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Anti-GQ1b antibody syndrome encompasses immune-mediated neuropathies targeting ganglioside GQ1b, classically presenting as Miller Fisher syndrome (MFS) with the triad of ophthalmoplegia, ataxia, and areflexia. While bilateral ophthalmoplegia is typical, unilateral presentations represent a recognized variant phenotype. We report a case of a 17-year-old male with unilateral complete oculomotor nerve palsy, confirmed by positive serum anti-GQ1b IgG antibodies. We also conducted a literature review identifying 17 additional cases of anti-GQ1b associated unilateral ophthalmoplegia, summarizing clinical features, investigations, management, and outcomes for all 18 patients. Among the 18 patients, a male predominance was observed (13 males, 5 females), with a median age of 31 years (range 10-68). Most patients (17/18, 94.4%) reported a preceding illness. Unilateral external ophthalmoplegia was universal, most commonly affecting adduction (55.6%) and vertical gaze (55.6%). Internal ophthalmoplegia (IO) occurred in 6 cases (33.3%), including 4 unilaterally. Cerebrospinal fluid (CSF) protein was mildly elevated (23-97 mg/dL) in 7 of 18 cases. Treatments varied and prognosis was uniformly favorable, with most patients recovering within 3 months. Unilateral ophthalmoplegia, particularly when complicated by ipsilateral internal ophthalmoplegia, constitutes a distinct regional variant of anti-GQ1b antibody syndrome. Early serological testing for anti-GQ1b antibodies is key to diagnosis, especially in patients with antecedent infection.

Summary Aim To examine whether the velocity of saccadic eye movements in internuclear ophthalmoparesis (INO) improves with fampridine treatment in patients with multiple sclerosis (MS). Methods Randomized, double‐blind, placebo‐controlled, cross‐over trial with fampridine in patients with MS and INO. Horizontal saccades were recorded at baseline and at multiple time points post‐dose. Main outcome measures were the change of peak velocity versional dysconjugacy index (PV‐VDI) and first‐pass amplitude VDI (FPA‐VDI). Both parameters were compared between fampridine and placebo using a mixed model analysis of variance taking patients as their own control. Pharmacokinetics was determined by serial blood sampling. Results Thirteen patients had a bilateral and 10 had a unilateral INO. One patient had an INO of abduction (posterior INO of Lutz) and was excluded. Fampridine significantly reduced both PV‐VDI (−17.4%, 95% CI: −22.4%, −12.1%; P < 0.0001) and FPA‐VDI (−12.5%, 95% CI: −18.9%, −5.5%; P < 0.01). Pharmacokinetics demonstrated that testing coincided with the average tmax at 2.08 hours (SD 45 minutes). The main adverse event reported after administration of fampridine was dizziness (61%). Conclusion Fampridine improves saccadic eye movements due to INO in MS. Treatment response to fampridine may gauge patient selection for inclusion to remyelination strategies in MS using saccadic eye movements as primary outcome measure.

Stiff-person syndrome (SPS) is a rare neuroimmune disorder that is associated with a variety of symptoms and varying degrees of disability. SPS has multiple phenotypes and different immunological bases, and the lack of clinical awareness of these various clinical phenotypes often leads to misdiagnosis and inappropriate treatment of SPS patients in the early stage of the disease course. We report a distinctive case of SPS with a 4-year follow-up. The patient was a 56-year-old middle-aged woman who initially presented with diplopia and atypical muscle tension. Treatment with baclofen and lorazepam showed poor efficacy, and she was once misdiagnosed with anxiety and depression as well as oculomotor nerve palsy. During the 4-year follow-up period, the patient gradually developed typical clinical manifestations and signs of SPS and was diagnosed with positive GAD antibodies. In the later stage, the patient's symptoms were exacerbated by the serotonin receptor partial agonist tandospirone; further testing revealed a significant increase in GAD antibody titer. As the patient could not tolerate hormone pulse therapy, she was administered rituximab and two sessions of intravenous immunoglobulin (IVIG). After adjustment of the relevant treatment regimen, the patient's symptoms were significantly alleviated. SPS is relatively uncommon and prone to misdiagnosis. Therefore, we need to understand the various clinical manifestations of SPS, achieve early intervention, and thereby improve the prognosis and quality of life of patients.

Advances in next-generation sequencing have significantly improved the molecular diagnosis of mitochondrial diseases (MDs), a group of heterogeneous neurogenetic disorders. However, progress in understanding their pathogenic mechanisms and translating this knowledge into effective therapies remains limited. Elucidating the molecular determinants of phenotypic variability in primary MDs is essential to uncover disease mechanisms and identify novel therapeutic targets. We investigated a cohort of eight adult patients with genetically confirmed Progressive External Ophthalmoplegia (PEO)—an extremely rare mitochondrial disorder—and compared them with eight age- and sex-matched healthy controls. A comprehensive multi-omics approach combining LC–MS/MS-based proteomics, UPLC–MS/MS-based metabolomics, ATR–FTIR spectroscopy, and chemometric multivariate analysis was employed to identify molecular alterations associated with mitochondrial dysfunction. Distinct proteomic and metabolic patterns related to energy metabolism were observed in PEO patients, correlating with their genetic background. Metabolomic analysis showed altered amino acid levels (seven statistically relevant) and disruptions in the metabolism of cysteine, methionine, and glutathione; proteomics finding (154 differentially expressed proteins) revealed dysregulation in extracellular matrix (ECM) organization and immune response pathways. This integrative analytical strategy offers new insights into the molecular complexity of PEO and mitochondrial disorders. The identification of disease-associated molecular signatures may enhance the understanding of pathogenic mechanisms and support the development of improved diagnostic and therapeutic approaches for MDs.

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 myopathy, typically manifesting as progressive external ophthalmoplegia (PEO), is among the most common mitochondrial phenotypes. The purpose of this study is to better define the clinical phenotypes associated with ocular myopathy. This is a retrospective study on a large cohort from the database of the “Nation-wide Italian Collaborative Network of Mitochondrial Diseases”. We distinguished patients with ocular myopathy as part of a multisystem mitochondrial encephalomyopathy (PEO-encephalomyopathy), and then PEO with isolated ocular myopathy from PEO-plus when PEO was associated with additional features of multisystemic involvement. Ocular myopathy was the most common feature in our cohort of mitochondrial patients. Among the 722 patients with a definite genetic diagnosis, ocular myopathy was observed in 399 subjects (55.3%) and was positively associated with mtDNA single deletions and POLG mutations. Ocular myopathy as manifestation of a multisystem mitochondrial encephalomyopathy (PEO-encephalomyopathy, n  = 131) was linked to the m.3243A>G mutation, whereas the other “PEO” patients ( n  = 268) were associated with mtDNA single deletion and Twinkle mutations. Increased lactate was associated with central neurological involvement. We then defined, among the PEO group, as “pure PEO” the patients with isolated ocular myopathy and “PEO-plus” those with ocular myopathy and other features of neuromuscular and multisystem involvement, excluding central nervous system. The male proportion was significantly lower in pure PEO than PEO-plus. This study reinforces the need for research on the role of gender in mitochondrial diseases. The phenotype definitions here revisited may contribute to a more homogeneous patient categorization, useful in future studies and clinical trials.

Background Progressive external ophthalmoplegia (PEO) is a common subtype of mitochondrial encephalomyopathy. Objective The study aimed to investigate the relationship between mitochondrial DNA (mtDNA) abnormalities, muscle pathology, and clinical manifestations in Chinese patients with single large‐scale mtDNA deletion presenting with PEO. Methods This is a retrospective single‐center study. Patients with PEO who had a single large deletion in mitochondrial DNA were included in this study. The associations were analyzed between mtDNA deletion patterns, myopathological changes, and clinical characteristics. Results In total, 155 patients with mitochondrial PEO carrying single large‐scale mtDNA mutations were enrolled, including 137 chronic progressive external ophthalmoplegia (CPEO) and 18 Kearns–Sayre syndrome (KSS) patients. The onset ages were 9.61 ± 4.12 in KSS and 20.15 ± 9.06 in CPEO. The mtDNA deletions ranged from 2225 bp to 9131 bp, with m.8470_13446del being the most common. The KSS group showed longer deletions than the CPEO group (p = 0.004). Additionally, a higher number of deleted genes encoding respiratory chain complex subunits (p = 0.001) and tRNA genes (p = 0.009) were also observed in the KSS group. A weak negative correlation between the mtDNA deletion size and ages of onset (p < 0.001, r = −0.369) was observed. The proportion of ragged red fibers, ragged blue fibers, and cytochrome c negative fibers did not correlate significantly with onset ages (p > 0.05). However, a higher percentage of abnormal muscle fibers corresponds to an increased prevalence of exercise intolerance, limb muscle weakness, dysphagia, and cerebellar ataxia. Conclusion We reported a large Chinese cohort consisting of mitochondrial PEO patients with single large‐scale mtDNA deletions. Our results demonstrated that the length and locations of mtDNA deletions may influence onset ages and clinical phenotypes. The severity of muscle pathology could not only indicate diagnosis but also may be associated with clinical manifestations beyond the extraocular muscles. Figure A illustrates the ROC curve depicting the relationship between the age of onset and the disease diagnosis. The AUC for distinguishing CPEO and KSS by ages of onset was 0.874, having a maximum Youden index of 0.594, resulting in an optimum cut‐off point of 15.5 years. Figure B displays a moderate negative correlation between the mtDNA deletion size and onset ages (correlation coefficient r = −0.369).

Depression is a common debilitating human disease whose etiology has defied decades of research. A critical bottleneck is the difficulty in modeling depressive episodes in animals. Here, we show that a transgenic mouse with chronic forebrain expression of a dominant negative mutant of Polg1 , a mitochondrial DNA (mtDNA) polymerase, exhibits lethargic behavioral changes, which are associated with emotional, vegetative and psychomotor disturbances, and response to antidepression drug treatment. The results suggested a symptomatic similarity between the lethargic behavioral change that was recurrently and spontaneously experienced by the mutant mice and major depressive episode as defined by DSM-5. A comprehensive screen of mutant brain revealed a hotspot for mtDNA deletions and mitochondrial dysfunction in the paraventricular thalamic nucleus (PVT) with similar defects observed in postmortem brains of patients with mitochondrial disease with mood symptoms. Remarkably, the genetic inhibition of PVT synaptic output by Cre-loxP-dependent expression of tetanus toxin triggered de novo depression-like episodes. These findings identify a novel preclinical mouse model and brain area for major depressive episodes with mitochondrial dysfunction as its cellular mechanism.

PurposeCongenital fibrosis of extraocular muscles type 1 (CFEOM1), a classical subtype of CFEOM, is characterized by restrictive ophthalmoplegia and ptosis. It is mainly caused by aberrant neural innervation of the extraocular muscles. This study aimed to investigate the genetic characteristics and clinical manifestations of CFEOM1 in Chinese families.MethodsThe clinical data, including ocular examinations, magnetic resonance imaging (MRI), and surgical procedures of affected individuals from 16 Chinese CFEOM1 families, were collected. The genomic DNA of 16 probands and their family members were sequenced for causative KIF21A gene mutations. Linkage analysis using microsatellite markers across KIF21A was also conducted.ResultsAffected individuals were presented with bilateral non-progressive ptosis, restricted horizontal eye movement, fixed infraduction of both eyes, compensatory chin-up head position, and neuromuscular abnormalities. Three heterozygous KIF21A mutations, c.2860C > T (p.R954W) (in eight families), c.2861G > T (p.R954L) (in two families), and c.2861G > A (p.R954Q) (in two families) were identified, which implied that hotspot mutations were common in Chinese CFEOM1 families. Germline Mosaicism was likely to be the cause of affected individuals with asymptomatic parents without KIF21A mutations presented in the eight families. Two affected individuals underwent modified levator muscle complex suspension surgery and achieved a good result without any complications.ConclusionInstead of evaluating the whole CFEOM1 gene variant, hotspot mutations could be given priority for screening. The occurrence of germline mosaicism has to be taken into account in genetic counseling. Patients with CFEOM1 who have ptosis may benefit from an innovative surgical procedure called modified levator muscle complex suspension.

Purpose Chronic progressive external ophthalmoplegia (CPEO) is a mitochondrial disease characterized by slowly progressive ptosis and limitations in ocular motility. Although exophthalmos is not considered to be a common feature of CPEO, this study focused on the incidence of exophthalmos in patients with CPEO. Study design Retrospective observational case series Methods We reviewed the clinical charts of patients who received a diagnosis of CPEO sometime during the period between January 2010 and December 2018. CPEO was diagnosed on the basis of detection of a deletion of mitochondrial DNA (mtDNA) from saliva, buccal mucosa, or extraocular muscle specimens obtained during strabismus surgery. Horizontal MRI/CT images or Hertel ophthalmometry was used in determining exophthalmos. Results Seven patients (4 males) were identified. The mean age at diagnosis was 32.6 years (range 13–53 years). mtDNA deletion mutations were detected in the buccal mucous membrane DNA in 5 patients and in the saliva and extraocular muscle DNA in 2 patients. MRI/CT was recorded in 6 patients, four of whom showed exophthalmos (cases 1–4), and case 5 was determined as exophthalmos on the basis of a Hertel ophthalmometer reading. Exophthalmos was bilateral in 4 of the patients (cases 1, 2, 4, and 5) and unilateral in 1 patient (case 3). Exophthalmos was the chief concern of 2 of the patients; however, it was not clinically significant in the other patients. Conclusions Although exophthalmos may not be recognized by either the patient or the clinician, it may be one of the common features of CPEO. A large multiethnic study should be performed.