing (r = 0.90, p < 0.001). CONCLUSIONS: The identification of medial wall bowing on CT or MRI is associated with clinical measures of disease severity, including diplopia and DON.

Quantitative measurement of retinal vascular diameter changes in the early postoperative period after strabismus surgery.

PURPOSE: To investigate quantitatively the retinal vascular diameter changes before and after strabismus surgery, analyzing the potential hemodynamic changes that may occur in the retinal circulation. METHODS: Consecutive patients with horizontal strabismus who underwent strabismus surgery were prospectively enrolled. Color fundus photographs were taken of each eye before and 1 day after surgery. The retinal vessel diameters were measured using computer-assisted quantitative assessment software. Paired-sample t test was used to evaluate the central retinal arteriolar equivalent (CRAE), central retinal venular equivalent (CRVE), and arteriovenous ratio (AVR) before and 1 day after surgery. We also analyzed those changes in different subgroups according to surgical protocols. RESULTS: A total of 217 eyes of 148 patients were included. Compared with the data before surgery, the mean CRAE significantly increased 1 day after surgery (P = 0.01), so did the AVR (P = 0.003). There was no significant difference with respect to CRVE (P = 0.43). The CRAE and AVR were not significantly different in the lateral rectus recession group. CONCLUSIONS: Strabismus surgery on horizontal rectus muscles may change retinal hemodynamics by increasing the central retinal arteriolar diameter during the early postoperative period.

Role of magnetic resonance imaging in heavy eye syndrome.

PurposeThe aim of this study is to assess the importance of magnetic resonance imaging (MRI) before surgery in highly myopic patients, evaluating the capability of imaging to identify muscles displacement and orbital pulley abnormalities and their role in the pathogenesis of heavy eye syndrome (HES).MethodsWe reviewed the medical records and high-resolution orbital MRIs of highly myopic adults with HES, who underwent surgery for strabismus at the Sant'Orsola-Malpighi University Hospital of Bologna from January 2007 to June 2016. The measure of the angle of dislocation between lateral rectus and superior rectus and lateral rectus-superior rectus band (LR-SR band) were evaluated on coronal MRI imaging.ResultsA total of 54 patients with HES were evaluated by MRI. Mean axial length was 30.5±3 mm. Mean distance esotropia was 49.2±14.4 prism diopters (PD) and the mean hypotropia was 4.3±4.4 PD. All subjects exhibited severe superotemporal globe prolapse that displaced the lateral rectus inferiorly and the superior rectus muscle medially with mean angle of dislocation of 167.5±12.9° on MRI. The LR-SR band was thinned in 56 eyes, ruptured in 8 and not evaluable in 1 case.ConclusionsIn our study, we detected muscles displacement in all subjects and we discovered alteration of the LR-SR band in patients with HES, suggesting a possible role in the pathogenesis of this disease. The evaluation of preoperative orbital MRI imaging in patients with highly myopic strabismus is helpful to detect different anatomical etiology and eventually to drive the choice of appropriate surgery.

[Ultrastructural alteration of extraocular muscle proprioceptor in congenital idiopathic nystagmus].

Objective: To explore the ultrastructural alteration of extraocular muscle proprioceptor in congenital idiopathic nystagmus (CIN). Methods: Case-control study. Ten extraocular muscle samples were collected from five CIN children who underwent nystagmus surgeries in Beijing Children's Hospital from March 2015 to March 2016. Another ten extraocular muscle specimens were collected from five strabismus children in surgery at the same period as normal contrast. There were 3 male patients and 2 female patients of CIN with age of 61-147 months (median age: 91 months). The ultrastructure of extraocular muscle proprioceptors was compared between these two groups by transmission electron microscope. Results: Twenty-three proprioceptors were found in extraocular muscle specimens of CIN children, whereas thirty-three proprioceptors were detected in strabismus children. The ultrastructure of extraocular muscle proprioceptor of CIN altered greatly comparing with that of the control. Fourteen extraocular muscle proprioceptors of CIN were discovered much smaller and vacuolated not only at inner capsules but also at the space between inner and outer capsules with lipofuscins and myeloid bodies in the intrafusal muscle fibers. Sensory nerve fibers degenerated greatly with a lot of lipofuscins and myeloid bodies in these sensory nerve fibers. Demyelination also appeared in some severe cases. Nine extraocular muscle proprioceptors of CIN showed significant dissolving degeneration of myofibrils and proliferation of collagen fibrils. The normal structures could not be distinguished in these proprioceptors. And these structural disorders also appeared in extrafusal muscle fibers and nerve endings. Conclusion: The ultrastructure of extraocular muscle proprioceptor in CIN turned much smaller and had significantly structural disorder.(Chin J Ophthalmol, 2017, 53: 136-139).

Mosaicism in ATP1A3-related disorders: not just a theoretical risk.

Mutations in ATP1A3 are involved in a large spectrum of neurological disorders, including rapid onset dystonia parkinsonism (RDP), alternating hemiplegia of childhood (AHC), and cerebellar ataxia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS), with recent descriptions of overlapping phenotypes. In AHC, a few familial cases of autosomal dominant inheritance have been reported, along with cases of de novo sporadic mutations. In contrast, autosomal dominant inheritance has frequently been associated with RDP and CAPOS. Here, we report on two unrelated sets of full siblings with ATP1A3 mutations, (c.2116G>A) p. Gly706Arg in the first family, and (c.2266C>T) p. Arg756Cys in the second family, presenting with familial recurrence of the disease. Both families displayed parental germline mosaicism. In the first family, the brother and sister presented with severe intellectual deficiency, early onset pharmacoresistant epilepsy, ataxia, and autistic features. In the second family, both sisters demonstrated severe encephalopathy with ataxia and dystonia following a regression episode during a febrile episode during infancy. To our knowledge, mosaicism has not previously been reported in ATP1A3-related disorders. This report, therefore, provides evidence that germline mosaicism for ATP1A3 mutations is a likely explanation for familial recurrence and should be considered during recurrence risk counseling for families of children with ATP1A3-related disorders.

Altered Protein Composition and Gene Expression in Strabismic Human Extraocular Muscles and Tendons.

PURPOSE: To determine whether structural protein composition and expression of key regulatory genes are altered in strabismic human extraocular muscles. METHODS: Samples from strabismic horizontal extraocular muscles were obtained during strabismus surgery and compared with normal muscles from organ donors. We used proteomics, standard and customized PCR arrays, and microarrays to identify changes in major structural proteins and changes in gene expression. We focused on muscle and connective tissue and its control by enzymes, growth factors, and cytokines. RESULTS: Strabismic muscles showed downregulation of myosins, tropomyosins, troponins, and titin. Expression of collagens and regulators of collagen synthesis and degradation, the collagenase matrix metalloproteinase (MMP)2 and its inhibitors, tissue inhibitor of metalloproteinase (TIMP)1 and TIMP2, was upregulated, along with tumor necrosis factor (TNF), TNF receptors, and connective tissue growth factor (CTGF), as well as proteoglycans. Growth factors controlling extracellular matrix (ECM) were also upregulated. Among 410 signaling genes examined by PCR arrays, molecules with downregulation in the strabismic phenotype included GDNF, NRG1, and PAX7; CTGF, CXCR4, NPY1R, TNF, NTRK1, and NTRK2 were upregulated. Signaling molecules known to control extraocular muscle plasticity were predominantly expressed in the tendon rather than the muscle component. The two horizontal muscles, medial and lateral rectus, displayed similar changes in protein and gene expression, and no obvious effect of age. CONCLUSIONS: Quantification of proteins and gene expression showed significant differences in the composition of extraocular muscles of strabismic patients with respect to important motor proteins, elements of the ECM, and connective tissue. Therefore, our study supports the emerging view that the molecular composition of strabismic muscles is substantially altered.