AAV gene therapy for Duchenne muscular dystrophy: the EMBARK phase 3 randomized trial.

Duchenne muscular dystrophy (DMD) is a rare, X-linked neuromuscular disease caused by pathogenic variants in the DMD gene that result in the absence of functional dystrophin, beginning at birth and leading to progressive impaired motor function, loss of ambulation and life-threatening cardiorespiratory complications. Delandistrogene moxeparvovec, an adeno-associated rh74-viral vector-based gene therapy, addresses absent functional dystrophin in DMD. Here the phase 3 EMBARK study aimed to assess the efficacy and safety of delandistrogene moxeparvovec in patients with DMD. Ambulatory males with DMD, ≥4 years to <8 years of age, were randomized and stratified by age group and North Star Ambulatory Assessment (NSAA) score to single-administration intravenous delandistrogene moxeparvovec (1.33 × 1014 vector genomes per kilogram; n = 63) or placebo (n = 62). At week 52, the primary endpoint, change from baseline in NSAA score, was not met (least squares mean 2.57 (delandistrogene moxeparvovec) versus 1.92 (placebo) points; between-group difference, 0.65; 95% confidence interval (CI), -0.45, 1.74; P = 0.2441). Secondary efficacy endpoints included mean micro-dystrophin expression at week 12: 34.29% (treated) versus 0.00% (placebo). Other secondary efficacy endpoints at week 52 (between-group differences (95% CI)) included: Time to Rise (-0.64 (-1.06, -0.23)), 10-meter Walk/Run (-0.42 (-0.71, -0.13)), stride velocity 95th centile (0.10 (0.00, 0.19)), 100-meter Walk/Run (-3.29 (-8.28, 1.70)), time to ascend 4 steps (-0.36 (-0.71, -0.01)), PROMIS Mobility and Upper Extremity (0.05 (-0.08, 0.19); -0.04 (-0.24, 0.17)) and number of NSAA skills gained/improved (0.19 (-0.67, 1.06)). In total, 674 adverse events were recorded with delandistrogene moxeparvovec and 514 with placebo. There were no deaths, discontinuations or clinically significant complement-mediated adverse events; 7 patients (11.1%) experienced 10 treatment-related serious adverse events. Delandistrogene moxeparvovec did not lead to a significant improvement in NSAA score at week 52. Some of the secondary endpoints numerically favored treatment, although no statistical significance can be claimed. Safety was manageable and consistent with previous delandistrogene moxeparvovec trials. ClinicalTrials.gov: NCT05096221.

Longitudinal Incidence of Kidney/Urinary Stones in Individuals With Severe Motor and Intellectual Disabilities.

OBJECTIVE AND RATIONALE: To investigate the longitudinal incidence of kidney/urinary stones in patients with severe motor and intellectual disabilities and explore health burden events in patients with stone formation. METHODS: This was a retrospective, observational study. We identified patients with severe motor and intellectual disabilities who had the following: 1) admission to our hospital wards for >10 years; 2) two or more assessments for stone formation by ultrasonography or computed tomography; and 3) absence of kidney/urinary stones in the first imaging study. The Kaplan-Meier method was used to analyze the cumulative incidence of kidney/urinary stones. Recurrent urinary tract infections, hydronephrosis, renal dysfunction, and death were identified as health burdens. RESULTS: Among the 41 patients (19 men, 22 women; median age, 28 years; range, 8-50 years), stone formation was detected in 11 (27%) patients during the observation period. The cumulative incidence rate of stone formation was 9.8% (95% confidence interval, 3.8-23.9) and 18.7% (95% confidence interval, 9.2-35.7) at five and 10 years, respectively. Death was frequently observed in patients with stone formation; six (55%) of the 11 patients with stone formation died during the follow-up period; two (15%) died among the other 30 patients without stone formation. However, only one patient with stone formation died in a renal event; the causal relationship between the stone formation and the deaths was not clarified. CONCLUSION: The longitudinal incidence of kidney/urinary stones was higher in patients with severe motor and intellectual disabilities than in the general population. Considering the difficulty of patients with severe motor and intellectual disabilities in conveying their symptoms, regular assessment of the kidney using abdominal imaging may be recommended.

The Efficacy of a Ketogenic Diet in a Case With Febrile Infection-Related Epilepsy Syndrome in the Chronic Phase: A Case Report.

Although the treatment strategy for febrile infection-related epilepsy syndrome (FIRES) is improving, current research focuses on acute management. Evidence for the management of the chronic phase is limited. We present the case of a 19-year-old woman with FIRES who showed excellent response to a ketogenic diet (KD) administered in the chronic phase. At the age of four years, she presented with new-onset super-refractory status epilepticus after a febrile episode. She was diagnosed with FIRES and had profound motor and cognitive deterioration and drug-resistant epilepsy. From the age of 17, she experienced numerous seizures that often led to status epilepticus with respiratory failure, necessitating laryngotracheal separation and nocturnal mechanical ventilation. To improve seizure control, we planned a KD for the first time 15 years after the onset of FIRES. We introduced a classic KD (ketogenic ratio, 3:1) using blended meals through gastrotomy. Two months after starting the KD, she experienced a decrease in seizure frequency and duration. Moreover, as unexpected stabilization of respiration was achieved, mechanical ventilation was stopped. Our case implies that KD may be a promising treatment option for patients with FIRES in the chronic phase, as is believed to be the case in the acute phase.

Psychological distress mediates the association between COVID-19-related discrimination and subsequent PTSD symptom severity in healthcare workers: a two-year follow-up study.

BACKGROUND: Past research has suggested a cross-sectional association between COVID-19-related discrimination and PTSD symptom severity. However, no cohort study has examined the longitudinal association that better supports causal interpretation. Also, even if such an association genuinely exists, the specific pathway remains unclear. METHODS: We conducted a two-year follow-up study, obtaining data from healthcare workers in a hospital setting. We first evaluated how COVID-19-related discrimination in 2021 was associated with subsequent PTSD symptom severity in 2023. Thereafter, we conducted causal mediation analysis to examine how this association was mediated by psychological distress in 2022, accounting for exposure-mediator interaction. Missing data were handled using random forest imputation. RESULTS: A total of 660 hospital staff were included. The fully adjusted model showed greater PTSD symptom severity in individuals who experienced any COVID-19-related discrimination compared with those without such experiences (ß, 0.44; 95% CI, 0.04-0.90). Regarding each type of discrimination, perceived discrimination was associated with greater PTSD symptom severity (ß, 0.52; 95% CI, 0.08-0.96), whereas verbal discrimination did not reach statistical significance. Psychological distress mediated 28.1%-38.8% of the observed associations. CONCLUSIONS: COVID-19-related discrimination is associated with subsequent PTSD symptom severity in healthcare workers. Psychological distress may serve as an important mediator, underscoring the potential need for interventions targeting this factor.

A novel heterozygous TMEM63A variant in a familial case with early onset nystagmus, severe hypomyelination, and a favorable adult prognosis.

Heterozygous transmembrane protein 63A (TMEM63A) variants cause transient infantile hypomyelinating leukodystrophy-19, which features remarkable natural resolution of clinical and imaging findings during childhood. Previous reports have mainly described de novo variants lacking detailed familial cases. Herein, we describe the clinical course of familial cases with a TMEM63A variant. A 5-month-old girl presented with nystagmus, global hypotonia, and difficulty swallowing since birth. Brain magnetic resonance imaging at 1.5 and 5 months revealed diffuse hypomyelination. Her mother, maternal aunt, and grandfather had nystagmus and motor developmental delays in infancy, which resolved spontaneously during childhood. Compared with these cases, the proband's motor developmental delay was profound, and she was the only one with feeding difficulties, necessitating nasogastric tube feeding. Genetic testing revealed a heterozygous TMEM63A variant (NM_014698.3:c.1658G>A, p.(Gly553Asp)) in the proband and her family. This is the first three-generation familial report of a TMEM63A variant that provides insight into its history and heterogeneity.

Steroid-Responsive Involuntary Movements as a Remote Symptom of Febrile Infection-Related Epilepsy Syndrome.

Febrile infection-related epilepsy syndrome (FIRES) is a rare epileptic encephalopathy that occurs in children or adolescents. To date, evidence for the management of the post-acute phase of FIRES is focused on drug-resistant epilepsy that continues from the acute phase. Information on involuntary movements, which are newly developed in the chronic phase, is limited. We report a 13-year-old boy, who had a history of FIRES at nine years of age and experienced worsening seizure control that was accompanied by unremitting involuntary　movements after two years of a fairly controlled period. The involuntary movements resulted in motor deterioration and forced him to be bedridden. Although no neuronal autoantibodies were detected, we hypothesized that the boy's neurological deterioration was triggered by an autoimmune response based on the elevation of serum anti-glutamic acid decarboxylase and serum anti-thyroid peroxidase antibodies and hypermetabolism of bilateral lenticular nuclei on 18-fluorodeoxyglucose positron emission tomography that resembled those reported in patients with other types of autoimmune encephalitis. Serial methylprednisolone pulse therapy and intravenous immunoglobulin therapy ameliorated involuntary movements and improved his activities of daily living. Late-onset involuntary movements, along with seizure exacerbation, may appear in the chronic phase of FIRES. Immunotherapy could be effective in treating these symptoms.

Epidemiological study on pediatric-onset dystonia in Japan: A questionnaire-based survey.

OBJECTIVE: This study aimed to investigate the clinical characteristics of pediatric-onset dystonia in Japan, addressing the diagnostic challenges arising from symptom variations and etiological diversity. METHODS: From 2020 to 2022, questionnaires were distributed to 1218 board certified child neurologists (BCCNs) by Japanese Society of Child Neurology. In the primary survey, participants were asked to report the number of patients with pediatric-onset dystonia under their care. Subsequently, the follow-up secondary survey sought additional information on the clinical characteristics of these patients. RESULTS: The primary survey obtained 550 responses (response rate: 45 %) from BCCNs for their 736 patients with dystonia. The predominant etiologies included inherited cases (with DYT10   being the most prevalent, followed by DYT5 and ATP1A3-related neurologic disorders), acquired cases (with perinatal abnormalities being the most common), and idiopathic cases. The secondary survey provided clinical insights into 308 cases from 82 BCCNs. Infancy-onset dystonia presented as persistent and generalized with diverse symptoms, primarily linked to ATP1A3-related neurologic disorders and other genetic disorders resembling acquired dystonia. Conversely, childhood/adolescent-onset dystonia showed paroxysmal, fluctuating courses, predominantly affecting limbs. The most common etiologies were DYT5 and DYT10 , leading to therapeutic diagnoses. CONCLUSION: Pediatric-onset dystonia in Japan was treated by 28 % of BCCNs. The majority of cases were inherited, with high prevalence rates of DYT5 and DYT10 . Infancy-onset dystonia exhibits diverse etiologies and symptoms, emphasizing the utility of various examinations, including genetic testing. These findings significantly contribute to our understanding of pediatric-onset dystonia in Japan, although this study has the limitation of questionnaire survey.

Treatment odyssey to epilepsy surgery in children with focal cortical dysplasia: Risk factors for delayed surgical intervention.

OBJECTIVE: To elucidate the patient's journey to epilepsy surgery and identify the risk factors contributing to surgical delay in pediatric patients with drug-resistant epilepsy (DRE) due to focal cortical dysplasia (FCD). METHODS: A retrospective review was conducted of 93 pediatric patients who underwent curative epilepsy surgery for FCD between January 2012 and March 2023 at a tertiary epilepsy center. The Odyssey plot demonstrated the treatment process before epilepsy surgery, including key milestones of epilepsy onset, first hospital visit, epilepsy diagnosis, MRI diagnosis, DRE diagnosis, and surgery. The primary outcome was surgical delay; the duration from DRE to surgery. Multivariate linear regression models were used to examine the association between surgical delay and clinical, investigative, and treatment characteristics. RESULTS: The median age at seizure onset was 1.3 years (interquartile range [IQR] 0.14-3.1), and at the time of surgery, it was 6 years (range 1-11). Notably, 46% experienced surgical delays exceeding two years. The Odyssey plot visually highlighted that surgical delay comprised a significant portion of the patient journey. Although most patients underwent MRI before referral, MRI abnormalities were identified before referral only in 39% of the prolonged group, compared to 70% of the non-prolonged group. Multivariate analyses showed that delayed notification of MRI abnormalities, longer duration from epilepsy onset to DRE, older age at onset, number of antiseizure medications tried, and moderate to severe intellectual disability were significantly associated with prolonged surgical delay. CONCLUSION: Pediatric DRE patients with FCD experienced a long journey until surgery. Early and accurate identification of MRI abnormalities is important to minimize surgical delays.

Pneumatosis Cystoides Intestinalis in Muscular Dystrophy and Congenital Myopathies: A Report of Five Cases.

Pneumatosis cystoides intestinalis (PCI) is a rare disease wherein air accumulates in the intestinal subserosa and submucosa, causing multiple gaseous cysts within the gastrointestinal wall. While PCI has various known risk factors, reports identifying muscular diseases as a factor are scarce. The aim of this study is to elucidate the clinical characteristics of PCI in muscle disease. We present a case series of five cases, including two cases of Duchenne muscular dystrophy (DMD) and three cases of rare congenital myopathies. All cases are of male patients, with poor intestinal peristalsis and constipation, who underwent tube feeding and mechanical ventilation via tracheostomy. They had no signs of severe complications, such as intestinal necrosis, and all of them improved with conservative treatment. Case 1 is a 23-year-old man with DMD who developed cardiopulmonary arrest at the age of 20 years. Pulmonary hemorrhage occurred three months before the incidental detection of PCI in the ascending colon, which resolved with conservative oxygen treatment. Case 2 is a 25-year-old man with DMD who progressed to immobility necessitating tracheostomy at the age of 20 years. He experienced persistent abdominal pain and nausea, and PCI was detected in the cecum and ascending colon. He showed near-complete resolution of PCI after three months of conservative treatment. Case 3 is a six-year-old boy with reducing body myopathy. Constipation was diagnosed at four years of age. He experienced intermittent bloody stools, leading to the incidental detection of PCI at six years of age. After two months of conservative treatment, the PCI resolved with no subsequent recurrence. Case 4 is a 33-year-old man with infantile severe myotubular myopathy. He required mechanical ventilation immediately after birth and later underwent tracheostomy and tube feeding due to complications. At the age of 27 years, PCI was incidentally detected on abdominal CT. He had episodes of remission and worsening for a few years; however, PCI completely resolved after three years. Case 5 is a 27-year-old man with nemaline myopathy. At the age of 14 years, he had persistent bloody stools. After lower gastrointestinal endoscopy, he was diagnosed with PCI with numerous rectal cysts. PCI required no specific therapeutic intervention. There was spontaneous resolution of PCI and bloody stools. Given that PCI lacks specific symptoms and cases with muscular diseases often experience abdominal issues, many cases are liable to be overlooked or misdiagnosed. Cases with muscular diseases complaining of persistent abdominal symptoms should undergo radiographic imaging to rule out PCI.

Validity of the Functional Classification of the Upper Extremities for Duchenne Muscular Dystrophy.

Objectives: Some upper-limb function assessments can evaluate treatments in the non-ambulatory stage of Duchenne muscular dystrophy (DMD). The Functional Classification of the Upper Extremities (FCUE) was developed for DMD in Japan. The FCUE is easier to use than the Performance of Upper Limb (PUL) and is more detailed than the Brooke Upper Extremity Scale. This study aimed to determine the concurrent validity of FCUE with other methods of assessment for DMD. Methods: This retrospective study reviewed the medical records of 39 boys with DMD from the National Center of Neurology and Psychiatry to evaluate the concurrent validity of the FCUE and PUL using non-parametric Spearman rank correlation (ρ). We also determined the concurrent validity of the Brooke Upper Extremity Scale and PUL for comparison. Results: The ρ value between the FCUE and PUL was -0.914 (P<0.001). The FCUE showed robust concurrent validity with the PUL. That correlation between the FCUE and Brooke Upper Extremity Scale gave a ρ value of -0.854 (P<0.001). Conclusions: The FCUE had a higher concurrent validity with the PUL than with the Brooke Upper Extremity Scale. The FCUE is considered a valid assessment tool of upper-limb function in boys with DMD. Selecting the best assessment method depends on the severity of the patient's condition and a balance between assessment accuracy and evaluation time.

Association of COVID-19 preventive behavior and job-related stress with the sleep quality of healthcare workers one year into the COVID-19 outbreak: a Japanese cross-sectional survey.

BACKGROUND: This study aimed to evaluate the association of COVID-19 preventive behavior and job-related stress with sleep quality among healthcare workers (HCWs). We conducted a cross-sectional survey using a questionnaire at the National Center of Neurology and Psychiatry, Tokyo, Japan. METHODS: A total of 586 participants who completed the questionnaire were eligible for the study. The Pittsburgh Sleep Quality Index was used to evaluate sleep quality. We examined the level of engagement between poor sleep and COVID-19-related infection preventive behaviors, such as avoiding closed spaces, crowded places, and close contact (three Cs), a distance of at least one meter from others, wearing a face mask regularly, washing hands regularly, and working remotely, as well as job-related stress in the work environment, exposure to patients, potential risk of infection, fear of infecting others, need for social confinement, and financial instability. We conducted a hierarchical logistic regression analysis to examine the relationship between poor sleep and COVID-19 preventive behavior, job-related stress, and other covariates, including age, sex, and the Kessler Psychological Distress Scale (K6), which was used to measure non-specific psychological distress. RESULTS: Poor sleep was observed in 223 (38.1%) participants. Adherence to COVID-19 preventive measures was relatively high: 84.1% of participants answered "always" for wearing a face mask regularly and 83.4% for washing hands regularly. In the multivariate logistic regression analysis, stress in the work environment (odds ratio [OR] = 2.09, 95% confidence interval [CI], 1.37-3.20; p < 0.001), financial instability (OR = 1.73, 95% CI, 1.12-2.67; p < 0.05), and low adherence to working remotely (OR = 1.65, 95% CI, 1.06-2.57; p < 0.05) were independently and significantly associated with poor sleep after controlling for the covariates. CONCLUSIONS: One year into the COVID-19 pandemic, the poor sleep rates of HCWs remained high. These results emphasize the need to protect HCWs from work environment stress and financial concerns.

Erythromycin for myotonic dystrophy type 1: a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial.

Background: Myotonic dystrophy type 1 (DM1) is a devastating multisystemic disorder caused by a CTG repeat expansion in the DMPK gene, which subsequently triggers toxic RNA expression and dysregulated splicing. In a preclinical study, we demonstrated that erythromycin reduces the toxicity of abnormal RNA and ameliorates the aberrant splicing and motor phenotype in DM1 model mice. Methods: This multicentre, randomised, double-blind, placebo-controlled, phase 2 trial was conducted at three centres in Japan to translate preclinical findings into practical applications in patients with DM1 by evaluating the safety and efficacy of erythromycin. Between Nov 29, 2019, and Jan 20, 2022, a total of 30 adult patients with DM1 were enrolled and randomly assigned in a 1:2:2 ratio to receive either placebo or erythromycin at two daily doses (500 mg or 800 mg) for 24 weeks. The primary outcome included the safety and tolerability of erythromycin. The secondary efficacy measures included splicing biomarkers, 6-min walk test results, muscle strength, and serum creatinine kinase (CK) values. This trial is registered with the Japan Registry of Clinical Trials, jRCT2051190069. Findings: Treatment-related gastrointestinal symptoms occurred more frequently in the erythromycin group, but all adverse events were mild to moderate and resolved spontaneously. No serious safety concerns were identified. The CK levels from baseline to week 24 decreased in the overall erythromycin group compared with the placebo group (mean change of -6.4 U/L [SD 149] vs +182.8 [SD 228]), although this difference was not statistically significant (p = 0.070). Statistically significant improvements in the overall erythromycin treated groups compared to placebo were seen for two of the eleven splicing biomarkers that were each evaluated in half of the trial sample. These were MBNL1 (p = 0.048) and CACNA1S (p = 0.042). Interpretation: Erythromycin demonstrated favourable safety and tolerability profiles in patients with DM1. A well-powered phase 3 trial is needed to evaluate efficacy, building on the preliminary findings from this study. Funding: Japan Agency for Medical Research and Development.

Myelin abnormalities in merosin-deficient congenital muscular dystrophy.

INTRODUCTION/AIMS: Merosin is a protein complex located in the basement membrane of skeletal muscles and laminin α2-containing regions of the central and peripheral nervous systems. However, because of the prominence of muscle-related symptoms, peripheral neuropathy associated with merosin-deficient congenital muscular dystrophy type 1A (MDC1A) has received little clinical attention. This study aimed to present pathological changes in intramuscular nerves of three patients with MDC1A and discuss their relationship with electrophysiological findings to provide new evidence of peripheral nerve involvement in MDC1A. METHODS: MDC1A was confirmed by clinical features, muscle biopsy, and genetic testing for variants in LAMA2. To clarify peripheral nerve involvement, we statistically evaluated electrophysiological and muscle pathology findings of intramuscular nerves. These findings were compared with those of age-matched boys with Duchenne muscular dystrophy (DMD) as controls with normal nerves. Nerve conduction studies (NCS) were performed before biopsy. Biopsied intramuscular nerves were examined with electron microscopy using g-ratio, which is the ratio of axon diameter to myelinated fiber diameter. RESULTS: The myelin sheaths were significantly thinner in MDC1A patients than in age-matched DMD patients, with a mean g-ratio of 0.76 ± 0.07 in MDC1A patients and 0.65 ± 0.14 in DMD patients (p < .0001). No neuropathic changes were identified in muscle pathology. Low compound muscle action potential amplitudes, positive sharp waves and fibrillation potentials, and low-amplitude motor unit potentials with increased polyphasia indicated myopathic changes; no neurogenic changes were seen. DISCUSSION: We postulate that the thin myelin associated with MDC1A reflects the role of merosin in myelin maturation.

Association between health anxiety dimensions and preventive behaviors during the COVID-19 pandemic among Japanese healthcare workers.

Objective: Health anxiety (HA), defined as excessive worry about having a serious medical condition, may affect preventive behaviors during the coronavirus disease 2019 (COVID-19) pandemic. We examined the distinct role of two dimensions of HA-perceived likelihood (probability dimension) and awfulness of illness (awfulness dimension)-in self-protection, as reflected in preventive behaviors during the pandemic. Methods: Participants comprised 657 healthcare workers. Data were collected between February 24 and 26, 2021. The Short Health Anxiety Inventory determined the HA dimensions. Adherence to the government's recommendations for COVID-19 preventive behaviors was self-rated. An independent association between each HA dimension and participants' adherence to the recommendations was examined using multivariable regression. Results: Within the analyzed sample of 560 subjects, severe HA was observed in 9.1 %. The more the participants felt awful, the less frequently they engaged in the recommended preventive behaviors (adjusted odds ratio = 0.993, 95 % confidence interval: 0.989, 0.998, p = 0.003) regardless of their profession, working position, psychological distress, sleep disturbance, and current physical diseases. However, the probability dimension was not associated with their preventive behaviors. Conclusion: The awfulness dimension of HA could be a more sensitive marker of preventive behaviors than the probability dimension. Paying particular attention to the awfulness dimension may help optimize self-protection strategies during the COVID-19 pandemic. A two-dimensional understanding of HA may be useful for the maintenance of the healthcare system and public health as well as healthcare workers' own health.

Long-term Observation in Patients with Duchenne Muscular Dystrophy with Early Introduction of a Standing Program Using Knee-ankle-foot Orthoses.

Objectives: This study investigated the outcomes of the early introduction of a standing program for patients with Duchenne muscular dystrophy (DMD). Methods: This was a retrospective observational study of 41 outpatients with DMD aged 15-20 years. We introduced the standing program using knee-ankle-foot orthoses (KAFO) to slow the progression of scoliosis when ankle dorsiflexion became less than 0° in the ambulatory period. Results: Thirty-two patients with DMD were offered the standing program with KAFO; 12 continued the program until the age of 15 years (complete group) and 20 discontinued the program before the age of 15 years (incomplete group). The non-standing program group included 9 patients. The standing program with KAFO was significantly associated with the Cobb angle at the age of 15 years after adjustment for the duration of corticosteroid use and DMD mutation type (P=0.0004). At the age of 15 years, significant correlations were found between the ankle dorsiflexion range of motion (ROM) and non-ambulatory period (P=0.0010), non-ambulatory period and Cobb angle (P<0.0001), Cobb angle and percent predicted forced vital capacity (P=0.0004), and ankle dorsiflexion ROM and Cobb angle (P=0.0066). In the complete group, the age at ambulation loss (log-rank P=0.0015), scoliosis progression (log-rank P=0.0032), and pulmonary dysfunction (log-rank P=0.0006) were significantly higher than in the non-standing program group. Conclusions: The early introduction of a standing program for DMD patients may prolong the ambulation period and slow the progression of scoliosis and pulmonary dysfunction.

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.

Factors influencing the decision to introduce alternative nutrition in patients with Duchenne muscular dystrophy.

INTRODUCTION/AIMS: Nutritional management of adults with Duchenne muscular dystrophy (DMD) is an important clinical issue. However, it is not clear which dysphagia-related factors should prompt introduction of alternative nutrition (AN). We aimed to determine which patients with DMD were introduced to AN. METHODS: This retrospective study included 56 patients with DMD (median age, 23.5 years). They were divided into patients able to continue oral feeding (OF) and those introduced to AN. Body weight, frequency of ventilator use, daily meals, history of steroid treatment, results of videofluoroscopic examination of swallowing (VF), and awareness of dysphagia were evaluated. RESULTS: Of 56 patients, 19 were in the AN group. After AN introduction, 93% of the patients continued oral intake. The proportion of patients who consumed chopped and liquid diets was higher, and body weight was lower, in the AN than in the OF group. There were no significant differences in age, upper limb function of feeding, frequency of ventilator use, or history of steroid therapy between the two groups. The frequencies of aspiration and residue in the pyriform sinus in VF were higher in the AN group than in the OF group. Decision-tree analysis showed that food form and subjective difficulty swallowing solid foods were the most important factors affecting the decision-making for AN. DISCUSSION: Patients with DMD who had difficulty eating solid foods were started on AN because they were unable to maintain their weight. These findings provide information for future longitudinal studies to assess the value of AN.

Systemic administration of the antisense oligonucleotide NS-089/NCNP-02 for skipping of exon 44 in patients with Duchenne muscular dystrophy: Study protocol for a phase I/II clinical trial.

AIM: The purpose of this study is to evaluate the safety and pharmacokinetics of the novel morpholino oligomer NS-089/NCNP-02 which can induce exon 44 skipping, in patients with DMD. Additionally, we aimed to identify markers predictive of therapeutic efficacy and determine the optimal dosing for future studies. METHODS: This is an open-label, dose-escalation, two-center phase I/II trial in ambulant patients with DMD, presence of an out-of-frame deletion, and a mutation amenable to exon 44 skipping. Part 1 is a stepwise dose-finding stage (4 weeks) during which NS-089/NCNP-02 will be administered intravenously at four dose levels once weekly (1.62, 10, 40, and 80 mg/kg); Part 2 is a 24-week evaluation period based on the dosages determined during Part 1. The primary (safety) endpoints are the results of physical examinations, vital signs, 12-lead electrocardiogram and echocardiography tests, and adverse event reporting. Secondary endpoints include expression of dystrophin protein, motor function assessment, exon 44 skipping efficiency, plasma and urinary NS-089/NCNP-02 concentrations, and changes in blood creatine kinase levels. DISCUSSION: Exon-skipping therapy using ASOs shows promise in selected patients, and this first-in-human study is expected to provide critical information for subsequent clinical development of NS-089/NCNP-02.

Muscle impairment in MRI affect variability in treatment response to nusinersen in patients with spinal muscular atrophy type 2 and 3: A retrospective cohort study.

BACKGROUND: Real-world data have shown variability in treatment responses to nusinersen in spinal muscular atrophy (SMA). We investigated whether the magnitude of muscle impairment assessed by magnetic resonance imaging (MRI) at baseline can predict the treatment response. METHODS: We retrospectively assessed the clinical data in relevance to the thigh and pelvic MRI taken before the nusinersen treatment. A total of 16 patients with SMA types 2 and 3 (age = mean [SD]; 9.2 [4.6] year) receiving nusinersen treatment were enrolled. The T1-weighted MRI images of the pelvis and thigh were scored for muscle fatty infiltration and atrophy. The minimally clinically important difference (MCID) was considered as gaining at least 3 points of Hammersmith Functional Motor Scale-Expanded (HFMSE) from baseline. RESULTS: Of these 16 individuals, 14 had been treated for at least 15 months with baseline data. At 15 months, seven individuals obtained MCID in HFMSE. Baseline muscle MRI score could not differentiate the two groups; however, individuals who obtained MCID had significantly less severe scoliosis. In addition, there was a significant and negative relationship between baseline MRI score and the change of score in HFMSE after 15 months of treatment. Further, baseline Cobb angle along with MRI score also indicated the correlation to the degree of change in motor function. CONCLUSION: The degree of muscle damage may confer the variability in response to nusinersen in SMA types 2 and 3. Muscle MRI score along with the severity of scoliosis assessed at baseline may help to predict the motor function change.