TWIST1, a gene associated with Saethre-Chotzen syndrome, regulates extraocular muscle organization in mouse.

Heterozygous loss of function mutations in TWIST1 cause Saethre-Chotzen syndrome, which is characterized by craniosynostosis, facial asymmetry, ptosis, strabismus, and distinctive ear appearance. Individuals with syndromic craniosynostosis have high rates of strabismus and ptosis, but the underlying pathology is unknown. Some individuals with syndromic craniosynostosis have been noted to have absence of individual extraocular muscles or abnormal insertions of the extraocular muscles on the globe. Using conditional knock-out alleles for Twist1 in cranial mesenchyme, we test the hypothesis that Twist1 is required for extraocular muscle organization and position, attachment to the globe, and/or innervation by the cranial nerves. We examined the extraocular muscles in conditional Twist1 knock-out animals using Twist2-cre and Pdgfrb-cre drivers. Both are expressed in cranial mesoderm and neural crest. Conditional inactivation of Twist1 using these drivers leads to disorganized extraocular muscles that cannot be reliably identified as specific muscles. Tendons do not form normally at the insertion and origin of these dysplastic muscles. Knock-out of Twist1 expression in tendon precursors, using scleraxis-cre, however, does not alter EOM organization. Furthermore, developing motor neurons, which do not express Twist1, display abnormal axonal trajectories in the orbit in the presence of dysplastic extraocular muscles. Strabismus in individuals with TWIST1 mutations may therefore be caused by abnormalities in extraocular muscle development and secondary abnormalities in innervation and tendon formation.

Decreased ACKR3 (CXCR7) function causes oculomotor synkinesis in mice and humans.

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

TUBB3 Arg262His causes a recognizable syndrome including CFEOM3, facial palsy, joint contractures, and early-onset peripheral neuropathy.

Microtubules are formed from heterodimers of alpha- and beta-tubulin, each of which has multiple isoforms encoded by separate genes. Pathogenic missense variants in multiple different tubulin isoforms cause brain malformations. Missense mutations in TUBB3, which encodes the neuron-specific beta-tubulin isotype, can cause congenital fibrosis of the extraocular muscles type 3 (CFEOM3) and/or malformations of cortical development, with distinct genotype-phenotype correlations. Here, we report fourteen individuals from thirteen unrelated families, each of whom harbors the identical NM_006086.4 (TUBB3):c.785G>A (p.Arg262His) variant resulting in a phenotype we refer to as the TUBB3 R262H syndrome. The affected individuals present at birth with ptosis, ophthalmoplegia, exotropia, facial weakness, facial dysmorphisms, and, in most cases, distal congenital joint contractures, and subsequently develop intellectual disabilities, gait disorders with proximal joint contractures, Kallmann syndrome (hypogonadotropic hypogonadism and anosmia), and a progressive peripheral neuropathy during the first decade of life. Subsets may also have vocal cord paralysis, auditory dysfunction, cyclic vomiting, and/or tachycardia at rest. All fourteen subjects share a recognizable set of brain malformations, including hypoplasia of the corpus callosum and anterior commissure, basal ganglia malformations, absent olfactory bulbs and sulci, and subtle cerebellar malformations. While similar, individuals with the TUBB3 R262H syndrome can be distinguished from individuals with the TUBB3 E410K syndrome by the presence of congenital and acquired joint contractures, an earlier onset peripheral neuropathy, impaired gait, and basal ganglia malformations.

Ocular congenital cranial dysinnervation disorders (CCDDs): insights into axon growth and guidance.

Unraveling the genetics of the paralytic strabismus syndromes known as congenital cranial dysinnervation disorders (CCDDs) is both informing physicians and their patients and broadening our understanding of development of the ocular motor system. Genetic mutations underlying ocular CCDDs alter either motor neuron specification or motor nerve development, and highlight the importance of modulations of cell signaling, cytoskeletal transport, and microtubule dynamics for axon growth and guidance. Here we review recent advances in our understanding of two CCDDs, congenital fibrosis of the extraocular muscles (CFEOM) and Duane retraction syndrome (DRS), and discuss what they have taught us about mechanisms of axon guidance and selective vulnerability. CFEOM presents with congenital ptosis and restricted eye movements, and can be caused by heterozygous missense mutations in the kinesin motor protein KIF21A or in the ß-tubulin isotypes TUBB3 or TUBB2B. CFEOM-causing mutations in these genes alter protein function and result in axon growth and guidance defects. DRS presents with inability to abduct one or both eyes. It can be caused by decreased function of several transcription factors critical for abducens motor neuron identity, including MAFB, or by heterozygous missense mutations in CHN1, which encodes α2-chimaerin, a Rac-GAP GTPase that affects cytoskeletal dynamics. Examination of the orbital innervation in mice lacking Mafb has established that the stereotypical misinnervation of the lateral rectus by fibers of the oculomotor nerve in DRS is secondary to absence of the abducens nerve. Studies of a CHN1 mouse model have begun to elucidate mechanisms of selective vulnerability in the nervous system.

Bifocals Fail to Improve Stereopsis Outcomes in High AC/A Accommodative Esotropia.

PURPOSE: To assess whether stereopsis outcomes of patients with accommodative esotropia with high accommodative convergence/accommodation relationship (AC/A) were improved after treatment with bifocal glasses compared with single-vision lenses. DESIGN: Retrospective cohort study. PARTICIPANTS: Patients with high AC/A accommodative esotropia; evidence of stereopsis, binocularity (on Worth 4-dot testing), or improvement in near angle with +3.00 D lenses; and at least 4 years of records available for review, who were seen in the Department of Ophthalmology at Boston Children's Hospital between 2006 and 2014. METHODS: Use of bifocal or single-vision glasses. Charts were reviewed retrospectively. Stereopsis was log transformed for statistical analysis. Linear (for stereopsis) or logistic (for surgery) regression was used to control for confounders. MAIN OUTCOME MEASURES: Stereopsis at final follow-up, difference in stereopsis between final and initial visits, and progression to strabismus surgery. Secondary outcomes included final near and distance deviations. RESULTS: Of the 180 patients who met inclusion criteria, 77 used bifocals and 103 used single-vision lenses. Bifocals did not improve stereopsis outcomes compared with single-vision lenses. In both groups, stereopsis was similar at the initial and final visits, with similar improvement in both groups. Children in the bifocal group had a 3.6-fold higher rate of strabismus surgery than children in the single-lens group (P = 0.04.) Additionally, children in the bifocal group had near deviations 4 PD larger than those with single lenses at final follow-up, even after controlling for age and initial deviation (P = 0.02). These results did not change if surgical patients were eliminated or in the subgroup with initial distance deviation of 0 PD in full hyperopic correction. CONCLUSIONS: Despite their widespread use, there is no evidence that bifocals improve outcomes in children with accommodative esotropia with high AC/A. In our retrospective review, children with bifocals had higher surgical rates and a smaller improvement in near deviation over time. Although our results suggest that eliminating bifocals could reduce the cost and complexity of care while potentially improving quality, prospective, randomized controlled trials are needed to determine whether a change in practice is warranted.

Two unique TUBB3 mutations cause both CFEOM3 and malformations of cortical development.

One set of missense mutations in the neuron specific beta tubulin isotype 3 (TUBB3) has been reported to cause malformations of cortical development (MCD), while a second set has been reported to cause isolated or syndromic Congenital Fibrosis of the Extraocular Muscles type 3 (CFEOM3). Because TUBB3 mutations reported to cause CFEOM had not been associated with cortical malformations, while mutations reported to cause MCD had not been associated with CFEOM or other forms of paralytic strabismus, it was hypothesized that each set of mutations might alter microtubule function differently. Here, however, we report two novel de novo heterozygous TUBB3 amino acid substitutions, G71R and G98S, in four patients with both MCD and syndromic CFEOM3. These patients present with moderately severe CFEOM3, nystagmus, torticollis, and developmental delay, and have intellectual and social disabilities. Neuroimaging reveals defective cortical gyration, as well as hypoplasia or agenesis of the corpus callosum and anterior commissure, malformations of hippocampi, thalami, basal ganglia and cerebella, and brainstem and cranial nerve hypoplasia. These new TUBB3 substitutions meld the two previously distinct TUBB3-associated phenotypes, and implicate similar microtubule dysfunction underlying both.

Congenital cranial dysinnervation disorder with homozygous KIF26A variant.

Congenital fibrosis of the extraocular muscles (CFEOM) type 1 is associated with heterozygous missense variants in KIF21A, which encodes a kinesin-like motor protein. Individuals with CFEOM1 have severe paralysis of upgaze and ptosis, resulting in a pronounced chin-up head posture. There can also be limitations of horizontal eye movements. Loss of function of KIF26A, an unconventional kinesin motor protein that lacks ATP-dependent motor activity, has been recently reported to cause a spectrum of congenital brain malformations associated with defects in migration, localization, and growth of excitatory neurons. It has also been associated with megacolon resembling Hirschsprung's disease. We report the case of a boy with homozygous loss of function of KIF26A with restricted eye movements, specifically restricted upgaze and downgaze with variable nystagmus and dissociated vertical eye movements. This case represents a congenital cranial dysinnervation disorder, most similar to CFEOM, and is the first report of a congenital cranial dysinnervation disorder caused by a kinesin other than KIF21A.

Neuromuscular Junction Development Differs Between Extraocular and Skeletal Muscles and Between Different Extraocular Muscles.

Purpose: To determine whether development of neuromuscular junctions (NMJs) differs between extraocular muscles (EOMs) and other skeletal muscles. Methods: Mouse EOMs, diaphragm, and tibialis anterior (TA) were collected at postnatal day (P)0, P3, P7, P10, P14, and P21, and 12 weeks. Whole muscles were stained with α-bungarotoxin, anti-neurofilament antibody, and slow or fast myosin heavy chain antibody, and imaged with a confocal microscope. Images were quantified using Imaris software. Results: NMJs in the EOMs show a unique pattern of morphological development compared to diaphragm and TA. At P0, diaphragm and TA NMJs were oval plaques; EOM single NMJs were long, thin rods. NMJs in the three muscle types progress to mature morphology at different rates. At all ages, EOM single NMJs were larger, especially relative to myofiber size. The inferior oblique and inferior rectus muscles show delayed single NMJ development compared to other EOMs. NMJs on multiply-innervated fibers in the EOMs vary widely in size, and there were no consistent differences between muscles or over time. Incoming motor nerves formed complex branching patterns, dividing first into superficial and deep branches, each of which branched extensively over the full width of the muscle. Motor axons that innervate multiply-innervated fibers entered the muscle with the axons that innervate singly-innervated fibers, then extended both proximally and distally. EOM NMJs had more subsynaptic nuclei than skeletal muscle NMJs throughout development. Conclusions: EOMs show a unique pattern of NMJ development and have more subsynaptic nuclei than other muscles, which may contribute to the exquisite control of eye movements.

Mental Health Conditions Associated With Strabismus in a Diverse Cohort of US Adults.

Importance: Greater understanding of the association between strabismus and mental health conditions across sociodemographic backgrounds may inform strategies to improve mental well-being in this population. Objective: To describe the association of strabismus with mental health conditions in a diverse cohort of US adults. Design, Setting, and Participants: This cross-sectional study used data from the National Institutes of Health's All of Us Research Program, an ongoing program launched in 2015. The study included 3646 adults (aged ≥18 years) with strabismus and 3646 propensity score-matched controls. Statistical analysis was conducted from September 12, 2023, to January 29, 2024. Main Outcomes and Measures: Adults with strabismus were propensity score matched on age, gender, race and ethnicity, income, educational level, and insurance status in a 1:1 ratio with adults without strabismus. The prevalences of anxiety, depression, substance use and addiction, bipolar disorder, and schizophrenia spectrum disorder among adults with strabismus were compared with controls. Logistic regression was used to evaluate the association of mental health conditions with sociodemographic factors in each group. Results: This study included 3646 adults with strabismus (median age, 67 years [IQR, 53-76 years]; 2017 women [55%]) and 3646 propensity score-matched controls (median age, 67 years [IQR, 53-76 years]; 2017 women [55%]). Individuals with strabismus had higher prevalences of anxiety (1153 [32%] vs 519 [14%]; difference, 17%; 95% CI, 15%-19%; P < .001), depression (1189 [33%] vs 514 [14%]; difference, 19%; 95% CI, 17%-20%; P < .001), substance use and addiction (116 [3%] vs 51 [1%]; difference, 2%; 95% CI, 1%-3%; P < .001), bipolar disorder (253 [7%] vs 101 [3%]; difference, 4%; 95% CI, 3%-5%; P < .001), and schizophrenia spectrum disorder (103 [3%] vs 36 [1%]; difference, 2%; 95% CI, 1%-3%; P < .001) compared with individuals without strabismus. Among adults with strabismus, higher odds of mental health conditions were associated with younger age (odds ratio [OR], 1.11 per 10-year decrease; 95% CI, 1.06-1.16 per 10-year decrease), female gender (OR, 1.62; 95% CI, 1.41-1.85), Black or African American race and ethnicity (OR, 1.22; 95% CI, 1.01-1.48), low income (OR, 3.06; 95% CI, 2.56-3.67), and high school education or less (OR, 1.58; 95% CI, 1.34-1.85). Conclusions and Relevance: In a diverse and nationwide cohort, adults with strabismus were more likely to have mental health conditions compared with adults without strabismus. Further investigation into the risk factors for poor mental health among adults with strabismus across sociodemographic backgrounds may offer novel opportunities for interventions to improve mental well-being in this population.

Presence of Copy Number Variants Associated With Esotropia in Patients With Exotropia.

Importance: Strabismus is a common ocular disorder of childhood. There is a clear genetic component to strabismus, but it is not known if esotropia and exotropia share genetic risk factors. Objective: To determine whether genetic duplications associated with esotropia are also associated with exotropia. Design, Setting, and Participants: This was a cross-sectional study conducted from November 2005 to December 2023. Individuals with constant or intermittent exotropia of any magnitude or a history of surgery for exotropia were recruited from pediatric ophthalmic practices. Data were analyzed from March to December 2023. Exposure: Genetic duplication. Main Outcomes and Measures: Presence of genetic duplications at 2p11.2, 4p15.2, and 10q11.22 assessed by digital droplet polymerase chain reaction. Orthoptic measurements and history of strabismus surgery were performed. Results: A total of 234 individuals (mean [SD] age, 19.5 [19.0] years; 127 female [54.3%]) were included in this study. The chromosome 2 duplication was present in 1.7% of patients with exotropia (4 of 234; P = .40), a similar proportion to the 1.4% of patients with esotropia (23 of 1614) in whom it was previously reported and higher than the 0.1% of controls (4 of 3922) previously reported (difference, 1.6%; 95% CI, 0%-3.3%; P < .001). The chromosome 4 duplication was present in 3.0% of patients with exotropia (7 of 234; P = .10), a similar proportion to the 1.7% of patients with esotropia (27 of 1614) and higher than the 0.2% of controls (6 of 3922) in whom it was previously reported (difference, 2.8%; 95% CI, 0.6%-5.0%; P < .001). The chromosome 10 duplication was present in 6.0% of patients with exotropia (14 of 234; P = .08), a similar proportion to the 4% of patients with esotropia (64 of 1614) and higher than the 0.4% of controls (18 of 3922) in whom it was previously reported (difference, 5.6%; 95% CI, 2.5%-8.6%; P < .001). Individuals with a duplication had higher mean (SD) magnitude of deviation (31 [13] vs 22 [14] prism diopters [PD]; difference, 9 PD; 95% CI, 1-16 PD; P = .03), were more likely to have constant (vs intermittent) exotropia (70% vs 29%; difference, 41%; 95% CI, 20.8%-61.2%; P < .001), and had a higher rate of exotropia surgery than those without a duplication (58% vs 34%; difference, 24%; 95% CI, 3%-44%; P = .02). Conclusions and Relevance: In this cross-sectional study, results suggest that the genetic duplications on chromosomes 2, 4, and 10 were risk factors for exotropia as well as esotropia. These findings support the possibility that esotropia and exotropia have shared genetic risk factors. Whether esotropia or exotropia develops in the presence of these duplications may be influenced by other shared or independent genetic variants or by environmental factors.

Expanding the genetics and phenotypes of ocular congenital cranial dysinnervation disorders.

Purpose: To identify genetic etiologies and genotype/phenotype associations for unsolved ocular congenital cranial dysinnervation disorders (oCCDDs). Methods: We coupled phenotyping with exome or genome sequencing of 467 pedigrees with genetically unsolved oCCDDs, integrating analyses of pedigrees, human and animal model phenotypes, and de novo variants to identify rare candidate single nucleotide variants, insertion/deletions, and structural variants disrupting protein-coding regions. Prioritized variants were classified for pathogenicity and evaluated for genotype/phenotype correlations. Results: Analyses elucidated phenotypic subgroups, identified pathogenic/likely pathogenic variant(s) in 43/467 probands (9.2%), and prioritized variants of uncertain significance in 70/467 additional probands (15.0%). These included known and novel variants in established oCCDD genes, genes associated with syndromes that sometimes include oCCDDs (e.g., MYH10, KIF21B, TGFBR2, TUBB6), genes that fit the syndromic component of the phenotype but had no prior oCCDD association (e.g., CDK13, TGFB2), genes with no reported association with oCCDDs or the syndromic phenotypes (e.g., TUBA4A, KIF5C, CTNNA1, KLB, FGF21), and genes associated with oCCDD phenocopies that had resulted in misdiagnoses. Conclusion: This study suggests that unsolved oCCDDs are clinically and genetically heterogeneous disorders often overlapping other Mendelian conditions and nominates many candidates for future replication and functional studies.

Genetics of strabismus.

Strabismus, or misalignment of the eyes, is the most common ocular disorder in the pediatric population, affecting approximately 2%-4% of children. Strabismus leads to the disruption of binocular vision, amblyopia, social and occupational discrimination, and decreased quality of life. Although it has been recognized since ancient times that strabismus runs in families, its inheritance patterns are complex, and its precise genetic mechanisms have not yet been defined. Family, population, and twin studies all support a role of genetics in the development of strabismus. There are multiple forms of strabismus, and it is not known if they have shared genetic mechanisms or are distinct genetic disorders, which complicates studies of strabismus. Studies assuming that strabismus is a Mendelian disorder have found areas of linkage and candidate genes in particular families, but no definitive causal genes. Genome-wide association studies searching for common variation that contributes to strabismus risk have identified two risk loci and three copy number variants in white populations. Causative genes have been identified in congenital cranial dysinnervation disorders, syndromes in which eye movement is limited or paralyzed. The causative genes lead to either improper differentiation of cranial motor neurons or abnormal axon guidance. This article reviews the evidence for a genetic contribution to strabismus and the recent advances that have been made in the genetics of comitant strabismus, the most common form of strabismus.

Noncoding variants alter GATA2 expression in rhombomere 4 motor neurons and cause dominant hereditary congenital facial paresis.

Hereditary congenital facial paresis type 1 (HCFP1) is an autosomal dominant disorder of absent or limited facial movement that maps to chromosome 3q21-q22 and is hypothesized to result from facial branchial motor neuron (FBMN) maldevelopment. In the present study, we report that HCFP1 results from heterozygous duplications within a neuron-specific GATA2 regulatory region that includes two enhancers and one silencer, and from noncoding single-nucleotide variants (SNVs) within the silencer. Some SNVs impair binding of NR2F1 to the silencer in vitro and in vivo and attenuate in vivo enhancer reporter expression in FBMNs. Gata2 and its effector Gata3 are essential for inner-ear efferent neuron (IEE) but not FBMN development. A humanized HCFP1 mouse model extends Gata2 expression, favors the formation of IEEs over FBMNs and is rescued by conditional loss of Gata3. These findings highlight the importance of temporal gene regulation in development and of noncoding variation in rare mendelian disease.

First Visit Characteristics Associated with Future Surgery in Intermittent Exotropia.

PURPOSE: Identify demographic and clinical characteristics at the first presentation associated with later having surgery for intermittent exotropia (IXT). METHODS: Retrospective cohort study of 228 children with IXT and 5+ years of follow-up. Demographic and clinical data were extracted from medical records. A total 97 participants who underwent surgery during follow-up were compared to 131 participants who did not. Best subset regression was used to identify first visit variables associated with later having strabismus surgery. Surgery was then regressed on the selected variables using logistic models. RESULTS: Age and control were the only first visit variables significantly associated with having surgery for IXT. Notably, neither angle of deviation nor stereopsis were associated with later surgery. In an adjusted logistic model, each one-month increase in age at presentation was associated with a 1% decrease in the odds of having surgery (OR = 0.991, 95% CI: 0.982-0.999, P = .04). Children with poor control at initial visit had almost five times greater odds of having surgery than those with good control (OR = 4.95, 95% CI: 2.31-10.98, P < .0001). CONCLUSIONS: Age and control of IXT are important factors at presentation associated with future surgical intervention for IXT. The magnitude of deviation and stereopsis was not significantly associated with future surgical treatment for IXT.

Impaired Extraocular Muscle Innervation Is Present Before Eye Opening in a Mouse Model of Infantile Nystagmus Syndrome.

Purpose: To determine if extraocular muscles (EOMs) from mice with nystagmus show abnormalities in myofiber composition and innervation, as seen in EOMs from human nystagmus patients, and to determine when in development those changes occur. Methods: Balb/c albino mice were crossed to pigmented mice to generate heterozygous mice, which were mated to create experimental litters containing albinos and wild-type controls. Orbits were harvested from adult animals (12 weeks old); on postnatal day (P)0, P10, P14, and P21; and from 6-week-old animals. EOM sections were collected from the intraorbital portion of the muscles. Sections were immunostained for slow and fast myosin and for neuromuscular junctions (NMJs). The proportion of each myofiber subtype and the density and size of NMJs were quantified. Initial innervation patterns were assessed using whole-mount immunostaining of embryonic day (E)13.5 embryos expressing IslMN:GFP. Results: Adult albino EOMs display an increased proportion of slow myofibers, larger slow myofibers, and a decreased density of NMJs-similar to human nystagmus patients. The percentage of NMJs on slow myofibers is also lower in albino animals. The initial innervation pattern of the incoming ocular motor neurons is normal in E13.5 albino embryos. Differences in the proportion of slow and fast myofiber subtypes are present as early as P14, and a lower percentage of NMJs on slow myofibers is present by P21. There is a lower density of NMJs on albino EOMs as early as P10, prior to eye opening. Conclusions: Changes in NMJ development observed before eye opening indicate that nystagmus is not solely secondary to poor vision.

A case of lower extremity venous thrombosis in the pediatric emergency department: associations with May-Thurner syndrome and isotretinoin use.

Unilateral calf swelling and pain is not a common complaint in the pediatric emergency department. We present a case of a 17-year-old adolescent boy with no past medical history who presented with left leg swelling and pain while taking prednisone and isotretinoin. He was found to have an extensive occlusive thrombus throughout the deep venous system in his left leg. He was later diagnosed with May-Thurner syndrome, an anatomic variant in which the right iliac artery compresses the left iliac vein. We review the differential diagnosis, diagnostic workup, and initial ED management of deep venous thrombosis and provide a brief discussion of May-Thurner syndrome and the association of isotretinoin and vascular thrombi.

Axonal Growth Abnormalities Underlying Ocular Cranial Nerve Disorders.

Abnormalities in cranial motor nerve development cause paralytic strabismus syndromes, collectively referred to as congenital cranial dysinnervation disorders, in which patients cannot fully move their eyes. These disorders can arise through one of two mechanisms: (a) defective motor neuron specification, usually by loss of a transcription factor necessary for brainstem patterning, or (b) axon growth and guidance abnormalities of the oculomotor, trochlear, and abducens nerves. This review focuses on our current understanding of axon guidance mechanisms in the cranial motor nerves and how disease-causing mutations disrupt axon targeting. Abnormalities of axon growth and guidance are often limited to a single nerve or subdivision, even when the causative gene is ubiquitously expressed. Additionally, when one nerve is absent, its normal target muscles attract other motor neurons. Study of these disorders highlights the complexities of axon guidance and how each population of neurons uses a unique but overlapping set of axon guidance pathways.

Novel variants in TUBA1A cause congenital fibrosis of the extraocular muscles with or without malformations of cortical brain development.

Variants in multiple tubulin genes have been implicated in neurodevelopmental disorders, including malformations of cortical development (MCD) and congenital fibrosis of the extraocular muscles (CFEOM). Distinct missense variants in the beta-tubulin encoding genes TUBB3 and TUBB2B cause MCD, CFEOM, or both, suggesting substitution-specific mechanisms. Variants in the alpha tubulin-encoding gene TUBA1A have been associated with MCD, but not with CFEOM. Using exome sequencing (ES) and genome sequencing (GS), we identified 3 unrelated probands with CFEOM who harbored novel heterozygous TUBA1A missense variants c.1216C>G, p.(His406Asp); c.467G>A, p.(Arg156His); and c.1193T>G, p.(Met398Arg). MRI revealed small oculomotor-innervated muscles and asymmetrical caudate heads and lateral ventricles with or without corpus callosal thinning. Two of the three probands had MCD. Mutated amino acid residues localize either to the longitudinal interface at which α and ß tubulins heterodimerize (Met398, His406) or to the lateral interface at which tubulin protofilaments interact (Arg156), and His406 interacts with the motor domain of kinesin-1. This series of individuals supports TUBA1A variants as a cause of CFEOM and expands our knowledge of tubulinopathies.

Ocular injury via epinephrine auto-injector.

Intraocular injury by epinephrine auto-injector has been rarely reported. Toxic risk to the intraocular structures is suspected, but the evidence is inconclusive. We present the case of a 2-year-old girl who sustained an injury to her right eye by inadvertent epinephrine injection. Cataract surgery was performed to treat an increasingly opaque lens, and an intraocular lens was implanted. The visual outcome was good, with no retinal damage.