Clinical and genetic characteristics of Chinese patients with congenital fibrosis of the extraocular muscles.

OBJECTIVE: This study aimed to describe the clinical and genetic characteristics of Chinese patients with congenital fibrosis of the extraocular muscles (CFEOM), and to evaluate the phenotype-genotype correlations in these patients. METHODS: This was a retrospective study. Patients with CFEOM underwent detailed ophthalmic examinations and magnetic resonance imaging (MRI). Panel-based next-generation sequencing was performed to identify pathogenic variants of disease-causing genes. RESULTS: Sixty-two patients with CFEOM were recruited into this study. Thirty-nine patients were diagnosed with CFEOM1 and 23 with CFEOM3. Forty-nine of the 62 patients with CFEOM carried either KIF21A (41/49) or TUBB3 variants (8/49). Six known missense variants in the KIF21A and TUBB3 genes, and a novel variant (c.3906T > A, p.D1302E) in the KIF21A gene were detected. Most patients with CFEOM1 carrying the KIF21A mutation displayed isolated CFEOM, whereas patients with CFEOM3 carrying the TUBB3 mutation had a wide range of clinical manifestations, either CFEOM alone or syndromes. Nystagmus was also present in 12 patients with CFEOM. Furthermore, the MRI findings varied, ranging from attenuation of the extraocular muscles to dysgenesis of the cranial nerves and brain structure. CONCLUSIONS: The novel variants identified in this study will further expand the spectrum of pathogenic variants in CFEOM-related genes. However, no phenotype-genotype correlations were established because of the diversity of the clinical characteristics of these patients.

Understanding the diagnostic challenges of Miller Fisher syndrome in children: a case report from an ophthalmological perspective.

We report a case of a 6-year-old boy with autism spectrum disorder presenting with new-onset squint and 'ptosis' following a recent infection. Clinical examination revealed ataxia and areflexia alongside a dilated pupil poorly reactive to light. Subsequently, his eye movements deteriorated to near-complete ophthalmoplegia at 1-week review. Further investigations inclusive of a magnetic resonance imaging (MRI) brain scan, a computed tomography (CT) venogram and a lumbar puncture were conducted to consider and rule out differential diagnoses. Cerebrospinal fluid analysis revealed an albuminocytologic dissociation. The clinical triad of progressive ophthalmoplegia, areflexia and areflexia alongside albuminocytologic dissociation led to the diagnosis of Miller Fisher syndrome. The patient was commenced on intravenous immunoglobulin and his symptoms showed significant improvement. We use this interesting case to provide context for key learning points about diagnosing Miller Fisher syndrome in children.

Silent threat of isolated sphenoid sinus tuberculosis resulting in blindness and ophthalmoplegia.

A diabetic woman in her fifties presented with a sudden onset of failing vision and diplopia involving the right eye for two days, along with fever and headache. Radiological investigations revealed right sphenoid sinusitis along with inflammation around the right orbital apex and optic nerve. Functional endoscopic sinus surgery, with orbital and optic nerve decompression improved the ocular movements, but not the visual acuity. Histopathology was suggestive of a granulomatous inflammatory lesion, and high-resolution computed tommography (HRCT) of the thorax revealed lung lesions suggestive of an old tubercular infection, and antitubercular treatment (ATT) was then initiated.At the end of two months of ATT, there was complete resolution of ophthalmoplegia, relative afferent pupillary defect, direct and consensual light reflex however, failure of improvement in her visual acuity, indicated damage to the optic nerve.Extrapulmonary tuberculosis involving an isolated sphenoid sinus is rare and elusive. Prompt radiological investigations, followed by orbital decompression and ATT, provide the best possible outcomes.

Ophthalmoparesis as an unusual manifestation of anti-3­hydroxy-3-methyl-glutaryl-coenzyme A reductase antibody-associated myopathies.

We describe two anti-3­hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR) antibody-positive patients with treatment-responsive ophthalmoparesis. Patient 1 was a 53-year-old male with progressive proximal limb weakness, dysphagia, ptosis, and diplopia over 6 weeks and creatine kinase (CK) of 3,512 units/L. Patient 2 was a 55-year-old female with progressive proximal weakness, dysarthria, ptosis, diplopia, and dyspnea over 2 weeks with CK of 31,998 units/L. Both patients had normal thyroid studies and repetitive nerve stimulation, myopathic electromyography with fibrillation potentials, magnetic resonance imaging demonstrating abnormal enhancement of extraocular muscles, muscle biopsy showing necrotic myofibers, and positive anti-HMGCR antibodies. Patient 1 also had weakly positive anti-PM/Scl antibodies. Immunomodulatory therapies led to resolution of oculobulbar weakness and normalization of CK levels in both patients, while limb weakness resolved completely in patient 1 and partially in patient 2. These cases expand the phenotypic spectrum of anti-HMGCR antibody-associated myopathies to include subacute ophthalmoparesis with limb-girdle weakness and markedly elevated CK.

Clinical Reasoning: A 60-Year-Old Woman With Rapidly Progressive Muscle Weakness and Ophthalmoparesis.

The clinical assessment of patients with proximal muscle weakness represents a frequent yet intricate challenge. We present the case of a 60-year-old woman who experienced a progressive, symmetrical weakness in proximal limbs and bulbar muscles over 6 months. Notable clinical findings included bilateral ophthalmoparesis; widespread muscle atrophy; and pronounced weakness in craniobulbar, cervical, and proximal muscles, more severe than in distal ones. We elucidate a methodical diagnostic approach, focusing on constructing a comprehensive differential diagnosis and identifying potential causes of proximal muscle weakness. Special emphasis is placed on exploring the etiologies in cases presenting with both progressive muscle weakness and ophthalmoparesis. We further describe the role of muscle biopsy results and their integration with genetic testing outcomes.

Identification of a Novel Frameshift Variant in MYF5 Leading to External Ophthalmoplegia with Rib and Vertebral Anomalies.

Myogenic transcription factors with a basic helix-loop-helix (bHLH) such as MYOD, myogenin, MRF4, and MYF5 contribute to muscle differentiation and regulation. The MYF5 gene located on chromosome 12 encodes for myogenic factor 5 (MYF5), which has a role in skeletal and extraocular muscle development and rib formation. Variants in MYF5 were found to cause external ophthalmoplegia with rib and vertebral anomalies (EORVA), a rare recessive condition. To date, three homozygous variants in MYF5 have been reported to cause EORVA in six members of four unrelated families. Here, we present a novel homozygous MYF5 frameshift variant, c.596dupA p. (Asn199Lysfs*49), causing premature protein termination and presenting with external ophthalmoplegia, ptosis, and scoliosis in three siblings from a consanguineous family of Pakistani origin. With four MYF5 variants now discovered, genetic testing and paediatric assessment for extra-ocular features should be considered in all cases of congenital ophthalmoplegia.

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.

Expanding Clinical Spectrum of Anti-GQ1b Antibody Syndrome: A Review.

Importance: The discovery of the anti-GQ1b antibody has expanded the nosology of classic Miller Fisher syndrome to include Bickerstaff brainstem encephalitis, Guillain-Barré syndrome with ophthalmoplegia, and acute ophthalmoplegia without ataxia, which have been brought under the umbrella term anti-GQ1b antibody syndrome. It seems timely to define the phenotypes of anti-GQ1b antibody syndrome for the proper diagnosis of this syndrome with diverse clinical presentations. This review summarizes these syndromes and introduces recently identified subtypes. Observations: Although ophthalmoplegia is a hallmark of anti-GQ1b antibody syndrome, recent studies have identified this antibody in patients with acute vestibular syndrome, optic neuropathy with disc swelling, and acute sensory ataxic neuropathy of atypical presentation. Ophthalmoplegia associated with anti-GQ1b antibody positivity is complete in more than half of the patients but may be monocular or comitant. The prognosis is mostly favorable; however, approximately 14% of patients experience relapse. Conclusions and Relevance: Anti-GQ1b antibody syndrome may present diverse neurological manifestations, including ophthalmoplegia, ataxia, areflexia, central or peripheral vestibulopathy, and optic neuropathy. Understanding the wide clinical spectrum may aid in the differentiation and management of immune-mediated neuropathies with multiple presentations.

Lysosomal dysfunction and overload of nucleosides in thymidine phosphorylase deficiency of MNGIE.

Inherited deficiency of thymidine phosphorylase (TP), encoded by TYMP, leads to a rare disease with multiple mitochondrial DNA (mtDNA) abnormalities, mitochondrial neurogastrointestinal encephalomyopathy (MNGIE). However, the impact of TP deficiency on lysosomes remains unclear, which are important for mitochondrial quality control and nucleic acid metabolism. Muscle biopsy tissue and skin fibroblasts from MNGIE patients, patients with m.3243 A > G mitochondrial encephalopathy, lactic acidosis and stroke-like episodes (MELAS) and healthy controls (HC) were collected to perform mitochondrial and lysosomal functional analyses. In addition to mtDNA abnormalities, compared to controls distinctively reduced expression of LAMP1 and increased mitochondrial content were detected in the muscle tissue of MNGIE patients. Skin fibroblasts from MNGIE patients showed decreased expression of LAMP2, lowered lysosomal acidity, reduced enzyme activity and impaired protein degradation ability. TYMP knockout or TP inhibition in cells can also induce the similar lysosomal dysfunction. Using lysosome immunoprecipitation (Lyso- IP), increased mitochondrial proteins, decreased vesicular proteins and V-ATPase enzymes, and accumulation of various nucleosides were detected in lysosomes with TP deficiency. Treatment of cells with high concentrations of dThd and dUrd also triggers lysosomal dysfunction and disruption of mitochondrial homeostasis. Therefore, the results provided evidence that TP deficiency leads to nucleoside accumulation in lysosomes and lysosomal dysfunction, revealing the widespread disruption of organelles underlying MNGIE.

COQ7 defect causes prenatal onset of mitochondrial CoQ10 deficiency with cardiomyopathy and gastrointestinal obstruction.

COQ7 pathogenetic variants cause primary CoQ10 deficiency and a clinical phenotype of encephalopathy, peripheral neuropathy, or multisystemic disorder. Early diagnosis is essential for promptly starting CoQ10 supplementation. Here, we report novel compound heterozygous variants in the COQ7 gene responsible for a prenatal onset (20 weeks of gestation) of hypertrophic cardiomyopathy and intestinal dysmotility in a Bangladesh consanguineous family with two affected siblings. The main clinical findings were dysmorphisms, recurrent intestinal occlusions that required ileostomy, left ventricular non-compaction cardiomyopathy, ascending aorta dilation, arterial hypertension, renal dysfunction, diffuse skin desquamation, axial hypotonia, neurodevelopmental delay, and growth retardation. Exome sequencing revealed compound heterozygous rare variants in the COQ7 gene, c.613_617delGCCGGinsCAT (p.Ala205HisfsTer48) and c.403A>G (p.Met135Val). In silico analysis and functional in vitro studies confirmed the pathogenicity of the variants responsible for abolished activities of complexes I + III and II + III in muscle homogenate, severe decrease of CoQ10 levels, and reduced basal and maximal respiration in patients' fibroblasts. The first proband deceased at 14 months of age, whereas supplementation with a high dose of CoQ10 (30 mg/kg/day) since the first days of life modified the clinical course in the second child, showing a recovery of milestones acquirement at the last follow-up (18 months of age). Our study expands the clinical spectrum of primary CoQ10 deficiency due to COQ7 gene defects and highlights the essential role of multidisciplinary and combined approaches for a timely diagnosis.

Oculomasticatory rhythmic movements, insomnia and stroke-like episodes in a patient with POLG mutation.

The POLG mutation, a leading cause of mitochondrial diseases, exhibits a wide-ranging age of onset and a complex clinical presentation. We encountered an atypical clinical profile in an elderly man with a POLG mutation, characterised by a stroke-like episode, chronic insomnia and transient oculomasticatory rhythmic movement. History revealed chronic constipation since his 50s and progressive bilateral ophthalmoplegia since his early 60s. Subsequently, he had experienced acute encephalopathy and later developed chronic insomnia. The present neurological examination showed bilateral complete ophthalmoplegia, ptosis, and rhythmic ocular and jaw movements. Imaging indicated findings suggestive of a stroke-like episode and eventual genetic analysis revealed a homozygous missense mutation in the POLG gene. This case expands the clinical spectrum of POLG mutations in individuals over 60 years, showcasing the rare combination of a stroke-like episode, chronic insomnia and oculomasticatory rhythmic movement.

Juvenile ocular myasthenia gravis: a report of two cases.

We report 2 cases of pediatric ocular myasthenia gravis. The first case was a 7-year-old girl who presented with bilateral ophthalmoplegia and ptosis that correlated with the onset of upper respiratory symptoms. Neuroimaging and acetylcholine receptor antibody testing were unremarkable. The ice pack test was positive. Symptoms greatly improved with pyridostigmine, with full resolution of ophthalmoplegia achieved by 8-month follow-up. The second case was a 4-year-old girl who presented emergently with ptosis and bilateral ophthalmoplegia. Acetylcholine receptor antibodies testing was positive. The patient was started on pyridostigmine and intravenous immunoglobulin and is scheduled to follow-up with pediatric ophthalmology in the outpatient setting.

Uraemic brainstem encephalopathy mimicking ocular myasthenia: a case report.

BACKGROUND: Uraemia causes a generalised encephalopathy as its most common neurological complication. Isolated brainstem uraemic encephalopathy is rare. We report a case of fatigable ptosis and complex ophthalmoplegia in brainstem uraemic encephalopathy. CASE PRESENTATION: A 22-year-old Sri Lankan man with end stage renal failure presented with acute onset diplopia and drooping of eyelids progressively worsening over one week. The patient had not complied with the prescribed renal replacement therapy which was planned to be initiated 5 months previously. On examination, his Glasgow coma scale score was 15/15, He had a fatigable asymmetrical bilateral ptosis. The ice-pack test was negative. There was a complex ophthalmoplegia with bilateral abduction failure and elevation failure of the right eye. The diplopia did not worsen with prolonged stare. The rest of the neurological examination was normal. Serum creatinine on admission was 21.81 mg/dl. The repetitive nerve stimulation did not show a decremental pattern. Magnetic resonance imaging (MRI) of the brain demonstrated diffuse midbrain and pontine oedema with T2 weighted/FLAIR hyperintensities. The patient was haemodialyzed on alternate days and his neurological deficits completely resolved by the end of the second week of dialysis. The follow up brain MRI done two weeks later demonstrated marked improvement of the brainstem oedema with residual T2 weighted/FLAIR hyperintensities in the midbrain. CONCLUSIONS: Uraemia may rarely cause an isolated brainstem encephalopathy mimicking ocular myasthenia, which resolves with correction of the uraemia.

Surgery for longer duration supranuclear ophthalmoplegia secondary to brain stem cavernoma: A case report and literature review.

BACKGROUND: Previous reports revealed that patients with acquired paralytic strabismus caused by central nervous system diseases are primarily affected by the etiology and treatment of the condition. Strabismus correction for these acquired paralytic strabismus should be performed as soon as the primary disease has been stabilized for 6 months in order to archive a favorable surgical outcome. CASE: We followed an infrequent case of longer-lasting supranuclear ophthalmoplegia secondary to brain stem cavernoma. OBSERVATION: A 25-year-old Chinese Han female developed aberrant head posture and ipsilateral conjugate gaze palsies 8 years after the first brainstem hemorrhage caused by pontine cavernoma. The patient was diagnosed with supranuclear ophthalmic palsy and brain stem cavernoma after surgery. A resection-recession procedure along with a rectus muscle transposition was performed. The patient's abnormal head position disappeared, with a normal primary position. CONCLUSION: Resection-recession procedures combined with rectus muscle transposition works very well for longer duration large-angle strabismus caused by brain stem cavernoma.

[Clinical effect of superior oblique re-tucking for recurrent or residual compensatory head position].

Objective: To evaluate the effects of re-tucking the superior oblique muscle on recurrent or residual compensatory head position. Methods: A retrospective case series study was conducted. 12 recurrent or residual compensatory head position patients (12 eyes) with congenital superior oblique palsy who underwent superior oblique re-tucking in Tianjin Eye Hospital from March 2015 to February 2021 were included. All patients had a history of superior oblique tucking procedure and showed signs of superior oblique muscle palsy without inferior oblique muscle overaction. During surgery, the Guyton forced duction test is used to evaluate the relaxation of the superior oblique muscle tendon, which affects the re-tucking length of the muscle.Their head position, vertical deviation, eye movement, fovea-disa angle, and Bielschowsky head tilt test were assessed pre-and post-surgery. Statistical analysis was performed using ttest and paired samples Wilcoxon signed rank test. Results: Out of the 12 patients, 8 were male and 4 were female, aged between 2 and 9 years. The initial surgery was done at age 6, with a superior oblique recession length of (7.17±1.03) mm. Recurrent head tilt occurred in 11 patients after (3.82±0.98) months postoperatively, and 1 patient had residual head tilt, with a followup period of six months or more. Ocular motility examination revealed underaction of the superior oblique muscle, positive Bielschowsky's head tilt test, and Guyton forced duction tese indicating relaxation of the paralyzed superior oblique muscle tendon. Scar adhesion was observed at the stop of the superior oblique muscle, as well as the previous sutures. The scar and the sutures around the stop of the superior oblique muscle were released, the mean re-tucking amount was(7.83±1.59)mm. Follow-up at 12 to 18 months postoperatively showed disappearance of compensatory head position, significant improvement in superior oblique muscle lag, normal ocular motility, and no occurrence of Brown syndrome. The results of Bielschowsky head tilt were negative in 9 cases and still positive in 3 cases after superior oblique re-tucking. The primary vertical deviation was 2.5 (2.0, 5.3) prism diopter pre-operatively and 1 (0, 1) prism diopter post-operatively, respectively. The difference was statistically significant (U=6.00, P<0.001). The total amount of FDA in both eyes was (-22.04±5.47)° and (-15.27±6.08)° pre-and post-operatively, respectively. The difference was statistically significant (t=2.87, P=0.009). All 12 patients have normal eye movement after superior oblique re-tucking procedure. All patients had no compensatory head position at last follow-up. Conclusions: Superior oblique re-tucking is suitable for patients with relaxation of the superior oblique muscle tendon and extrocular rotation as the main sign. It can effectively and safely correct the recurrent or residual compensatory head position after re-tucking the superior oblique muscle.

Bilateral Low-Flow Type-D Dural Carotid-Cavernous Fistula: Diagnosis and Treatment with 3D Time-of-Flight Magnetic Resonance Angiography.

BACKGROUND Carotid-cavernous fistula (CCF) is a rare, atypical vascular shunt between the carotid arterial system and the venous channels of the cavernous sinus, classified according to the shunt's anatomy, by etiology (resulting from trauma or occurring spontaneously), or by hemodynamic characteristics (such as low- or high-flow fistulas). CASE REPORT A 62-year-old female patient with poorly controlled arterial hypertension presented with bilateral periorbital edema, conjunctival chemosis, ophthalmoplegia, diplopia, and diminished visual acuity. On magnetic resonance angiography (MRA), abnormal arterial flow along the cavernous sinuses was noted, suggestive of bilateral CCF. The diagnosis of indirect dural low-flow CCF (Barrow Type D) was later confirmed by digital subtraction angiography, with feeding arteries from intracavernous internal carotid artery branches, and meningeal branches of the external carotid artery, draining bilaterally to ophthalmic veins, the intracavernous sinus, and the inferior petrosal sinus. The patient was successfully treated with endovascular embolization. At 7-month follow-up, no residual arteriovenous shunting was detected. This case highlights the importance of non-invasive radiological methods for CCF, and presents rarely published radiological findings of bilateral Type-D dural CCFs on 3-dimensional time-of-flight MRA with post-treatment MRA follow-up. CONCLUSIONS Regardless of the patient's history of possible trauma, a patient presenting with bilateral periorbital edema, conjunctival chemosis, ophthalmoplegia, diplopia, and diminished visual acuity should have a spontaneous bilateral CCF investigated to prevent delayed treatment. Experienced neuroradiologists are needed to accurately detect indirect CCF, since this condition often does not demonstrate classic symptoms.