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.

Unilateral periorbital swelling in children: avoid delays in diagnosis.

A 10-year-old child had painful periorbital swelling in the left eye. It was diagnosed as preseptal cellulitis and treated with oral antibiotics. Three days later, the ocular condition worsened so the child was referred for further management. On examination, the child had a temperature of 102 °F. Ocular examination revealed proptosis, restricted ocular movements and a relative afferent pupillary defect in the left eye. Ocular examination of the right eye was normal. There was a history of recurrent episodes of cold in the past. CT scan orbit and sinuses revealed signs of orbital cellulitis with sinusitis on the left side. The child was treated with parenteral antibiotics and endoscopic sinus surgery. A child presenting with unilateral periorbital swelling needs to be thoroughly evaluated. It is important to differentiate orbital cellulitis from preseptal cellulitis. Orbital cellulitis is an emergency and delay in diagnosis can lead to vision and life-threatening intracranial complications.

Invasive fungal disease misdiagnosed as tumour in association with orbital apex syndrome.

Invasive sino-orbital aspergillosis is a rare cause of orbital apex syndrome (OAS) in immunocompetent patients and often misdiagnosed as tumour because of its aggressive nature and invasive patterns. We report a 23-year-old immunocompetent man presenting with painful progressive loss of vision, ophthalmoplegia and proptosis of the right eye suggestive of OAS. MRI with gadolinium contrast showed an enhancing heterogeneous mass filling the paranasal sinuses, extraconal space and extending up to the right orbital apex. A functional endoscopic biopsy reported as invasive sino-orbital aspergillosis. He was started on intravenous voriconazole and maximal surgical debridement was done. He gradually regained his vision to 20/30 in the right eye. A review of literature reported several such cases which were managed medically or surgically but with poor visual recovery. This case highlights the need for awareness among clinicians for early diagnosis and treatment to prevent vision loss and better survival.

Vestibular-ocular reflex dysfunction following mild traumatic brain injury: A narrative review.

Mild traumatic brain injury (mTBI) is a prevalent injury which occurs across many populations, including children and adolescents, athletes, military personnel, and the elderly. mTBI can result in various subjective symptoms and clinical deficits, such as abnormalities to the vestibulo-ocular reflex (VOR). Over 50% of individuals with mTBI are reported to have VOR abnormalities, which strongly contribute to feelings of dizziness and unsteadiness. Dizziness is a strong predictor for prolonged recovery following mTBI and is additionally linked with mental health difficulties and functional limitations affecting likelihood of return to work. Early diagnosis, and subsequent treatment, of VOR deficits following mTBI may greatly improve recovery outcomes and a patient's quality of life, but a thorough comprehension of the related pathophysiology is necessary to understand the assessments used to diagnose VOR abnormalities. Therefore, the purpose of this article is i) provide readers with an introduction on the VOR physiology to facilitate understanding about mTBI-related abnormalities, and ii) to discuss current assessments that are commonly used to measure VOR function following mTBI. As the VOR and oculomotor (OM) systems are heavily linked and often work in tandem, discussion of the relevant aspects of the OM system is also provided.

Strabismus in chronic progressive external ophthalmoplegia.

PURPOSE: To elucidate the patterns of strabismus and ophthalmoplegia associated with chronic progressive external ophthalmoplegia (CPEO) confirmed by mitochondrial DNA (mtDNA) deletions in Asians. METHODS: A total of 10 patients confirmed to have mtDNA deletion associated with CPEO were included. Long-range PCR encompassing the entire mtDNA was carried out. In the cases with mtDNA deletion, the exact deletion ranges of mtDNA were identified by sequencing. A full ophthalmologic examination including prism and alternate cover test in the primary position, evaluation of ductions and versions, and binocularity was performed in 10 patients with confirmed mtDNA deletions associated with CPEO. RESULTS: All of the patients showed ophthalmoplegia as well as ptosis, even after eyelid surgeries. Ophthalmoplegia was symmetric between both eyes in nine patients (90%) while one patient (10%) showed asymmetric ophthalmoplegia with esotropia and left hypotropia. Among the nine patients with symmetric involvement, four patients (44%) showed exotropia, three (33%) had exotropia with vertical deviation, and the remaining two patients (22%) showed orthotropia. Five out of 10 patients (50%) complained of diplopia associated with strabismus, four of whom (80%) had vertical deviation. Three out of five patients (60%) without diplopia showed exotropia of 20 prism diopters (PD) to 50 PD. CONCLUSIONS: Exotropia with/without vertical deviation is the most common form of strabismus in Asian patients with CPEO and only one of them showed a small angle of esotropia. Ophthalmoplegia could be asymmetric in 10% of CPEO patients.

Visual loss from dermal fillers.

BACKGROUND: An increasing number of people are undergoing non-surgical aesthetic procedures, especially injections of botulinum toxin and dermal fillers. While toxin injections have lower rates of complications, profound and serious consequences can arise with the use of dermal fillers. CASE: A 29-year-old woman presented to the eye casualty department with sudden visual loss, ptosis and ophthalmoplegia after having had non-surgical rhinoplasty in a beauty salon in West London. The filler was administered by a healthcare professional not registered with the General Medical Council (GMC) or similar governing body. DISCUSSION: Despite prompt measures on arrival at our service, the symptoms of visual loss, ptosis and ophthalmoplegia persisted. Attempts from the patient and medical services to report the incident (to trading standards and the police) were to no avail. CONCLUSION: This case highlights the poor treatment response to filler-related ophthalmic complications. It is also evident that in the United Kingdom, there appears to be poor regulation in the use of these products, a lack of clear guidelines for the management of their complications and finally no recourse for patients to challenge practitioners who lack medical registration and are not held accountable.

The Wide Spectrum of Pathophysiologic Mechanisms of Paraproteinemic Neuropathy.

Monoclonal gammopathy is encountered quite frequently in the general population. This type of hematologic abnormality may be mild, referred to as monoclonal gammopathy of undetermined significance or related to different types of hematologic malignancies. The association of a peripheral neuropathy with monoclonal gammopathy is also fairly common, and hemopathy may be discovered in an investigation of peripheral neuropathy. In such a situation, it is essential to determine the exact nature of the hematologic process in order not to miss a malignant disease and thus initiate the appropriate treatment (in conjunction with hematologists and oncologists). In this respect, nerve biopsy (discussed on a case-by-case basis) is of great value in the management of such patients. We therefore propose to present the objectives and main interests of nerve biopsy in this situation.

The Novel Compound Heterozygous Mutations of ECEL1 Identified in a Family with Distal Arthrogryposis Type 5D.

INTRODUCTION: Distal arthrogryposis type 5D (DA5D) is an autosomal recessive disease. The clinical symptoms include contractures of the joints of limbs, especially camptodactyly of the hands and/or feet, unilateral ptosis, a round-shaped face, arched eyebrows, and micrognathia, without ophthalmoplegia. ECEL1 is a DA5D causative gene that encodes a membrane-bound metalloprotease. ECEL1 plays important roles in the final axonal arborization of motor nerves in limb skeletal muscles and neuromuscular junction formation during prenatal development. METHODS: A DA5D family with webbing of the elbows and fingers was recruited. We performed whole-exome sequencing (WES) and filtered mutations by disease-causing genes of arthrogryposis multiplex congenita (AMC). Mutational analysis and cosegregation confirmation were then performed. RESULTS: We identified novel compound heterozygous mutations of ECEL1 (NM_004826: c.69C>A, p.C23∗ and c.1810G>A, p.G604R) in the proband. CONCLUSIONS: We detected causative mutations in a DA5D family, expanding the spectrum of known ECEL1 mutations and contributing to the clinical diagnosis of DA5D.

Identification of a novel heterozygous guanosine monophosphate reductase (GMPR) variant in a patient with a late-onset disorder of mitochondrial DNA maintenance.

Autosomal dominant progressive external ophthalmoplegia (adPEO) is a late-onset, Mendelian mitochondrial disorder characterised by paresis of the extraocular muscles, ptosis, and skeletal-muscle restricted multiple mitochondrial DNA (mtDNA) deletions. Although dominantly inherited, pathogenic variants in POLG, TWNK and RRM2B are among the most common genetic defects of adPEO, identification of novel candidate genes and the underlying pathomechanisms remains challenging. We report the clinical, genetic and molecular investigations of a patient who presented in the seventh decade of life with PEO. Oxidative histochemistry revealed cytochrome c oxidase-deficient fibres and occasional ragged red fibres showing subsarcolemmal mitochondrial accumulation in skeletal muscle, while molecular studies identified the presence of multiple mtDNA deletions. Negative candidate screening of known nuclear genes associated with PEO prompted diagnostic exome sequencing, leading to the prioritisation of a novel heterozygous c.547G>C variant in GMPR (NM_006877.3) encoding guanosine monophosphate reductase, a cytosolic enzyme required for maintaining the cellular balance of adenine and guanine nucleotides. We show that the novel c.547G>C variant causes aberrant splicing, decreased GMPR protein levels in patient skeletal muscle, proliferating and quiescent cells, and is associated with subtle changes in nucleotide homeostasis protein levels and evidence of disturbed mtDNA maintenance in skeletal muscle. Despite confirmation of GMPR deficiency, demonstrating marked defects of mtDNA replication or nucleotide homeostasis in patient cells proved challenging. Our study proposes that GMPR is the 19th locus for PEO and highlights the complexities of uncovering disease mechanisms in late-onset PEO phenotypes.

Prevalence and Improvement of Caine-Positive Wernicke-Korsakoff Syndrome in Psychiatric Inpatient Admissions.

BACKGROUND: Wernicke-Korsakoff Syndrome (WKS) resulting from thiamine deficiency is classically defined as including encephalopathy, ataxia, and ophthalmoplegia. Only 16% of autopsy-confirmed patients with WKS exhibit all three signs. Caine-positive WKS criteria include two or more of the following: nutritional deficiency, delirium or mild memory impairment, cerebellar dysfunction/ataxia, and oculomotor abnormalities. OBJECTIVE: We describe Caine-positive WKS prevalence among psychiatric inpatients and compare pretreatment-versus-posttreatment neurocognitive improvement to an unaffected group. METHODS: This 6-month quality-improvement evaluation included two-stage screening for Caine-positive WKS, administering high-dose intravenous thiamine (day 1: 1200 mg; days 2-4: 200 mg) with reexamination on day 5. We used descriptive statistics and fitted random effects models to examine rate-of-change differences in pre-/posttreatment Montreal Cognitive Assessment (MoCA), delayed 5-item recall, and gait/coordination scores between treated Caine-positive patients with WKS and untreated Caine-negative patients. RESULTS: Of 262 patients, 32 (12%) had Caine-positive WKS; 17 (53%) used alcohol currently. Treated Caine-positive WKS (n = 26) versus Caine-negative comparison (n = 34) before and after treatment observed a mean change (standard deviation) in the MoCA score of 3.6 (2.5) versus 1.8 (2.5) (P < 0.01); 5-item recall: 1.8 (1.4) versus 0.5 (1.4) (P < 0.001); gait/coordination scores: -0.6 (1.2) versus -0.1 (0.6) (P < 0.001). Oculomotor abnormalities were infrequent (n = 4 in Caine-positive WKS, n = 2 in Caine-negative comparison groups). CONCLUSIONS: Caine-positive WKS prevalence among psychiatric inpatients was 12%; only half used alcohol. Patients treated with high-dose thiamine demonstrated clinically significant neurocognitive improvement.

Surgical management of pediatric patients with congenital fibrosis of the extraocular muscles.

PURPOSE: Congenital fibrosis of the extraocular muscles (CFEOM) is a rare nonprogressive disorder characterized by bilateral ptosis, with severely limited ocular motility. We report the treatment outcomes and problems in 3 cases of pediatric CFEOM in which extraocular muscle surgery was performed. CASES: All the cases showed bilateral ptosis and a chin-up abnormal head posture (AHP). Case 1 A 6-year-old girl. Both eyes were fixed downward with esotropia and could not elevate above the horizontal midline. She underwent simultaneous bilateral inferior rectus (IR) and medial rectus (MR) recession. Postoperatively, 8-prism-diopter (PD) exotropia was observed, and the AHP were improved, but MR advancement in the right eye was necessary because A-pattern exotropia became prominent starting about 10 months postoperatively. Case 2 A 7-year-old girl. Both eyes were fixed downward and did not elevate over the midline. She underwent bilateral IR recession. Postoperatively, 8-PD exotropia was observed; however, A-pattern exotropia became prominent gradually at about 1 year and 7 months postoperatively, and bilateral lateral rectus (LR) recession was added. Case 3 A 6-year-old girl. Both eyes were fixed downward but could be elevated above the horizontal midline by upward effort. She underwent bilateral IR recession, which resulted in improvement of the AHP and ptosis. About 8 months postoperatively, exotropia was evident only in the downward gaze. CONCLUSIONS: Bilateral IR recession in pediatric patients with CFEOM was effective in improving AHP, but postoperative exotropia appeared to be inevitable owing to the diminished adducted function caused by IR recession. Thus, horizontal strabismus surgery should be planned after the results of IR recession become evident.

Wernekink commissure syndrome secondary to a rare 'V'-shaped pure midbrain infarction: a case report and review of the literature.

Purpose: Wernekink commissure syndrome is a typical but extremely rare mesencephalic syndrome, and generally presents with bilateral cerebellar dysfunction, diverse oculomotor disorders and occasionally delayed-onset palatal myoclonus or tremor. However, it has been reported infrequently.Methods: We report a case of a 55-year-old man who suffered an acute paramedian midbrain infarction presenting with bilateral cerebellar ataxia, bilateral anterior internuclear ophthalmoplegia and unilateral pseudoabducens palsy, which is confirmed as Wernekink commissure syndrome by magnetic resonance imaging (MRI). We summarized the clinical data of this entity and performed a literature review of 20 previous reports of patients with this syndrome.Results: In combination with previous reports, we found that the most common symptom was bilateral cerebellar ataxia (100%) and other frequent symptoms were oculomotor disorders (81%), delayed palatal myoclonus or tremor (33%) and consciousness dysfunction (33%). Lesions on brain MRI of all patients affected the area of caudal paramedian midbrain (CPM).Conclusion: Bilateral cerebellar ataxia and lesions involved in the area of CPM on MRI are the major features of Wernekink commissure syndrome and should be the necessary conditions of diagnostic criteria. The simultaneous occurrence of bilateral cerebellar ataxia and oculomotor disorders is significant for localization diagnosis. Consciousness dysfunction is also a relatively frequent symptom of this syndrome. Moreover, pseudoabducens palsy might be attributed to a midbrain lesion. Clinicians should be familiar with and early to recognize this unique syndrome to avoid misdiagnosis.

Cored in the act: the use of models to understand core myopathies.

The core myopathies are a group of congenital myopathies with variable clinical expression - ranging from early-onset skeletal-muscle weakness to later-onset disease of variable severity - that are identified by characteristic 'core-like' lesions in myofibers and the presence of hypothonia and slowly or rather non-progressive muscle weakness. The genetic causes are diverse; central core disease is most often caused by mutations in ryanodine receptor 1 (RYR1), whereas multi-minicore disease is linked to pathogenic variants of several genes, including selenoprotein N (SELENON), RYR1 and titin (TTN). Understanding the mechanisms that drive core development and muscle weakness remains challenging due to the diversity of the excitation-contraction coupling (ECC) proteins involved and the differential effects of mutations across proteins. Because of this, the use of representative models expressing a mature ECC apparatus is crucial. Animal models have facilitated the identification of disease progression mechanisms for some mutations and have provided evidence to help explain genotype-phenotype correlations. However, many unanswered questions remain about the common and divergent pathological mechanisms that drive disease progression, and these mechanisms need to be understood in order to identify therapeutic targets. Several new transgenic animals have been described recently, expanding the spectrum of core myopathy models, including mice with patient-specific mutations. Furthermore, recent developments in 3D tissue engineering are expected to enable the study of core myopathy disease progression and the effects of potential therapeutic interventions in the context of human cells. In this Review, we summarize the current landscape of core myopathy models, and assess the hurdles and opportunities of future modeling strategies.

Anomalous superior oblique muscles and tendons in congenital fibrosis of the extraocular muscles.

PURPOSE: To evaluate the finding of anomalous superior oblique muscles in congenital fibrosis of the extraocular muscles (CFEOM), a feature not previously emphasized in this condition. METHODS: The medical records of all patients clinically or genetically diagnosed with CFEOM at Boston Children's Hospital between 2010 and 2018 were reviewed retrospectively. Those who underwent strabismus surgery during the study period were included in the analysis. Baseline patient characteristics, type of CFEOM, results of genetic testing, and intraoperative features of the superior oblique muscle or tendon were recorded. RESULTS: Of 24 patients identified (age range, 1 month to 62 years), 10 (42%) had genetically confirmed CFEOM, and 22 underwent strabismus surgery, 14 (64%) involving the superior oblique muscle. Of these, 7 (50%) had anomalously inserted tendons (most commonly attached nasal to the superior rectus muscle), whereas 7 (50%) had increased superior oblique muscle tension. CONCLUSIONS: Half of CFEOM patients who underwent superior oblique surgery had abnormally inserted superior oblique tendons, and 50% had tight muscles or abnormally thin tendons, findings that have not been well-characterized in this condition. The findings suggest that abnormal insertion of the superior oblique muscles and tendons are additional features of the disease process in CFEOM that have not been described previously. These features may contribute to the severe upgaze limitation in CFEOM and highlight the importance of superior oblique tenotomy in surgical management.

Outcomes of strabismus surgery in genetically confirmed congenital fibrosis of the extraocular muscles.

PURPOSE: To detail surgical strategy and strabismus outcomes in a genetically defined cohort of patients with congenital fibrosis of the extraocular muscles (CFEOM). METHODS: A total of 13 patients with genetically confirmed CFEOM (via genetic testing for mutations in KIF21A, PHOX2A, and TUBB3) were retrospectively identified after undergoing strabismus surgery at Boston Children's Hospital and surgical outcomes were compared. RESULTS: Age at first surgery ranged from 11 months to 63 years, with an average of 3 strabismus procedures per patient. Ten patients had CFEOM1, of whom 9 had the KIF21A R954W amino acid substitution and 1 had the M947T amino acid substitution. Of the 3 with CFEOM3, 2 had the TUBB3 E410K amino acid substitution, and 1 had a previously unreported E410V amino acid substitution. CFEOM1 patients all underwent at least 1 procedure to address chin-up posture. Chin-up posture improved from 24° ± 8° before surgery to 10.0° ± 8° postoperatively (P < 0.001). Three CFEOM1 patients developed exotropia after vertical muscle surgery alone; all had the R954W amino acid substitution. Postoperatively, 1 CFEOM1 patient developed a corneal ulcer. All CFEOM3 patients appeared to have underlying exposure keratopathy, successfully treated with prosthetic replacement of the ocular surface ecosystem (PROSE) lens in 2 patients. CONCLUSIONS: CFEOM is a complex strabismus disorder for which surgical management is difficult. Despite an aggressive surgical approach, multiple procedures may be necessary to achieve a desirable surgical effect. Knowledge of the underlying genetic diagnosis may help to inform surgical management.