Serial Nerve Conduction Studies in Guillain-Barré Syndrome: Its Usefulness and Precise Timing.

PURPOSE: Nerve conduction study (NCS) is essential for subclassifying Guillain-Barré syndrome (GBS). It is well known that the GBS subclassification can change through serial NCSs. However, the usefulness of serial NCSs is debatable, especially in patients with early stage GBS. METHODS: Follow-up NCS data within 3 weeks (early followed NCS, EFN) and within 3 to 10 weeks (late-followed NCS, LFN) were collected from 60 patients with GBS who underwent their first NCS (FN) within 10 days after symptom onset. Each NCS was classified into five subtypes (normal, demyelinating, axonal, inexcitable, and equivocal), according to Hadden's and Rajabally's criteria. We analyzed the frequency of significant changes in classification (SCCs) comprising electrodiagnostic aggravation and subtype shifts between demyelinating and axonal types according to follow-up timing. RESULTS: Between FN and EFN, 33.3% of patients with Hadden's criteria and 18.3% with Rajabally's criteria showed SCCs. Between FN and LFN, 23.3% of patients with Hadden's criteria and 21.7% with Rajabally's criteria showed SCCs, of which 71.4% (Hadden's criteria) and 46.2% (Rajabally's criteria) already showed SCCs from the EFN. The conditions of delayed SCCs between EFN and LFN were very early FN, mild symptoms at the FN, or persistent electrophysiological deterioration 3 weeks after symptom onset. CONCLUSIONS: A substantial proportion of patients with GBS showed significant changes in neurophysiological classification at the early stage. Serial NCS may be helpful for precise neurophysiological classification. This study suggests that follow-up NCSs should be performed within 3 weeks of symptom onset in patients with GBS in whom FN was performed within 10 days of symptom onset.

Prognostic factors of first-onset optic neuritis based on diagnostic criteria and antibody status: a multicentre analysis of 427 eyes.

BACKGROUND: Optic neuritis (ON) prognosis is influenced by various factors including attack severity, underlying aetiologies, treatments and consequences of previous episodes. This study, conducted on a large cohort of first ON episodes, aimed to identify unique prognostic factors for each ON subtype, while excluding any potential influence from pre-existing sequelae. METHODS: Patients experiencing their first ON episodes, with complete aquaporin-4 (AQP4) and myelin oligodendrocyte glycoprotein (MOG) antibody testing, and clinical data for applying multiple sclerosis (MS) diagnostic criteria, were enrolled. 427 eyes from 355 patients from 10 hospitals were categorised into four subgroups: neuromyelitis optica with AQP4 IgG (NMOSD-ON), MOG antibody-associated disease (MOGAD-ON), ON in MS (MS-ON) or idiopathic ON (ION). Prognostic factors linked to complete recovery (regaining 20/20 visual acuity (VA)) or moderate recovery (regaining 20/40 VA) were assessed through multivariable Cox regression analysis. RESULTS: VA at nadir emerged as a robust prognostic factor for both complete and moderate recovery, spanning all ON subtypes. Early intravenous methylprednisolone (IVMP) was associated with enhanced complete recovery in NMOSD-ON and MOGAD-ON, but not in MS-ON or ION. Interestingly, in NMOSD-ON, even a slight IVMP delay in IVMP by >3 days had a significant negative impact, whereas a moderate delay up to 7-9 days was permissible in MOGAD-ON. Female sex predicted poor recovery in MOGAD-ON, while older age hindered moderate recovery in NMOSD-ON and ION. CONCLUSION: This comprehensive multicentre analysis on first-onset ON unveils subtype-specific prognostic factors. These insights will assist tailored treatment strategies and patient counselling for ON.

Clinical value of vestibulo-ocular reflex in the differentiation of spinocerebellar ataxias.

The diagnosis of spinocerebellar ataxia (SCA) currently depends upon genetic testing. Although genetic testing for SCA is highly specific, clinical parameters for the differentiation of SCAs are still insufficient. We aimed to assess the vestibulo-ocular reflex (VOR) parameters of various SCA subtypes to determine whether they have substantial value in differential diagnosis. We consecutively enrolled 33 genetically confirmed SCA patients (SCA2 = 8, SCA3 = 6, SCA6 = 10, SCA7 = 9). Normative data were obtained from 36 age- and gender-matched healthy controls. Quantitative indicators of VOR were measured using video head impulse test (HIT) and combined ocular motor dysfunctions were investigated using video-oculography. Compared with the control group, the VOR gains in SCA2 were relatively spared, but were markedly decreased for all six canals in SCA3. The VOR gains for the posterior canals (PCs) were significantly decreased in SCA6, and for both vertical canals were decreased in SCA7. The VOR gains for the horizontal canals in SCA3 were negatively correlated with disease severity (R = -0.900, p = 0.037). Abnormal catch-up saccades were common in SCA3 and SCA6, rare in SCA7 and absent in SCA2. Spontaneous, headshaking-induced, and positional nystagmus were only documented in SCA6. SCA3 and SCA6 commonly showed horizontal gaze-evoked nystagmus, but SCA2 and SCA7 had characteristic saccadic slowing without gaze-evoked nystagmus. VOR impairments are common in SCAs, but their patterns vary depending on subtype. In addition to ocular motor characteristics, distinctive VOR performance for each subtype using video HIT may aid the differential diagnosis of the SCA genotypes.

Older adult-onset Alexander disease with atypical clinicoradiological features: a case report.

Alexander disease (AxD) is a rare autosomal dominant astrogliopathy caused by mutations in the gene encoding for glial fibrillary acidic protein. AxD is divided into two clinical subtypes: type I and type II AxD. Type II AxD usually manifests bulbospinal symptoms and occurs in the second decade of life or later, and its radiologic features include tadpole-like appearance of the brainstem, ventricular garlands, and pial signal changes along the brainstem. Recently, eye-spot signs in the anterior medulla oblongata (MO) have been reported in patients with elderly-onset AxD. In this case, an 82-year-old woman presented with mild gait disturbance and urinary incontinence without bulbar symptoms. The patient died 3 years after symptom onset as a result of rapid neurological deterioration after a minor head injury. MRI showed signal abnormalities resembling angel wings in the middle portion of the MO along with hydromyelia of the cervicomedullary junction. Herein, we report the case of this patient with older adult-onset AxD with an atypical clinical course and distinctive MRI findings.

Clinical analysis in patients with SPG11 hereditary spastic paraplegia.

Background: To analyze the clinical phenotype of hereditary spastic paraplegia (HSP) caused by SPG11 mutations (SPG11-HSP). Methods: Among the 17 patients with sporadic HSP who performed whole exome sequencing analysis, six were diagnosed with SPG11-HSP. The clinical and radiologic findings and the results of the electrodiagnostic and neuropsychologic tests were reviewed retrospectively. Results: The median age at onset was 16.5 years (range, 13-38 years). Progressive spastic paraparesis was a core feature, and the median spastic paraplegia rating scale score was 24/52 (range, 16-31 points). Additional major symptoms were pseudobulbar dysarthria, intellectual disability, bladder dysfunction, and being overweight. Minor symptoms included upper limbs rigidity and sensory axonopathy. The median body mass index was 26.2 kg/m2 (range, 25.2-32.3 kg/m2). The thin corpus callosum (TCC) was predominant at the rostral body or anterior midbody, and the ears of the lynx sign was seen in all. The follow-up MRI showed the worsening of periventricular white matter (PVWM) signal abnormalities with ventricular widening or the extension of the TCC. Motor evoked potentials (MEP) to the lower limbs showed an absent central motor conduction time (CMCT) in all subjects. The upper limb CMCT was initially absent in three subjects, although it became abnormal in all at the follow-up. The mini-mental state examination median score was 27/30 (range, 26-28) with selective impairment of the attention/calculation domain. The median score of the full-scale intelligence quotient was 48 (range, 42-72) on the Wechsler Adult Intelligence Scale test. Conclusion: Attention/calculation deficits and being overweight as well as pseudobulbar dysarthria were common additional symptoms in patients with SPG11-HSP. The rostral body and anterior midbody of the corpus callosum were preferentially thinned, especially in the early stage of the disease. The TCC, PVWM signal changes, and MEP abnormality worsened as the disease progressed.

Early rituximab treatment reduces long-term disability in aquaporin-4 antibody-positive neuromyelitis optica spectrum.

BACKGROUND: Neuromyelitis optica spectrum disorder (NMOSD) causes relapsing inflammatory attacks in the central nervous system, leading to disability. As rituximab, a B-lymphocyte-depleting monoclonal antibody, is an effective in preventing NMOSD relapses, we hypothesised that earlier initiation of rituximab can also reduce long-term disability of patients with NMOSD. METHODS: This multicentre retrospective study involving 19 South Korean referral centres included patients with NMOSD with aquaporin-4 antibodies receiving rituximab treatment. Factors associated with the long-term Expanded Disability Status Scale (EDSS) were assessed using multivariable regression analysis. RESULTS: In total, 145 patients with rituximab treatment (mean age of onset, 39.5 years; 88.3% female; 98.6% on immunosuppressants/oral steroids before rituximab treatment; mean disease duration of 121 months) were included. Multivariable analysis revealed that the EDSS at the last follow-up was associated with time to rituximab initiation (interval from first symptom onset to initiation of rituximab treatment). EDSS at the last follow-up was also associated with maximum EDSS before rituximab treatment. In subgroup analysis, the time to initiation of rituximab was associated with EDSS at last follow-up in patients aged less than 50 years, female and those with a maximum EDSS score ≥6 before rituximab treatment. CONCLUSIONS: Earlier initiation of rituximab treatment may prevent long-term disability worsening in patients with NMOSD, especially among those with early to middle-age onset, female sex and severe attacks.

Characteristics of spinal and bulbar muscular atrophy in South Korea: a cross-sectional study of 157 patients.

Spinal and bulbar muscular atrophy, namely Kennedy disease, is a rare progressive neurodegenerative disorder caused by the expansion of a CAG repeat in the first exon of the androgen receptor gene on the X chromosome. We assessed the clinical history, laboratory findings, functional scales and electrophysiological data, as well as the levels of luteinizing hormone, follicle-stimulating hormone and testosterone, in 157 Korean patients with genetically confirmed spinal and bulbar muscular atrophy (mean age at data collection = 56.9 years; range = 33-83 years). Hand tremor was the first symptom noticed by patients at a median age of 35 years, followed by gynaecomastia, orofacial fasciculation, cramps and fatigability in ascending order. Clinical symptoms such as paraesthesia and dysphagia appeared during the later stages of the disease. Cane use during ambulation began at a median age of 62 years. There were statistically significant differences between patients and controls in the results of sensory nerve studies, motor conduction velocity, and distal latencies. Furthermore, among the hormone markers analysed, the level of luteinizing hormone exhibited a negative correlation with the spinal and bulbar muscular atrophy functional rating scale, Korean version. However, among the patients with a disease duration of ≤5 years, the levels of luteinizing hormone showed a significant correlation with assessments using the amyotrophic lateral sclerosis functional rating scale-revised, spinal and bulbar muscular atrophy functional rating scale, Korean version and the 6-minute walk test. In conclusion, our findings provide clinical information from a substantial number of patients with spinal and bulbar muscular atrophy in Korea that accorded with that of patients with this disease worldwide but with updated clinical features.

Clinical pitfalls and serological diagnostics of MuSK myasthenia gravis.

BACKGROUND: We aimed to evaluate the diagnostic accuracy of enzyme-linked immunosorbent assay (ELISA) for anti-muscle specific tyrosine kinase (MuSK) antibody (Ab) in a large cohort of anti-acetylcholine receptor (AChR) Ab-negative generalized myasthenia gravis (MG), and also to investigate clinical contexts for the diagnosis of MuSK MG. METHODS: A retrospective study of 160 patients with a clinical suspicion of AChR Ab-negative generalized MG was performed. The serum samples were tested for anti-clustered AChR Ab by cell-based assay (CBA), anti-MuSK Ab by ELISA, CBA and/or radioimmunoprecipitation assay (RIPA). Clinical data were compared between anti-MuSK Ab-positive MG and double seronegative (AChR and MuSK) MG groups. RESULTS: After excluding non-MG and clustered AChR Ab-positive patients, we identified 89 patients as a cohort of AChR Ab-negative generalized MG. Anti-MuSK Ab was positive by ELISA in 22 (24.7%) patients. While CBA identified five additional anti-MuSK Ab-positive patients, the results of ELISA were mostly consistent with CBA and RIPA with Cohen's kappa of 0.80 and 0.90, respectively (p < 0.001). The most frequent differential diagnosis was motor neuron disease particularly of bulbar onset which showed remarkably overlapping clinical and electrophysiological features with MuSK MG at presentation. CONCLUSION: While confirming the highest sensitivity of CBA for detecting anti-MuSK Ab, our results highlight the clinical pitfalls in making a diagnosis of MuSK MG and may support a diagnostic utility of MuSK-ELISA in clinical practice.

Safety and Temporal Pattern of the Lymphocyte Count During Fingolimod Therapy in Patients With Multiple Sclerosis: Real-World Korean Experience.

BACKGROUND AND PURPOSE: Fingolimod (FTY) inhibits lymphocyte egress from lymphoid organs to cause lymphopenia, but the clinical implications of FTY-induced lymphopenia are not fully understood. We aimed to determine the frequency and severity of lymphopenia during FTY treatment among Korean patients with multiple sclerosis (MS), and its association with infections. METHODS: We retrospectively reviewed the medical records of patients with MS treated using FTY from 12 referral centers in South Korea between March 2013 and June 2021. Patients were classified according to their nadir absolute lymphocyte count (ALC) during treatment: grade 1, 800-999/µL; grade 2, 500-799/µL; grade 3, 200-499/µL; and grade 4, <200/µL. RESULTS: FTY treatment was administered to 69 patients with a median duration of 18 months (range=1-169 months), with 11 patients being treated for ≥7 years. During FTY treatment, mean ALCs were reduced after the first month (653.0±268.9/µL, mean±standard deviation) (p<0.0001) and remained low during treatment lasting up to 84 months. During follow-up, 41 (59.4%) and 7 (10.1%) patients developed grade-3 and grade-4 lymphopenia, respectively. No significant difference was found in age at FTY initiation, sex, baseline ALC, body mass index, or prior disease-modifying treatment between patients with and without grade-4 lymphopenia. Infections were observed in 11 (15.9%) patients, and the frequencies of patients with and without grade-4 lymphopenia were similar. CONCLUSIONS: FTY treatment induced grade-4 lymphopenia in 10% of South Korean patients with MS, but did not appear to be associated with an increased infection risk.

Sensory neuronopathy in a patient with neurofibromatosis type 1: A case report.

RATIONALE: Neurofibromatosis type 1 (NF-1) can manifest with various neurological symptoms. However, sensory ataxia has not been reported. PATIENT CONCERNS: A 44-year-old man with NF-1 presented with several weeks of unsteady gait. He was diagnosed with gastric neuroendocrine tumor with multiple hepatic metastases 6 years ago and received palliative chemotherapy. Neurological examination revealed ataxia veering to the right side with no motor weakness. DIAGNOSES: Clinical manifestations and electrodiagnostic studies suggested the dysfunction of the thoracic dorsal column (DC). Initial magnetic resonance imaging showed a lateral thoracic meningocele (LTM) located in the right paravertebral area at the T3-T4 vertebral level, but the spinal cord was unremarkable. Gait disturbance worsened after 9 months, and follow-up magnetic resonance imaging showed high signal intensity involving the right DC at the level adjacent to the LTM and spinal cord atrophy distal to the DC lesion. Tests for well-characterized paraneoplastic antibodies were negative. Ultimately, the patient was assumed to have sensory neuronopathy due to compressive damage to the dorsal root ganglia within the intervertebral foramina by LTM. INTERVENTIONS: Empirical treatment with vitamin B12 supplementation and corticosteroids failed to improve his condition. The patient underwent decompressive laminectomy and excision of the meningocele with dura repair. OUTCOMES: The patient temporarily improved to walk with assistance postoperatively. However, he developed dyspnea and hypotension 5 weeks later. Carcinoid heart disease confined the patient to the bed. The patient died of pneumonia 3 months after the operation. LESSONS: This case with NF-1 shows asymmetric sensory ataxia of subacute progression. LTM may contribute to the development of sensory neuronopathy by damaging sensory neurons of the dorsal root ganglia. The comorbidities of the patient, including gastric neuroendocrine tumor and LTM, made it challenging to investigate the pathomechanism.

A novel in-frame GFAP p.E138_L148del mutation in Type II Alexander disease with atypical phenotypes.

Alexander disease (AxD) is a neurodegenerative astrogliopathy caused by mutation in the glial fibrillary acidic protein (GFAP) gene. A 42-year-old Korean man presented with temporary gait disturbance and psychiatric regression after a minor head trauma in the absence of bulbar symptoms and signs. Magnetic resonance images of the brain and spinal cord showed significant atrophy of the medulla oblongata and the entire spinal cord as well as contrast-enhanced T2 hypointensity in the basal ganglia. DNA sequencing revealed a novel 33-bp in-frame deletion mutation (p.Glu138_Leu148del) within the 1B rod domain of GFAP, which was predicted to be deleterious by PROVEAN analysis. To test whether the deletion mutant is disease-causing, we performed in vitro GFAP assembly and sedimentation assays, and GFAP aggregation assays in human adrenal carcinoma SW13 (Vim-) cells and rat primary astrocytes. All the assays revealed that GFAP p.Glu138_Leu148del is aggregation prone. Based on these findings, we diagnosed the patient with Type II AxD. This is a report that demonstrates the pathogenicity of InDel mutation of GFAP through functional studies. This patient's atypical presentation as well as the discrepancy between clinical symptoms and radiologic findings may extend the scope of AxD.

Characteristics of patients with meningitis after lumbar epidural steroid injection.

To investigate the clinical, laboratory, and radiological features of meningitis after lumbar epidural steroid injection (M-ESI) without accompanying spinal infection, data of patients with meningitis admitted between January 2014 and December 2021 in a single center were retrospectively reviewed. Among them, patients with a recent history of lumbar ESI were identified, and their medical records were collected. Patients with concomitant infections other than meningitis, including spinal epidural abscess, were excluded. Seven patients with M-ESI were identified. All patients presented with headache and fever without focal neurological deficits, and headache developed shortly after a procedure (median, 4 hours). Cerebrospinal fluid (CSF) analysis showed neutrophilic pleocytosis (median, 6729/µL), elevated protein level (median, 379.1 mg/dL), decreased ratio of CSF glucose to serum glucose (median, 0.29), and elevated lactate level (median, 8.64 mmol/L). Serum level of C-reactive protein was elevated in 6, but serum procalcitonin level was within normal range. No causative pathogen was identified in the microbiological studies. The most frequent radiologic feature was sulcal hyperintensity on fluid-attenuated inversion recovery images (57%), followed by pneumocephalus (43%). Symptoms subsided in a short period (median, 1 day) after initiating treatment with antibiotics and adjuvant intravenous corticosteroids. None of the patients experienced neurological sequelae. Though the cardinal symptoms and CSF findings of M-ESI were comparable to those of bacterial meningitis, M-ESI seems to have distinctive characteristics regarding the clinical course, laboratory parameters, and pneumocephalus.

Myelin Oligodendrocyte Glycoprotein-Immunoglobulin G in the CSF: Clinical Implication of Testing and Association With Disability.

BACKGROUND AND OBJECTIVE: To investigate the clinical relevance of CSF myelin oligodendrocyte glycoprotein-immunoglobulin G (MOG-IgG) testing in a large multicenter cohort. METHODS: In this multicenter cohort study, paired serum-CSF samples from 474 patients with suspected inflammatory demyelinating disease (IDD) from 11 referral hospitals were included. After serum screening, patients were grouped into seropositive myelin oligodendrocyte glycoprotein antibody associated disease (MOGAD, 31), aquaporin-4-IgG-positive neuromyelitis optica spectrum disorder (AQP4-IgG + NMOSD, 60), other IDDs (217), multiple sclerosis (MS, 45), and non-IDDs (121). We then screened CSF for MOG-IgG and compared the clinical and serologic characteristics of patients uniquely positive for MOG-IgG in the CSF to seropositive patients with MOGAD. RESULTS: Nineteen patients with seropositive MOGAD (61.3%), 9 with other IDDs (CSF MOG + IDD, 4.1%), 4 with MS (8.9%), but none with AQP4-IgG + NMOSD nor with non-IDDs tested positive in the CSF for MOG-IgG. The clinical, pathologic, and prognostic features of patients uniquely positive for CSF MOG-IgG, with a non-MS phenotype, were comparable with those of seropositive MOGAD. Intrathecal MOG-IgG synthesis, observed from the onset of disease, was shown in 12 patients: 4 of 28 who were seropositive and 8 who were uniquely CSF positive, all of whom had involvement of either brain or spinal cord. Both CSF MOG-IgG titer and corrected CSF/serum MOG-IgG index, but not serum MOG-IgG titer, were associated with disability, CSF pleocytosis, and level of CSF proteins. DISCUSSION: CSF MOG-IgG is found in IDD other than MS and also in MS. In IDD other than MS, the CSF MOG-IgG positivity can support the diagnosis of MOGAD. The synthesis of MOG-IgG in the CNS of patients with MOGAD can be detected from the onset of the disease and is associated with the severity of the disease. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that the presence of CSF MOG-IgG can improve the diagnosis of MOGAD in the absence of an MS phenotype, and intrathecal synthesis of MOG-IgG was associated with increased disability.

Comparison of MOG and AQP4 antibody seroprevalence in Korean adults with inflammatory demyelinating CNS diseases.

We aimed to compare seroprevalence of anti-myelin oligodendrocyte glycoprotein (MOG) and anti-aquaporin-4 (AQP4) antibodies in Korean adults with inflammatory demyelinating diseases (IDDs) of the central nervous system (CNS), based on a multicenter nationwide database. Sera were analyzed using a live cell-based assay for MOG and AQP4 antibodies. Of 586 Korean adults with IDDs of the CNS, 36 (6.1%) and 185 (31.6%) tested positive for MOG and AQP4 antibodies, respectively. No participant showed double positivity. Seroprevalence of MOG antibodies was about five times lower than that of AQP4 antibodies in a large cohort of Korean adults with IDDs of the CNS.

Cerebellar infarction presenting with isolated positional vertigo: differentiating factors for benign paroxysmal positional vertigo.

BACKGROUND: Isolated central positional vertigo (CPV) due to cerebellar infarction is often difficult to differentiate from benign paroxysmal positional vertigo (BPPV). Here, we aimed to evaluate whether vascular risk factors and serum vitamin D level can differentiate between positional vertigo types. METHODS: A total of 78 consecutive patients were consecutively enrolled from January 2017. All CPV patients had a National Institutes of Health Stroke Scale score of 0 and cerebellar infarctions confirmed by brain MR imaging. Vascular risk factors and serum 25-hydroxyvitamin D levels were compared between the two groups of patients. RESULTS: The proportion of men was higher in the CPV than in the BPPV group (p = 0.004). Atrial fibrillation was common in the CPV group on univariate analysis (p = 0.046). However, there were no independent differentiating factors between the two groups. The proportion of patients according to the number of risk factors was significantly different between the two groups (linear by linear association test, p = 0.02). The mean serum 25-hydroxyvitamin D level did not differ. Also, the proportions of vitamin D insufficiency and deficiency did not differ significantly between the two groups. CONCLUSIONS: Increased number of vascular risk factors including male sex suggested more CPV than BPPV. However, the serum vitamin D level was below the normal range in both groups. Our results demonstrate that serum vitamin D level has little value in the differential diagnosis of positional vertigo. Efforts to identify differentiating factors are warranted, and accumulating evidences including our research may lead to a diagnostic algorithm for isolated positional vertigo.

Fulminant Course of Neuromyelitis Optica in a Patient With Anti-MDA5 Antibody-Positive Dermatomyositis: A Case Report.

Anti-melanoma differentiation-associated gene 5 (anti-MDA5) antibody is a myositis-specific marker detected in clinically amyopathic dermatomyositis (DM). DM with anti-MDA5 antibody can be accompanied by rapidly progressive interstitial lung disease (RP-ILD) and other autoimmune disorders. Until now, only one case of neuromyelitis optica (NMO) with anti-MDA5-positive DM has been reported worldwide, in which the patient achieved a favorable outcome with intensive immunotherapy. We report a case of NMO in a patient with anti-MDA5-positive DM complicated by ILD and rheumatoid arthritis. Our patient experienced a fulminant course of NMO, rather than RP-ILD, in the presence of hyperferritinemia, which resulted in profound neurological sequelae despite immunotherapy including rituximab.

ACOX3 Dysfunction as a Potential Cause of Recurrent Spontaneous Vasospasm of Internal Carotid Artery.

Recurrent spontaneous vasospasm of the extracranial internal carotid artery (RSV-eICA) is a rarely recognized cause of ischemic stroke in young adults. However, its pathophysiology remains largely unknown. Through whole-exome sequencing of the ACOX3 gene of two dizygotic Korean twin brothers affected by RSV-eICA, we identified two compound heterozygous missense variants c.235 T > G (p.F79 V) and c.665G > A (p.G222E). In silico analysis indicated that both variants were classified as pathogenic. In vitro ACOX3 enzyme assay indicated practically no enzyme activity in both F79 V and G222E mutants. To determine the effect of the mutants on vasospasm, we used a collagen contraction assay on human aortic smooth muscle cells (HASMC). Carbachol, a cholinergic agonist, induces contraction of HASMC. Knockdown of ACOX3 in HASMC, using siRNA, significantly repressed HASMC contraction triggered by carbachol. The carbachol-induced HASMC contraction was restored by transfection with plasmids encoding siRNA-resistant wild-type ACOX3, but not by transfection with ACOX3 G222E or by co-transfection with ACOX3 F79 V and ACOX3 G222E, indicating that the two ACOX3 mutants suppress carbachol-induced HASMC contraction. We propose that an ACOX3 dysfunction elicits a prolonged loss of the basal aortic myogenic tone. As a result, smooth muscles of the ICA's intermediate segment, in which the sympathetic innervation is especially rich, becomes hypersensitive to sympathomimetic stimuli (e.g., heavy exercise) leading to a recurrent vasospasm. Therefore, ACOX3 dysfunction would be a causal mechanism of RSV-eICA. For the first time, we report the possible involvement of ACOX3 in maintaining the basal myogenic tone of human arterial smooth muscle.

A zebrafish model of nondystrophic myotonia with sodium channelopathy.

Nondystrophic myotonias are disorders of Na+ (Nav1.4 or SCN4A) and Cl- (CLCN1) channels in skeletal muscles, and frequently show phenotype heterogeneity. The molecular mechanism underlying their pathophysiology and phenotype heterogeneity remains unclear. As zebrafish models have been recently exploited for studies of the pathophysiology and phenotype heterogeneity of various human genetic diseases, a zebrafish model may be useful for delineating nondystrophic myotonias. Here, we generated transgenic zebrafish expressing a human mutant allele of SCN4A, referred to as Tg(mylpfa:N440K), and needle electromyography revealed increased number of myotonic discharges and positive sharp waves in the muscles of Tg(mylpfa:N440K) than in controls. In addition, forced exercise test at a water temperature of 24 °C showed a decrease in the distance moved, time spent in and number of visits to the zone with stronger swimming resistance. Finally, a forced exercise test at a water temperature of 18 °C exhibited a higher number of dive-bombing periods and drifting-down behavior than in controls. These findings indicate that Tg(mylpfa:N440K) is a good vertebrate model of exercise- and cold-induced human nondystrophic myotonias. This zebrafish model may contribute to provide insight into the pathophysiology of myotonia in sodium channelopathy and could be used to explore a new therapeutic avenue.