An autopsy case of progressive supranuclear palsy with severe corticospinal tract degeneration.

We report an autopsy case of a 70-year-old man who was clinically diagnosed with atypical progressive supranuclear palsy (PSP). He initially presented with gait ataxia and then showed vertical gaze palsy, rigidity, akinesia, dysphagia, and mild cognitive impairment, followed by prominent upper motor signs later in the course of the disease. Cranial magnetic resonance imaging revealed tegmental atrophy of the midbrain. Autopsy revealed severe neuronal loss and gliosis in the motor cortex and corticospinal degeneration and mild to moderate neuronal loss and gliosis in the basal ganglia, substantia nigra, midbrain, and pons. Tufted astrocytes were primarily found in the motor cortex and basal ganglia. Globose-type neurofibrillary tangles were observed in the locus coeruleus and nucleus olivaris inferior. In the cerebellar cortex, mild Purkinje cell loss and scattered axonal torpedoes were observed with tau-positive Purkinje cells. The dentate nucleus displayed severe neuronal loss and gliosis. The present case showed characteristics of both PSP with prominent cerebellar ataxia (PSP-C) and PSP-primary lateral sclerosis (PSP-PLS).

Safety and immunogenicity of mRNA COVID-19 vaccine in inpatients with muscular dystrophy.

INTRODUCTION/AIMS: Due to muscular weakness and cardiopulmonary dysfunction, patients with muscular dystrophy (MD) have an increased risk of serious complications from coronavirus disease-2019 (COVID-19). Although vaccination is recommended, COVID-19 vaccination safety and immunogenicity in these patients are unknown. We investigated reaction frequency, post-vaccine antibody titers after two mRNA COVID-19 vaccine doses, and clinical predictors of antibody response among patients with MD. METHODS: We recruited 171 inpatients with MD receiving two BNT162b2 mRNA COVID-19 vaccine doses from seven hospitals. Blood samples were obtained from 53 inpatients before the first dose and 28 to 30 days after the second dose, and antibody titers were measured. RESULTS: Overall, 104 (60.8%) and 115 (67.6%) patients had side effects after the first and second doses, respectively. These were generally mild and self-limited. Multiple logistic regression analysis showed that a bedridden state was associated with reduced side effects (odds ratio [OR] = 0.29; 95% confidence interval [CI], 0.12 to 0.71). The antibody titers of all participants changed from negative to positive after two vaccine doses. The geometric mean titer (GMT) of the inpatients was 239 (95% CI, 159.3 to 358.7). Older age (relative risk [RR] = 0.97; 95% CI, 0.95 to 0.99) and bedridden state (RR = 0.27; 95% CI, 0.14 to 0.51) were associated with a lower antibody titer. Patients with myotonic dystrophy type 1 (DM1) had a lower GMT than patients with other MDs (RR = 0.42; 95% CI, 0.21 to 0.85). DISCUSSION: COVID-19 vaccination is safe and immunogenic in inpatients with MD. Patients with DM1 appear to have a poorer COVID-19 antibody response than those with other MDs.

The current status of medical care for myotonic dystrophy type 1 in the national registry of Japan.

INTRODUCTION/AIMS: Myotonic dystrophy (DM) is a systemic disease with multiple organ complications, making the standardization of medical care a challenge. We analyzed data from Japan's national registry to clarify the current treatment patterns and demographic features of Japanese DM patients. METHODS: Using the Japanese National Registry of Muscular Dystrophy (Remudy), we analyzed medical care practice for the multisystemic issues associated with adult DM type 1 patients, excluding congenital DM. RESULTS: We included 809 patients with a median age of 44.2 years. Among these patients, 15.8% used ventilators; 31.7% met the index considered at risk for sudden death due to cardiac conduction defects (PR interval over 240 milliseconds or QRS duration over 120 milliseconds) and 2.8% had implanted cardiac devices. Medication for heart failure was prescribed to 9.6% of patients. Overall, 21.2% of patients had abnormal glucose metabolism, of whom 42.9% were treated with oral medications. Among the oral medications, dipeptidyl peptidase-4 inhibitors were the most common. Cancers were observed in 3.7% of the patients, and endometrial and breast cancers were dominant. Mexiletine was prescribed for myotonia in 1.9% of the patients, and only 1% of the patients received medication for daytime sleepiness. DISCUSSION: This study shows difference in treatment patterns for DM1 in Japan compared with other countries, such as lower rates of use of implantable cardiac devices and higher rates of ventilator use. These data may be useful in discussions aimed at standardizing medical care for patients with DM.

Biallelic Mutations in MYPN, Encoding Myopalladin, Are Associated with Childhood-Onset, Slowly Progressive Nemaline Myopathy.

Nemaline myopathy (NM) is a common form of congenital nondystrophic skeletal muscle disease characterized by muscular weakness of proximal dominance, hypotonia, and respiratory insufficiency but typically not cardiac dysfunction. Wide variation in severity has been reported. Intranuclear rod myopathy is a subtype of NM in which rod-like bodies are seen in the nucleus, and it often manifests as a severe phenotype. Although ten mutant genes are currently known to be associated with NM, only ACTA1 is associated with intranuclear rod myopathy. In addition, the genetic cause remains unclear in approximately 25%-30% of individuals with NM. We performed whole-exome sequencing on individuals with histologically confirmed but genetically unsolved NM. Our study included individuals with milder, later-onset NM and identified biallelic loss-of-function mutations in myopalladin (MYPN) in four families. Encoded MYPN is a sarcomeric protein exclusively localized in striated muscle in humans. Individuals with identified MYPN mutations in all four of these families have relatively mild, childhood- to adult-onset NM with slowly progressive muscle weakness. Walking difficulties were recognized around their forties. Decreased respiratory function, cardiac involvement, and intranuclear rods in biopsied muscle were observed in two individuals. MYPN was localized at the Z-line in control skeletal muscles but was absent from affected individuals. Homozygous knockin mice with a nonsense mutation in Mypn showed Z-streaming and nemaline-like bodies adjacent to a disorganized Z-line on electron microscopy, recapitulating the disease. Our results suggest that MYPN screening should be considered in individuals with mild NM, especially when cardiac problems or intranuclear rods are present.

Immunohistochemical localization of spatacsin in α-synucleinopathies.

Spatacsin (SPG11) is a major mutated gene in autosomal recessive spastic paraplegia with thin corpus callosum (ARHSP-TCC) and is responsible for juvenile Parkinsonism. To elucidate the role of spatacsin in the pathogenesis of α-synucleinopathies, an immunohistochemical investigation was performed on the brain of patients with Parkinson's disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy (MSA) using anti-spatacsin antibody. In PD, Lewy bodies (LBs) in the brain stem were positive for spatacsin. These LBs showed intense staining in their peripheral portions and occasionally in the central cores. Lewy neurites were also spatacsin-positive. In DLB, cortical LBs were immunolabeled by spatacsin. In MSA, glial cytoplasmic inclusions (GCI) and a small fraction of neuronal cytoplasmic inclusions (NCI) were positive for spatacsin. The widespread accumulation of spatacsin observed in pathologic α-synuclein-containing inclusions suggests that spatacsin may be involved in the pathogenesis of α-synucleinopathies.

The Association Between Physical Activity/Heart Rate Variability Data Obtained Using a Wearable Device and Timed Motor Functional Tests in Patients with Duchenne Muscular Dystrophy: A Pilot Study.

Background: Duchenne muscular dystrophy (DMD) is a devastating X-linked muscle disease. Clinical evaluation of DMD uses patient-intensive motor function tests, and the recent development of wearable devices allows the collection of a variety of biometric information, including physical activity. Objective: In this study, we examined differences in physical activity and heart rate variability (HRV) between patients with DMD and healthy subjects using a wearable device, and investigated any association between these parameters and motor function in patients with DMD. Methods: Participants were 7 patients with DMD and 8 healthy males, whose physical activity and HRV were provided by a wearable device. These data were used to investigate the relationship between both physical activity and HRV parameters and timed motor functional tests [Time to stand from supine, 10-meter walking time (10MWT), North Star Ambulatory Assessment (NSAA), and 6-minute walking test (6MWT)] in patients with DMD. Results: Results of 24-hours physical activity, fat burning, total number of steps and active distance, average step rate, average exercise intensity during walking, exercise, degree of forward lean during walking, maximum heart rate, normalized low frequency power (LF norm), and maximum exercise intensity in patients with DMD were lower than those in control subjects. Physical activity and HRV parameters did not correlate with the time to stand from supine. The 10MWT positively correlated with average heart rate, while NSAA negatively correlated with average heart rate, total frequency power (TF), and very low frequency power (VLF) during arousal. The 6MWT negatively correlated with ratio LF/high frequency power (HF). CONCLUSIONS: Physical activity and HRV indices that differ from those of normal children and that correlate with motor function assessment may serve as digital biomarkers.

Loss-of-function polymorphisms in NQO1 are not associated with the development of subacute myelo-optico-neuropathy.

BACKGROUND: Subacute myelo-optico-neuropathy (SMON) is a neurological disorder associated with the administration of clioquinol, particularly at very high doses. Although clioquinol has been used worldwide, there was an outbreak of SMON in the 1950s-1970s in which the majority of cases were in Japan, prompting speculation that the unique genetic background of the Japanese population may have contributed to the development of SMON. Recently, a possible association between loss-of-function polymorphisms in NQO1 and the development of SMON has been reported. In this study, we analyzed the relationship between NQO1 polymorphisms and SMON in Japan. METHODS: We analyzed 125 Japanese patients with SMON. NQO1 loss-of-function polymorphisms (rs1800566, rs10517, rs689452, and rs689456) were evaluated. The allele frequency distribution of each polymorphism was compared between the patients and the healthy Japanese individuals (Human Genomic Variation Database and Integrative Japanese Genome Variation Database), as well as our in-house healthy controls. RESULTS: The frequencies of the loss-of-function NQO1 alleles in patients with SMON and the normal control group did not differ significantly. CONCLUSION: We conclude that known NQO1 polymorphisms are not associated with the development of SMON.

Facioscapulohumeral muscular dystrophy Health Index: Japanese translation and validation study.

PURPOSE: The Facioscapulohumeral Muscular Dystrophy Health Index (FSHD-HI) is a patient-reported outcome measure developed for patients with FSHD. This study aimed to translate the FSHD-HI into Japanese (FSHD-HI-J), evaluate cultural adaptation, and examine its psychometric properties. MATERIALS AND METHODS: We created two forward translations, integrated them into a single Japanese version, and evaluated the back-translated version of the FSHD-HI. After finalizing the translation and cultural adaptation, we conducted a survey of 66 patients with FSHD to examine the reliability and validity of the FSHD-HI-J. For psychometric evaluations, we used Cronbach's alpha to assess internal consistency, the intraclass correlation coefficient (ICC) for test-retest reliability, and assessed validity based on the associations between FSHD-HI-J, clinical variables, and quality of life measures. RESULTS: The FSHD-HI-J was found to be clinically relevant, indicating high internal consistency and test-retest reliability (ICC = 0.92 [95% confidence interval: 0.86-0.95] for the total score), as well as significant associations with clinical variables (D4Z4 repeats and functional impairment) and other quality of life measures (|rho| = 0.25-0.73). CONCLUSIONS: The FSHD-HI-J is a valid and reliable patient-reported outcome measure for Japanese patients with FSHD. This validated, disease-specific patient-reported outcome is essential for future clinical practice and clinical trials.

Facioscapulohumeral muscular dystrophy (FSHD) affects not only a patient's physical abilities but also their social activities, participation, and overall quality of life.The FSHD-Health Index (FSHD-HI) is an instrument developed as a disease-specific patient-reported outcome measure to evaluate the burden experienced by patients.The Japanese version of the FSHD-HI has been established as a reliable and validated measure for Japanese-speaking patients with FSHD.The Japanese version of the FSHD-HI can serve as a useful instrument for evaluating the effectiveness of interventions in future trials.

CTG repeat length underlying cardiac events and sudden death in myotonic dystrophy type 1.

Aims: Myotonic dystrophy Type 1 (DM1) is caused by the expansion of CTG repeats (CTGn) in the DM1 protein kinase (DMPK) gene, while it remains unclear whether CTGn may be associated with the incidence of cardiac events or sudden death in Japan as well as Europe. The aim of this study was to investigate the association between CTGn and cardiac involvements. Methods and results: This cohort study included patients with DM1 who were retrospectively recruited from nine Japanese hospitals specializing in neuromuscular diseases. A total of 496 patients with DM1 who underwent a genetic test in the DMPK gene were analysed. Patients with congenital form or under 15 years old were excluded and patients were assigned into the quartiles. When we compared the incidence of cardiac events including advanced/complete atrioventricular block, pacemaker implantation, and ventricular tachycardias or mortality among four groups, patients with 1300 or longer CTGn experienced composite cardiac events [hazard ratio (HR): 3.19, 95% confidence interval (CI): 1.02-9.99, P = 0.014] more frequently and had significantly higher mortality rate (HR: 6.79, 95% CI: 2.05-22.49, P < 0.001) than those under 400 CTGn while the rate of sudden death was not significantly different. Conclusion: Regarding the cardiac events and mortality in patients with DM1, patients with 1300 or longer CTGn are at especially high risk.

Clinical features and a mutation with late onset of limb girdle muscular dystrophy 2B.

OBJECTIVE AND METHODS: Dysferlin encoded by DYSF deficiency leads to two main phenotypes, limb girdle muscular dystrophy (LGMD) 2B and Miyoshi myopathy. To reveal in detail the mutational and clinical features of LGMD2B in Japan, we observed 40 Japanese patients in 36 families with LGMD2B in whom dysferlin mutations were confirmed. RESULTS AND CONCLUSIONS: Three mutations (c.1566C>G, c.2997G>T and c.4497delT) were relatively more prevalent. The c.2997G>T mutation was associated with late onset, proximal dominant forms of dysferlinopathy, a high probability that muscle weakness started in an upper limb and lower serum creatine kinase (CK) levels. The clinical features of LGMD2B are as follows: (1) onset in the late teens or early adulthood, except patients homozygous for the c.2997G>T mutation; (2) lower limb weakness at onset; (3) distal change of lower limbs on muscle CT at an early stage; (4) impairment of lumbar erector spinal muscles on muscle CT at an early stage; (5) predominant involvement of proximal upper limbs; (6) preservation of function of the hands at late stage; (7) preservation of strength in neck muscles at late stage; (8) lack of facial weakness or dysphagia; (9) avoidance of scoliosis; (10) hyper-Ckaemia; (11) preservation of cardiac function; and (12) a tendency for respiratory function to decline with disease duration. It is important that the late onset phenotype is found with prevalent mutations.

Natural history of Becker muscular dystrophy: a multicenter study of 225 patients.

OBJECTIVE: Becker muscular dystrophy (BMD) is a milder variant of Duchenne muscular dystrophy (DMD), a lethal X-linked muscular disorder. Here, we aim to investigat the clinical involvement of skeletal, respiratory, cardiac, and central nervous systems in patients with BMD, as well as genotype-phenotype relationships. METHODS: This nationwide cohort study investigated the clinical manifestations and genotype-phenotype relationships in 225 patients with BMD having in-frame deletion from 22 medical centers. The primary outcome was to elucidate the association of genotype with skeletal muscle, respiratory, cardiac, and central nervous system disorders. Descriptive statistics were used to analyze the data. RESULTS: The average age of the subjects was 31.5 (range, 1-81) years. Initial symptoms of BMD were muscular (60%), followed by asymptomatic hypercreatine kinasemia (32.4%) and central nervous system disorders (5.3%). Gait disturbance was observed in 53.8% of patients and the average age at wheelchair introduction was 36.5 years. The ventilator introduction rate was 6.7% at an average age of 36.6 years. More than 30% of patients had an abnormal electrocardiogram and approximately 15% had heart failure symptoms. Cardiac function on echocardiography varied significantly among the patients. The frequencies of seizures and intellectual/developmental disability were 8.0% and 16.9%, respectively. Exon 45-47deletion (del) was the most common (22.6%), followed by exon 45-48del (13.1%). Patients with exon 45-49del patients demonstrated severe skeletal muscle damage. Patients with exon 45-47del and exon 45-55del patients did not require ventilator use. INTERPRETATION: The study provides important prognostic information for patients and clinicians to establish therapy plans and to implement preventative medicine.

Founder genetic variants of ABCC4 and ABCC11 in the Japanese population are not associated with the development of subacute myelo-optico-neuropathy (SMON).

BACKGROUND: Subacute myelo-optico-neuropathy (SMON) is a severe neurological disorder associated with clioquinol administration, which frequently occurred in Japan during the 1950s and 1960s. The unique genetic background of the Japanese population is considered to be strongly involved in the development of this neurological disease. Recently, genetic variants of ABCC4 (OMIM: 605250) and ABCC11 (OMIM: 607040), which are particularly common in the Japanese population, were suggested as possible genetic susceptibility factors for the development of SMON. METHODS: We analyzed 125 Japanese SMON patients who provided consent for this study. Patient DNA was collected from peripheral blood, and genetic analysis was performed for ABCC4 rs3765534 (c.2268G>A, p.Glu857Lys) and ABCC11 rs17822931 (c.538G>A, p.Gly180Arg) polymorphisms using the Sanger sequencing method and/or TaqMan PCR method. The frequency distribution of each polymorphism was compared with that in healthy Japanese people recorded in two genomic databases (Human Genomic Variation Database and Integrative Japanese Genome Variation Database), and each genotype was compared with the clinical features of patients. RESULTS: The frequencies of ABCC4 rs3765334 and ABCC11 rs17822931 polymorphisms in SMON patients and healthy Japanese people were not significantly different in the multifaceted analysis. CONCLUSION: We conclude that the ABCC4 rs3765334 and ABCC11 rs17822931 polymorphisms are not associated with the development of SMON.

Characteristics of myotonic dystrophy patients in the national registry of Japan.

Myotonic dystrophies (DM) are inherited autosomal dominant disorders affecting multiple organs. Currently available therapeutics for DM are limited; therefore, a patient registry is essential for therapeutic development and success of clinical trials targeting the diseases. We have developed a nationwide DM registry in Japan under the Registry of Muscular Dystrophy (Remudy). The registration process was patient-initiated; however, physicians certified the clinical information. The dataset includes all Naarden and TREAT-NMD core datasets and additional items covering major DM clinical features. As of March 2020, we enrolled 976 patients with genetically confirmed DM. The majority (99.9%) of these patients had DM1, with 11.4% having the congenital form. However, 1 patient had DM2. Upon classifying 969 symptomatic DM1 patients based on their age at onset, an earlier onset was associated with a longer CTG repeat length. Myotonia was the most frequent symptom, followed by hand disability, fatigue, and daytime sleepiness. The frequency of hand disabilities, constipation, and visual disturbances was higher for patients with congenital DM. According to a multiple regression analysis of objective clinical measurements related to prognosis and activities of daily living, CTG repeat length strongly influenced the grip strength, forced vital capacity, and QRS time in an electrocardiogram. However, the grip strength was only modestly related to disease duration. This report will shed light on the Japanese national DM registry, which has recruited a significant number of patients. The registry will provide invaluable data for planning clinical trials and improving the standard of care for patients.

Independent distribution between tauopathy secondary to subacute sclerotic panencephalitis and measles virus: An immunohistochemical analysis in autopsy cases including cases treated with aggressive antiviral therapies.

Subacute sclerotic panencephalitis (SSPE) is a refractory neurological disorder after exposure to measles virus. Recently, SSPE cases have been treated with antiviral therapies, but data on the efficacy are inconclusive. Abnormal tau accumulation has been reported in the brain tissue of SSPE cases, but there are few reports in which this is amply discussed. Five autopsied cases diagnosed as definite SSPE were included in this study. The subject age or disease duration ranged from 7.6 to 40.9 years old or from 0.5 to 20.8 years, respectively. Cases 3 and 4 had been treated with antiviral therapies. All evaluated cases showed marked brain atrophy with cerebral ventricle dilatation; additionally, marked demyelination with fibrillary gliosis were observed in the cerebral white matter. The brainstem, cerebellum, and spinal cord were relatively preserved. Immunoreactivity (IR) against measles virus was seen in the brainstem tegmentum, neocortex, and/or limbic cortex of the untreated cases but was rarely seen in the two treated cases. Activated microglia were broadly observed from the cerebrum to the spinal cord and had no meaningful difference among cases. Neurofibrillary tangles characterized by a combination of 3- and 4-repeat tau were observed mainly in the oculomotor nuclei, locus coeruleus, and limbic cortex. IR against phosphorylated tau was seen mainly in the cingulate gyrus, oculomotor nuclei, and pontine tegmentum, and tended to be observed frequently in cases with long disease durations but also tended to decrease along with neuronal loss, as in Case 5, which had the longest disease duration. Since the distribution of phosphorylated tau was independent from that of measles virus, the tauopathy following SSPE was inferred to be the result of diffuse brain inflammation triggered by measles rather than a direct result of measles virus. Moreover, antiviral therapies seemed to suppress measles virus but not the progression of tauopathy.

Metabolome and transcriptome analysis on muscle of sporadic inclusion body myositis.

OBJECTIVE: Sporadic inclusion body myositis (sIBM) is the most common acquired myopathy in patients older than 50 years of age. sIBM is hardly responds to any immunosuppressing theraphies, and its pathophysiology remains elusive. This study aims to explore pathogenic pathways underlying sIBM and identify novel therapeutic targets using metabolomic and transcriptomic analyses. METHODS: In this retrospective observational study, we analyzed biopsied muscle samples from 14 sIBM patients and six non-diseased subjects to identify metabolic profiles. Frozen muscle samples were used to measure metabolites with cation and anion modes of capillary electrophoresis time of flight mass spectrometry. We validated the metabolic pathway altered in muscles of sIBM patients through RNA sequencing and histopathological studies. RESULTS: A total of 198 metabolites were identified. Metabolomic and transcriptomic analyses identified specific metabolite changes in sIBM muscle samples. The pathways of histamine biosynthesis and certain glycosaminoglycan biosynthesis were upregulated in sIBM patients, whereas those of carnitine metabolism and creatine metabolism were downregulated. Histopathological examination showed infiltration of mast cells and deposition of chondroitin sulfate in skeletal muscle samples, supporting the results of metabolomic and transcriptomic analyses. INTERPRETATION: We identified alterations of several metabolic pathways in muscle samples of sIBM patients. These results suggest that mast cells, chondroitin sulfate biosynthesis, carnitine, and creatine play roles in sIBM pathophysiology.

Early immunological responses to the mRNA SARS-CoV-2 vaccine in patients with neuromuscular disorders.

Backgrounds: Intramuscular injection of the SARS-CoV-2 vaccine has raised concerns about its use in patients with neuromuscular disorders (NMDs). We evaluated the response of patients with NMDs to the BNT162b2 vaccine. Methods: Healthy subjects, patients with spinal muscular atrophy (SMA), and patients with Duchenne muscular dystrophy (DMD) were included. All participants received two BNT162b2 doses. SARS-CoV-2 antibody titers at baseline and 2 weeks after each vaccination were compared between groups. Residual muscle volume was evaluated in NMDs group. A questionnaire documented adverse reactions. Results: Eleven patients with NMDs (9 with SMA, 2 with DMD; 7 males; aged 32.7 ± 19.3 years) and 346 healthy subjects (60 males, aged 40.0 ± 12.4 years) were included. Antibody titers (U/mL) were similar between groups (baseline: <0.40 vs. <0.40, first vaccination, 145 ± 258 vs. 103 ± 1192, and second vaccination, 1528 ± 1265 vs. 1429 ± 944; p = 1.000, 0.909, and 0.736, respectively). A negative correlation was found between antibody titers and residual muscle volume but was not significant (Mercuri scale, r = -0.429, p = 0.249; fat infiltration rate, r = -0.194, p = 0.618). The adverse reactions were comparable between groups. Conclusion: The BNT162b2 vaccine is safe and effective in patients with NMDs.

Clinical implication of denervation in sporadic inclusion body myositis.

INTRODUCTION: Sporadic inclusion body myositis (sIBM) is often accompanied by signs suggestive of denervation on electromyography (EMG), which mimics neurogenic disorders. Hence, the current study aimed to assess reinnervation after denervation in sIBM and its clinical impllcation. METHODS: We retrospectively examined consecutive muscle biopsy specimens collected from 109 sIBM patients who were referred to our institution for diagnostic muscle biopsy from 2001 to 2018. Reinnervation after denervation in sIBM patients was assessed via muscle biopsy and EMG. The levels of acetylcholine receptor subunit γ (Chrng) and muscle-specific kinase (MuSK) mRNA, which are markers of denervation, were examined using real-time polymerase chain reaction. Response to treatment was defined as an increase of grade 1 or higher in two or more muscle groups as assessed using the Medical Research Council scale. RESULTS: In total, 93 (85.3%) of 109 sIBM patients had reinnervation after denervation on histological examination and/or EMG. The mean disease duration before biopsy was significantly longer in patients with reinnervation after denervation than in those without (p < 0.00001). Patients with denervation had significantly higher levels of Chrng and MuSK mRNA than those without. The proportion of patients who responded to immunosuppressive therapies was smaller in the patients with denervation than those without (p < 0.05). However, there was no significant difference regarding time from onset to using a walking aid between the two groups. DISCUSSION: Reinnervation after denervation is associated with disease duration and short-term response to therapy in individuals with sIBM.

Tranilast for advanced heart failure in patients with muscular dystrophy: a single-arm, open-label, multicenter study.

BACKGROUND: The transient receptor potential cation channel subfamily V member 2 (TRPV2) is a stretch-sensitive calcium channel. TRPV2 overexpression in the sarcolemma of skeletal and cardiac myocytes causes calcium influx into the cytoplasm, which triggers myocyte degeneration. In animal models of cardiomyopathy and muscular dystrophy (MD), TRPV2 inhibition was effective against heart failure and motor function. Our previous pilot study showed that tranilast, a TRPV2 inhibitor, reduced brain natriuretic peptide (BNP) levels in two MD patients with advanced heart failure. Thus, this single-arm, open-label, multicenter study aimed to evaluate the safety and efficacy of tranilast for heart failure. METHODS: The study enrolled MD patients with advanced heart failure whose serum BNP levels were > 100 pg/mL despite receiving standard cardioprotective therapy. Tranilast was administered orally at 100 mg, thrice daily. The primary endpoint was the change in log (BNP) (Δlog [BNP]) at 6 months from baseline. The null hypothesis was determined based on a previous multicenter study of carvedilol results in a mean population Δlog (BNP) of 0.18. TRPV2 expression on peripheral blood mononuclear cell surface, cardiac events, total mortality, left ventricular fractional shortening, human atrial natriuretic peptide, cardiac troponin T, and creatine kinase, and pinch strength were also assessed. RESULTS: Because of the poor general condition of many patients, only 18 of 34 patients were included and 13 patients could be treated according to the protocol throughout the 6-month period. However, there were no serious adverse events related to tranilast except diarrhea, a known adverse effect, and the drug was administered safely. TRPV2 expression on the mononuclear cell surface was elevated at baseline and reduced after treatment. Cardiac biomarkers such as BNP, human atrial natriuretic peptide, and fractional shortening remained stable, suggesting a protective effect against the progression of heart failure. In the per protocol set group, Δlog [BNP] was - 0.2 and significantly lower than that in the null hypothesis. CONCLUSIONS: Tranilast is safe and effective in inhibiting TRPV2 expression, even in MD patients with advanced heart failure. Further trials are needed to evaluate the efficacy of tranilast in preventing myocardial damage, heart failure, motor impairment, and respiratory failure. Clinical trial registration The study was registered in the UMIN Clinical Trials Registry (UMIN-CTR: UMIN000031965, URL: http://www.umin.ac.jp/ctr/ ) [March 30, 2018] and the Japan Registry of Clinical Trials (jRCT, registration number: jRCTs031180038, URL: https://jrct.niph.go.jp/ ) [November 12, 2021]. Patient registration was started in December 19, 2018.

Actin-binding protein filamin-A drives tau aggregation and contributes to progressive supranuclear palsy pathology.

While amyloid-ß lies upstream of tau pathology in Alzheimer's disease, key drivers for other tauopathies, including progressive supranuclear palsy (PSP), are largely unknown. Various tau mutations are known to facilitate tau aggregation, but how the nonmutated tau, which most cases with PSP share, increases its propensity to aggregate in neurons and glial cells has remained elusive. Here, we identified genetic variations and protein abundance of filamin-A in the PSP brains without tau mutations. We provided in vivo biochemical evidence that increased filamin-A levels enhance the phosphorylation and insolubility of tau through interacting actin filaments. In addition, reduction of filamin-A corrected aberrant tau levels in the culture cells from PSP cases. Moreover, transgenic mice carrying human filamin-A recapitulated tau pathology in the neurons. Our data highlight that filamin-A promotes tau aggregation, providing a potential mechanism by which filamin-A contributes to PSP pathology.