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.

A mutation in DOK7 in congenital myasthenic syndrome forms aggresome in cultured cells, and reduces DOK7 expression and MuSK phosphorylation in patient-derived iPS cells.

At the neuromuscular junction, the downstream of tyrosine kinase 7 (DOK7) enhances the phosphorylation of muscle-specific kinase (MuSK) and induces clustering of acetylcholine receptors (AChRs). We identified a patient with congenital myasthenic syndrome (CMS) with two heteroallelic mutations in DOK7, c.653-1G>C in intron 5 and c.190G>A predicting p.G64R in the pleckstrin homology domain. iPS cells established from the patient (CMS-iPSCs) showed that c.653-1G>C caused in-frame skipping of exon 6 (120 bp) and frame-shifting activation of a cryptic splice site deleting seven nucleotides in exon 6. p.G64R reduced the expression of DOK7 to 10% of wild-type DOK7, and markedly compromised AChR clustering in transfected C2C12 myotubes. p.G64R-DOK7 made insoluble aggresomes at the juxtanuclear region in transfected C2C12 myoblasts and COS7 cells, which were co-localized with molecules in the autophagosome system. A protease inhibitor MG132 reduced the soluble fraction of p.G64R-DOK7 and enhanced the aggresome formation of p.G64R-DOK7. To match the differentiation levels between patient-derived and control induced pluripotent stem cells (iPSCs), we corrected c.190G>A (p.G64R) by CRISPR/Cas9 to make isogenic iPSCs while retaining c.653-1G>C (CMS-iPSCsCas9). Myogenically differentiated CMS-iPSCs showed juxtanuclear aggregates of DOK7, reduced expression of endogenous DOK7 and reduced phosphorylation of endogenous MuSK. Another mutation, p.T77M, also made aggresome to a less extent compared with p.G64R in transfected COS7 cells. These results suggest that p.G64R-DOK7 makes aggresomes in cultured cells and is likely to compromise MuSK phosphorylation for AChR clustering.

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.

RNA-seq analysis, targeted long-read sequencing and in silico prediction to unravel pathogenic intronic events and complicated splicing abnormalities in dystrophinopathy.

Dystrophinopathy is caused by alterations in DMD. Approximately 1% of patients remain genetically undiagnosed, because intronic variations are not detected by standard methods. Here, we combined laboratory and in silico analyses to identify disease-causing genomic variants in genetically undiagnosed patients and determine the regulatory mechanisms underlying abnormal DMD transcript generation. DMD transcripts from 20 genetically undiagnosed dystrophinopathy patients in whom no exon variants were identified, despite dystrophin deficiency on muscle biopsy, were analyzed by transcriptome sequencing. Genome sequencing captured intronic variants and their effects were interpreted using in silico tools. Targeted long-read sequencing was applied in cases with suspected structural genomic abnormalities. Abnormal DMD transcripts were detected in 19 of 20 cases; Exonization of intronic sequences in 15 cases, exon skipping in one case, aberrantly spliced and polyadenylated transcripts in two cases and transcription termination in one case. Intronic single nucleotide variants, chromosomal rearrangements and nucleotide repeat expansion were identified in DMD gene as pathogenic causes of transcript alteration. Our combined analysis approach successfully identified pathogenic events. Detection of diseasing-causing mechanisms in DMD transcripts could inform the therapeutic options for patients with dystrophinopathy.

COVID-19-related discrimination, PTSD symptoms, and psychological distress in healthcare workers.

To date, little effort has been made to examine if frontline workers who deal with COVID-19 patients are more likely to experience discrimination than second-line workers. Also, little information has appeared on how COVID-19-related discrimination affects PTSD symptoms in healthcare workers. We aimed to examine the association between COVID-19-related discrimination and frontline worker status. We further aimed to examine how COVID-19-related discrimination was associated with PTSD symptoms and psychological distress. We studied 647 healthcare workers. For the association between COVID-19-related discrimination and frontline worker status, we conducted multivariable logistic regression adjusting for age, sex and living alone. For the association of COVID-19-related discrimination with PTSD symptoms and psychological distress, we performed multivariable regression using hierarchical adjustments for age, sex, living alone, alcohol consumption, exercise and frontline worker status. Bias-corrected and accelerated bootstrap confidence intervals (CIs) were used. A total of 136 individuals worked on the frontline and the largest group were nurses (n = 81, 59.6%). Frontline workers had increased odds of COVID-19-related discrimination compared with second-line workers (odds ratio = 2.60, 95% CI = 1.37-4.96). COVID-19-related discrimination was associated with PTSD symptoms and psychological distress even at the highest level of adjustment (ß = 0.67, 95% CI = 0.10-1.23; ß = 2.43, 95% CI = 0.91-3.95, respectively). Frontline workers are more likely to experience COVID-19-related discrimination than second-line workers. Such discrimination may result in PTSD symptoms and psychological distress. Interventions to prevent COVID-19-related discrimination against healthcare workers, for example anti-discrimination campaigns, are important.

Establishment of a Triple Quadrupole HPLC-MS Quantitation Method for Dystrophin Protein in Mouse and Human Skeletal Muscle.

Duchenne muscular dystrophy (DMD) is the most common type of neuromuscular disease caused by mutations in the DMD gene encoding dystrophin protein. To quantitively assess human dystrophin protein in muscle biopsy samples, it is imperative to consistently detect as low as 0.003% of the dystrophin protein relative to the total muscle protein content. The quantitation of dystrophin protein has traditionally been conducted using semiquantitative immunoblotting or immunohistochemistry; however, there is a growing need to establish a more precise quantitative method by employing liquid chromatography-mass spectrometry (LC-MS) to measure dystrophin protein. In this study, a novel quantification method was established using a mouse experiment platform applied to the clinical quantification of human dystrophin protein. The method using a spike-in approach with a triple quadrupole LC-MS quantitated the amount of dystrophin in wild-type and human DMD transgenic mice but not in DMD-null mice. In conclusion, we established a quantitating method of dystrophin using HPLC-LC-MS with a novel spike-in approach. These results indicate that our methodology could be applied to several LC-MS devices to enable the accurate measurement of dystrophin protein in patients with DMD.

Genetic and clinical landscape of childhood cerebellar hypoplasia and atrophy.

PURPOSE: Cerebellar hypoplasia and atrophy (CBHA) in children is an extremely heterogeneous group of disorders, but few comprehensive genetic studies have been reported. Comprehensive genetic analysis of CBHA patients may help differentiating atrophy and hypoplasia and potentially improve their prognostic aspects. METHODS: Patients with CBHA in 176 families were genetically examined using exome sequencing. Patients with disease-causing variants were clinically evaluated. RESULTS: Disease-causing variants were identified in 96 of the 176 families (54.5%). After excluding 6 families, 48 patients from 42 families were categorized as having syndromic associations with CBHA, whereas the remaining 51 patients from 48 families had isolated CBHA. In 51 patients, 26 aberrant genes were identified, of which, 20 (76.9%) caused disease in 1 family each. The most prevalent genes were CACNA1A, ITPR1, and KIF1A. Of the 26 aberrant genes, 21 and 1 were functionally annotated to atrophy and hypoplasia, respectively. CBHA+S was more clinically severe than CBHA-S. Notably, ARG1 and FOLR1 variants were identified in 2 families, leading to medical treatments. CONCLUSION: A wide genetic and clinical diversity of CBHA was revealed through exome sequencing in this cohort, which highlights the importance of comprehensive genetic analyses. Furthermore, molecular-based treatment was available for 2 families.

Determining neurodevelopmental manifestations in Duchenne muscular dystrophy using a battery of brief tests.

OBJECTIVE: We report neurodevelopmental manifestations in boys with Duchenne muscular dystrophy (DMD) and evaluate the correlations between mutation location and three neurodevelopmental abnormalities: intellectual disability, autism spectrum disorder, and attentional problems. METHODS: This cross-sectional study included 55 Japanese boys with genetically confirmed DMD who visited the outpatient department of the National Center for Psychiatry and Neurology of Japan from October 2017 to April 2018. Neurodevelopmental manifestations were evaluated using the Raven's Colored Progressive Matrices (RCPM), the Parent-Interview Autism Spectrum Disorder Rating Scale-Text Revision (PARS-TR), and the Attention-Deficit Hyperactivity Disorder-Rating Scale. RESULTS: Among the 55 boys (mean [standard deviation, SD] age, 9.5 [1.6] years), 24 (43.6%) scored below -2.0 SD in RCPM, indicating intellectual disability. Further, 83% had DMD variants in exon 45 or downstream to it (P = 0.005). On the PARS-TR, 30 (55%) and 21 boys (38%) scored higher than the clinical cutoff score in childhood and present scores, respectively. Stereotyped behavior and restricted interests scores were found to decrease with age (P = 0.003 and P = 0.01, respectively). DISCUSSION: The results show that boys with DMD who have intellectual disability commonly have DMD variants in exon 45 or downstream to it. Stereotyped behavior and restricted interests improved with age, while intellectual disability did not. CONCLUSION: Understanding these characteristics of neurodevelopmental disability may reduce risky behaviors and improve the overall quality of life of patients with DMD.

FKRP mutations cause congenital muscular dystrophy 1C and limb-girdle muscular dystrophy 2I in Asian patients.

Mutation in the fukutin-related protein (FKRP) gene causes alpha-dystroglycanopathies, a group of autosomal recessive disorders associated with defective glycosylated alpha-dystroglycan (α-DG). The disease phenotype shows a broad spectrum, from the most severe congenital form involving brain and eye anomalies to milder limb-girdle form. FKRP-related alpha-dystroglycanopathies are common in European countries. However, a limited number of patients have been reported in Asian countries. Here, we presented the clinical, pathological, and genetic findings of nine patients with FKRP mutations identified at a single muscle repository center in Japan. Three and six patients were diagnosed with congenital muscular dystrophy type 1C and limb-girdle muscular dystrophy 2I, respectively. None of our Asian patients showed the most severe form of alpha-dystroglycanopathy. While all patients showed a reduction in glycosylated α-DG levels, to variable degrees, these levels did not correlate to clinical severity. Fifteen distinct pathogenic mutations were identified in our cohort, including five novel mutations. Unlike in the populations belonging to European countries, no common mutation was found in our cohort.