Clinicopathological Reclassification of Idiopathic Inflammatory Myopathy to Match the Serological Results of Myositis-Specific Antibodies.

BACKGROUND AND PURPOSE: Advances in serological tests are transforming the classification of idiopathic inflammatory myopathy (IIM). The new criteria suggested by the 119th European Neuromuscular Center international workshop divide IIM cases into four main diseases according to clinical and pathological findings, adding immune-mediated necrotizing myositis and nonspecific myositis to the classic categories of polymyositis and dermatomyositis. METHODS: Seventy one cases of IIM with sufficient available clinical and pathological data were reviewed to be reclassified according to the new criteria. RESULTS: Most of the cases previously classified as polymyositis (77.8%, 35/45) were reclassified as immune-mediated necrotizing myopathy. The results of myositis-specific antibodies matched well with the new clinicopathological classification. CONCLUSIONS: This new clinicopathological classification for IIM in combination with serological test results could be applied to our previous case series. Adoption of the new criteria will lead to a better understanding of the disease and hence new therapeutic insights.

Life-Saving Treatments for Spinal Muscular Atrophy: Global Access and Availability.

Background and Objectives: Spinal muscular atrophy (SMA) is a neurodegenerative disorder manifesting with progressive muscle weakness and atrophy. SMA type 1 used to be fatal within the first 2 years of life, but is now treatable with therapies targeting splicing modification and gene replacement. Nusinersen, risdiplam, and onasemnogene abeparvovec-xioi improve survival, motor strength, endurance, and ability to thrive, allowing many patients to potentially attain a normal life; all have been recently approved by major regulatory agencies. Although these therapies have revolutionized the world of SMA, they are associated with a high economic burden, and access to these therapies is limited in some countries. The primary objective of this study was to compare the availability and implementation of treatment of SMA from different regions of the world. Methods: In this qualitative study, we surveyed health care providers from 21 countries regarding their experiences caring for patients with SMA. The main outcome measures were provider survey responses on newborn screening, drug availability/access, barriers to treatment, and related questions. Results: Twenty-four providers from 21 countries with decades of experience (mean 26 years) in treating patients with SMA responded to the survey. Nusinersen was the most available therapy for SMA. Our survey showed that while genetic testing is usually available, newborn screening is still unavailable in many countries. The provider-reported treatment cost also varied between countries, and economic burden was a major barrier in treating patients with SMA. Discussion: Overall, this survey highlights the global inequality in managing patients with SMA. The spread of newborn screening is essential in ensuring improved access to care for patients with SMA. With the advancement of neurotherapeutics, more genetic diseases will soon be treatable, and addressing the global inequality in clinical care will require novel approaches to mitigate such inequality in the future.

Pharmacokinetics and clinical efficacy of 6'-sialyllactose in patients with GNE myopathy: Randomized pilot trial.

GNE myopathy, caused by biallelic mutations in the GNE gene, is characterized by initial ankle dorsiflexor weakness and rimmed vacuoles in the muscle histopathology, resulting in reduced sialic acid production. Sialyllactose is a source of sialic acid. We performed a pilot clinical trial to analyze the pharmacokinetic properties of 6'-sialyllactose (6SL) and evaluated the safety, and efficacy of oral 6SL in patients with GNE myopathy. Ten participants were in the pharmacokinetic study, and 20 in the subsequent clinical trial. For the pharmacokinetic study, participants were administered either 3 g (low-dose) or 6 g (high-dose) of 6SL in a single dose. Plasma concentrations of 6SL, sialic acid, and sialic acid levels on the surface of red blood cells were periodically assessed in blood samples. Patients were randomly allocated to test (low- and high-dose groups) or placebo groups for the trial. Motor function, ambulation, plasma 6SL and sialic acid concentrations, GNE myopathy-functional activity scale scores, and MRI findings were assessed. 6SL was well tolerated, except for self-limited gastrointestinal discomfort. Free sialic acid in both low- and high-dose groups significantly increased at 6 and 12 weeks, but not in the placebo group. In the high-dose group, proximal limb powers improved with daily 6SL. Considering the fat fraction on muscle MRI, results in the high-dose group were superior to those in the low-dose group. 6SL may be a good candidate for GNE myopathy therapeutics as it induces an increase or reduces the decrease in limb muscle power, attenuates muscle degeneration, and improves the biochemical properties of sialic acid.

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.

Neuropsychological, neuroimaging and autopsy findings of butane encephalopathy.

BACKGROUND: Butane is an aliphatic hydrocarbon used in various commercial products. While numerous reports of sudden cardiac-related deaths from butane inhalation have been described, butane-associated acute encephalopathy has rarely been reported. CASE PRESENTATION: A 38-year-old man presented with cognitive dysfunction after butane gas inhalation. Neuropsychological test results showed impairments in verbal and visual memory, and frontal executive function. Diffusion weighted MRI revealed symmetric high-signal changes in the bilateral hippocampus and globus pallidus. FDG-PET demonstrated decreased glucose metabolism in the bilateral precuneus and occipital areas and the left temporal region. At the 8-month follow-up, he showed still significant deficits in memory and frontal functions. Diffuse cortical atrophy with white matter hyperintensities and extensive glucose hypometabolism were detected on follow-up MRI and FDG-PET, respectively. Brain autopsy demonstrated necrosis and cavitary lesions in the globus pallidus. CONCLUSIONS: Only a few cases of butane encephalopathy have been reported to date. Brain lesions associated with butane encephalopathy include lesions in the bilateral thalamus, insula, putamen, and cerebellum. To the best of our knowledge, this is the first report on bilateral hippocampal and globus pallidal involvement in acute butane encephalopathy. The pathophysiology of central nervous system complications induced by butane intoxication is not yet fully understood. However, the direct toxic effects of butane or anoxic injury secondary to cardiac arrest or respiratory depression have been suggested as possible mechanisms of edematous changes in the brain after butane intoxication.

Digital Biomarkers for Diagnosis of Muscle Disorders Using Stimulated Muscle Contraction Signal.

We propose a digital biomarker related to muscle strength and muscle endurance (DB/MS and DB/ME) for the diagnosis of muscle disorders based on a multi-layer perceptron (MLP) using stimulated muscle contraction. When muscle mass is reduced in patients with muscle-related diseases or disorders, measurement of DBs that are related to muscle strength and endurance is needed to suitably recover damaged muscles through rehabilitation training. Furthermore, it is difficult to measure DBs using traditional methods at home without an expert; moreover, the measuring equipment is expensive. Additionally, because traditional measurements depend on the subject's volition, we propose a DB measurement technique that is unaffected by the subject's volition. To achieve this, we employed an impact response signal (IRS) based on multi-frequency electrical stimulation (MFES) using an electromyography sensor. The feature vector was then extracted using the signal. Because the IRS is obtained from stimulated muscle contraction, which is caused by electrical stimulation, it provides biomedical information about the muscle. Finally, to estimate the strength and endurance of the muscle, the feature vector was passed through the DB estimation model learned through the MLP. To evaluate the performance of the DB measurement algorithm, we collected the MFES-based IRS database for 50 subjects and tested the model with quantitative evaluation methods using the reference for the DB. The reference was measured using torque equipment. The results were compared with the reference, indicating that it is possible to check for muscle disorders which cause decreased physical performance using the proposed algorithm.

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.

Lifelong Outcomes of Systemic Adeno-Associated Virus Micro-Dystrophin Gene Therapy in a Murine Duchenne Muscular Dystrophy Model.

Adeno-associated virus (AAV)-mediated systemic micro-dystrophin (µDys) therapy is currently in clinical trials. The hope is to permanently improve the life quality of Duchenne muscular dystrophy (DMD) patients. Numerous preclinical studies have been conducted to support these trials. However, none examined whether a single therapy at a young age can lead to lifelong disease amelioration. To address this critical question, we injected 1 × 1013 vg particles/mouse of an AAV serotype-9 µDys vector to 3-month-old mdx mice through the tail vein. Therapeutic outcomes were evaluated at the age of 11 months (adulthood, 8 months postinjection) and 21 months (terminal age, 18 months postinjection). Immunostaining and Western blot showed saturated supraphysiological levels of µDys expression in skeletal muscle and heart till the end of the study. Treatment significantly improved grip force and treadmill running, and significantly reduced the serum creatine kinase level at both time points. Since cardiac death is a major threat in late-stage patients, we evaluated cardiac electrophysiology and hemodynamics by ECG and the closed-chest cardiac catheter assay, respectively. Significant improvements were observed in these assays. Importantly, many ECG and hemodynamic parameters (heart rate, PR interval, QRS duration, QTc interval, end-diastolic/systolic volume, dP/dt max and min, max pressure, and ejection fraction) were completely normalized at 21 months of age. Our results have provided direct evidence that a single systemic AAV µDys therapy has the potential to provide lifelong benefits in the murine DMD model.

A novel nonsense mutation in the dimerization domain of FLNC causing mild myofibrillar myopathy.

Skeletal muscle filaminopathy is caused by mutations in the gene encoding filamin C (FLNC). The phenotypes include both proximal and distal myopathy, of which proximal myopathy phenotype pathologically displays myofibrillar myopathy as mutated filamin C produces protein aggregates. FLNC-related myofibrillar myopathy usually starts in the fourth to fifth decade and often progresses to cause inability to walk, respiratory muscle weakness requiring nocturnal ventilation, and cardiac abnormalities, such as conduction blocks and diastolic dysfunction. We report a 65-year-old patient with myofibrillar myopathy caused by a novel heterozygous nonsense mutation in the dimerization domain of FLNC, in whom histopathological features were highlighted by histological and immunohistochemical studies. The reported patient showed slow progression of mild limb weakness since her childhood.

Genotype-phenotype correlations in valosin-containing protein disease: a retrospective muticentre study.

BACKGROUND: Valosin-containing protein (VCP) disease, caused by mutations in the VCP gene, results in myopathy, Paget's disease of bone (PBD) and frontotemporal dementia (FTD). Natural history and genotype-phenotype correlation data are limited. This study characterises patients with mutations in VCP gene and investigates genotype-phenotype correlations. METHODS: Descriptive retrospective international study collecting clinical and genetic data of patients with mutations in the VCP gene. RESULTS: Two hundred and fifty-five patients (70.0% males) were included in the study. Mean age was 56.8±9.6 years and mean age of onset 45.6±9.3 years. Mean diagnostic delay was 7.7±6 years. Symmetric lower limb weakness was reported in 50% at onset progressing to generalised muscle weakness. Other common symptoms were ventilatory insufficiency 40.3%, PDB 28.2%, dysautonomia 21.4% and FTD 14.3%. Fifty-seven genetic variants were identified, 18 of these no previously reported. c.464G>A (p.Arg155His) was the most frequent variant, identified in the 28%. Full time wheelchair users accounted for 19.1% with a median time from disease onset to been wheelchair user of 8.5 years. Variant c.463C>T (p.Arg155Cys) showed an earlier onset (37.8±7.6 year) and a higher frequency of axial and upper limb weakness, scapular winging and cognitive impairment. Forced vital capacity (FVC) below 50% was as risk factor for being full-time wheelchair user, while FVC <70% and being a full-time wheelchair user were associated with death. CONCLUSION: This study expands the knowledge on the phenotypic presentation, natural history, genotype-phenotype correlations and risk factors for disease progression of VCP disease and is useful to improve the care provided to patient with this complex disease.

Efficacy and safety of Lenzumestrocel (Neuronata-R® inj.) in patients with amyotrophic lateral sclerosis (ALSUMMIT study): study protocol for a multicentre, randomized, double-blind, parallel-group, sham procedure-controlled, phase III trial.

BACKGROUND: A single cycle (two repeated treatments) with intrathecal autologous bone marrow-derived mesenchymal stem cells (BM-MSCs, 26-day interval) showed safety and provided therapeutic benefit lasting 6 months in patients with ALS but did not demonstrate long-term efficacy. This phase III clinical trial (ALSUMMIT) protocol was developed to evaluate the long-term efficacy and safety of the combined protocol of single-cycle intrathecal therapy and three additional booster injections of BM-MSC (Lenzumestrocel) treatment in patients with ALS. METHODS: ALSUMMIT is a multicentre, randomized, double-blind, parallel-group, sham procedure-controlled, phase III trial for ALS. The 115 subjects will be randomized (1:2:2) into three groups: (1) study Group 1 (single-cycle, two repeated injections with 26-day interval), (2) study Group 2 (single-cycle + three additional booster injections at 4, 7, and 10 months), and (3) the control group. Participants who have an intermediate rate of disease progression will be included in this trial to reduce clinical heterogeneity. The primary endpoint will be evaluated by combined assessment of function and survival (CAFS), also known as joint rank scores (JRS), at 6 months (study Group 1 vs. control) and 12 months (study Group 2 vs. control) after the first Lenzumestrocel or placebo administration. Safety assessment will be performed throughout the study period. Additionally, after the 56-week main study, a long-term follow-up observational study will be conducted to evaluate the long-term efficacy and safety up to 36 months. DISCUSSION: Lenzumestrocel is the orphan cell therapy product for ALS conditionally approved by the South Korea Ministry of Food and Drug Safety (MFDS). This ALSUMMIT protocol was developed for the adoption of enrichment enrolment, add-on design, and consideration of ethical issues for the placebo group. TRIAL REGISTRATION: ClinicalTrials.gov NCT04745299 . Registered on Feb 9, 2021. Clinical Research Information Service (CRIS) KCT0005954 . Registered on Mar 4, 2021.

Effect of Chelation Therapy on a Korean Patient With Brain Manganese Deposition Resulting From a Compound Heterozygous Mutation in the SLC39A14 Gene.

Mutations in the manganese transporter gene SLC39A14 lead to inherited disorders of manganese metabolism. Chelation therapy with edetate calcium disodium (CaNa2EDTA) is known to effectively reduce manganese deposition. We describe the first identified Korean case of SLC39A14-associated manganism and the treatment response to a 5-year chelation therapy. An 18-year-old female presented with childhood-onset dystonia. Magnetic resonance imaging showed T1 hyperintensity throughout the basal ganglia, brainstem, cerebellum, cerebral and cerebellar white matter, and pituitary gland. Blood manganese levels were elevated, and whole-exome sequencing revealed compound heterozygous mutations in SLC39A14. Treatment with intravenous CaNa2EDTA led to a significant reduction in serum manganese levels and T1 hyperintensities. However, her dystonia improved insignificantly. Hence, early diagnosis of this genetic disorder is essential because it is potentially treatable. Even though our treatment did not significantly reverse the establish deficits, chelation therapy could have been more effective if it was started at an earlier stage of the disease.

Serum progranulin is not associated with rs5848 polymorphism in Korean patients with neurodegenerative diseases.

Low serum progranulin (PGRN) is known to be associated with granulin (GRN) gene mutation and T alleles of GRN rs5848 polymorphism. However, there have been only a few Asian studies exploring these. We investigated the serum PGRN levels, rs5848 genotypes, and their relations with cerebrospinal fluid (CSF) Alzheimer's disease (AD) biomarkers in the Korean population. Serum PGRN levels, GRN rs5848 polymorphism, and GRN mutations were evaluated in 239 participants (22 cognitively unimpaired participants and 217 patients with neurodegenerative diseases). CSF AD biomarkers were also evaluated in 214 participants. There was no significant difference in the serum PGRN levels among the diagnostic groups. We could not find any GRN mutation carrier in our sample. The differences in the frequencies of the rs5848 genotypes among the clinical groups or the effects of the rs5848 genotypes on serum PGRN were not observed. There was no correlation between the serum PGRN level or rs5848 genotype and CSF AD biomarkers. Neither the T allele nor the TT genotype had an effect on the development of AD. Our results showed that serum PGRN levels were not associated with rs5848 genotypes, indicating that multiple single nucleotide polymorphisms might affect PGRN concentrations in an ethnicity-specific manner.

Clinical, electrophysiological, and genetic characteristics of cerebrotendinous xanthomatosis in South Korea.

Cerebrotendinous xanthomatosis (CTX) is an autosomal recessive lipid storage disorder caused by 27-hydroxylase deficiency. We report the clinical characteristics of six Korean CTX patients. The median age of onset was 22.5 years, the median age at diagnosis was 42 years, and the diagnostic delay was 18.1 years. The most common clinical symptoms were tendon xanthoma and spastic paraplegia. Four of five patients exhibited latent central conduction dysfunction. All patients carried the same mutation in CYP27A1 (c.1214 G>A [p.R405Q]). CTX is a treatable neurodegenerative disorder; however, our results revealed that patients with CTX in Korea might receive the diagnosis after a prolonged delay. .

Atypical Young-onset Dementia in Cerebral Thromboangiitis Obliterans: A Case Report.

Young-onset dementia (YOD, age at onset below 45 y) has a broad differential diagnosis. We describe a 41-year-old man with atypical manifestations of YOD syndrome in cerebral thromoboangiitis obliterans (CTAO). Extensive antemortem workup including clinical assessment, laboratory investigations, neuroimaging, and genetic testing did not elucidate a diagnosis. Postmortem neuropathologic examination revealed cortical sickle-shaped granular atrophy, resulting from numerous remote infarcts and cortical microinfarcts that mainly affected the bilateral frontal and parietal lobe, confirming CTAO. Although CTAO is a rare cause of vascular dementia, it should be considered as one of the differentials in patients with YOD with a history of heavy smoking and presence of symmetric damages of watershed-territory on neuroimaging.

A case of CSF1R-related leukoencephalopathy: serial neuroimaging and neuropsychological tests.

Colony-stimulating factor 1 receptor (CSF1R)-related leukoencephalopathy is one of the most common causes of adult-onset leukodystrophy and is caused by mutation of the CSF1R gene. Brain magnetic resonance imaging (MRI) findings in asymptomatic patients have not been well recognized. We report on the case of a patient with CSF1R-related leukoencephalopathy who had a novel missense variant of the CSF1R gene with a family history of early onset dementia. This is a representative case of CSF1R-related leukoencephalopathy, which shows the progression of brain MRI and cognitive decline from an asymptomatic state.

Autophagic defects observed in fibroblasts from a patient with ß-propeller protein-associated neurodegeneration.

Beta-propeller protein-associated neurodegeneration (BPAN) is associated with mutations in the autophagy gene WDR45. The aim of this study was to demonstrate autophagic defects in a patient with BPAN. We assayed autophagic markers using western blot analysis and immunocytochemistry and applied transmission electron microscopy (TEM) to visualize the autophagic structures in fibroblasts from a 7-year-old Korean female with WDR45 splice-site mutation (c.977-1G>A; NM_007075.3). The protein and mRNA expression levels of WDR45 gene were decreased in the patient-derived fibroblasts. The amount of increase in LC3-II upon treatment with an autophagy inducer and inhibitor was reduced in mutant cells compared to control cells, suggesting decreased autophagic flux. TEM showed the accumulation of large vacuoles in mutant cells with a decrease of autophagosomes. Our study demonstrated that the WDR45 mutation in this patient impaired autophagy and provided additional insight into ultrastructural changes of autophagic structures.

Functional recovery of a novel knockin mouse model of dysferlinopathy by readthrough of nonsense mutation.

Biallelic mutations in the dysferlin gene cause limb-girdle muscular dystrophy 2B or Miyoshi distal myopathy. We found that nonsense mutations are the most common mutation type among Korean patients with dysferlinopathy; more than half of the patients have at least one nonsense allele, which may be amenable to readthrough therapy. We generated a knockin mouse, dqx, harboring DYSF p.Q832∗ mutation. Homozygous dqx mice lacked dysferlin in skeletal muscle, while 2 weeks of oral ataluren restored dysferlin expression and ameliorated skeletal muscle pathology. Their physical performance improved, and protection against eccentric contractions was noted. The improvement was most evident in mice treated with oral ataluren of 0.9 mg/mL. These improvements were sustained for 8 weeks in ataluren-treated dqx mice, while the parameters of A/J mice treated with ataluren over the same period did not improve. These results support that readthrough therapy by oral ataluren may also be applicable to dysferlinopathy patients with nonsense mutation.

Diagnosis of Duchenne Muscular Dystrophy in a Presymptomatic Infant Using Next-Generation Sequencing and Chromosomal Microarray Analysis: A Case Report.

Duchenne muscular dystrophy is a progressive and lethal X-linked recessive neuromuscular disease caused by mutations in the dystrophin gene. It has a high rate of diagnostic delay; early diagnosis and treatment are often not possible due to delayed recognition of muscle weakness and lack of effective treatments. Current treatments based on genetic therapy can improve clinical results, but treatment must begin as early as possible before significant muscle damage. Therefore, early diagnosis and rehabilitation of Duchenne muscular dystrophy are needed before symptom aggravation. Creatine kinase is a diagnostic marker of neuromuscular disorders. Herein, the authors report a case of an infant patient with Duchenne muscular dystrophy with a highly elevated creatine kinase level but no obvious symptoms of muscle weakness. The patient was diagnosed with Duchenne muscular dystrophy via next-generation sequencing and chromosomal microarray analysis to identify possible inherited metabolic and neuromuscular diseases related to profound hyperCKemia. The patient is enrolled in a rehabilitation program and awaits the approval of the genetic treatment in Korea. This is the first report of an infantile presymptomatic Duchenne muscular dystrophy diagnosis using next-generation sequencing and chromosomal microarray analysis.