Explore the vast range of titles available.

Background and objectives Oculopharyngodistal myopathy (OPDM) is an autosomal dominant myopathy clinically characterized by distal muscle weakness. Even though the identification of four causative genes, LRP12 , GIPC1 , NOTCH2NLC and RILPL1 , it is unclear whether the myopathy progressed similarly among OPDM subtypes. We aimed to establish diagnostic clues in muscle imaging of OPDM in comparison with clinicopathologically similar oculopharyngeal muscular dystrophy (OPMD). Methods Axial muscle CT and/or T1-weighted MRI data from 54 genetically confirmed patients with OPDM (OPDM_LRP12; n = 43, OPDM_GIPC1; n = 6, OPDM_NOTCH2NLC; n = 5) and 57 with OPMD were evaluated. We scored the degree of fat infiltration in each muscle by modified Mercuri score and performed hierarchical clustering analyses to classify the patients and infer the pattern of involvement on progression. Results All OPDM subtypes showed a similar pattern of distribution in the affected muscles; soleus and medial gastrocnemius involved in the early stage, followed by tibialis anterior and extensor digitorum longus. For differentiating OPDM and OPMD, severely affected gluteus medius/minimus and adductor magnus was indicative of OPMD. Discussion We identified a diagnostic muscle involvement pattern in OPDM reflecting its natural history. The results of this study will help in the appropriate intervention based on the diagnosis of OPDM, including its stage.

ObjectiveTo determine the prevalence and characteristics of the cricopharyngeal bar (CPB), defined as marked protrusion with lacking relaxation and stricture of the upper esophageal sphincter on videofluoroscopy, in patients with inclusion body myositis (IBM).MethodsWe conducted a case–control study of comprehensive series of adult healthy individuals and consecutive patients with neuropsychiatric disorders aged over 45 (52 versus 2486). A standard videofluoroscopy was performed.ResultsOverall, 47 individuals with CPB were identified. Of the individuals with CPB, 36% were IBM followed by neurodegenerative disorders, muscular disorders, neuromuscular disorders, and others (32%, 21%, 2.1%, and 8.5%, respectively), indicating the heterogeneity of the etiologies. Against muscular disorders, the sensitivity and specificity of the CPB for IBM were 33% (= 17/52; 95% confidence interval [CI], 20–45%) and 96% (= 264/274; 95% CI, 94–99%), respectively. IBM with CPB showed a higher frequency of obstruction-related dysphagia (88% versus 22%, p < 0.001) and severe CPB (76% versus 23%, p < 0.001) than the control with one. The ratio of the upper esophageal distance at the maximum distension at the level of C6 to that of C4 was lower in IBM with CPB than in the controls with one (0.50 versus 0.77, p < 0.001), which suggests the insufficient opening of the upper esophageal sphincter.ConclusionA CPB could be indicative of IBM. The upper esophagus in IBM with CPB became narrow, like a bottleneck. We provide new perspectives of dysphagia diagnosis by videofluoroscopy, especially for IBM-associated dysphagia, to expand the knowledge on the CPB.

Background Water T2 (T2H2O) mapping is increasingly being used in muscular dystrophies to assess active muscle damage. It has been suggested as a surrogate outcome measure for clinical trials. Here, we investigated the prognostic utility of T2H2O to identify changes in muscle function over time in limb girdle muscular dystrophies. Methods Patients with genetically confirmed dysferlinopathy were assessed as part of the Jain Foundation Clinical Outcomes Study in dysferlinopathy. The cohort included 18 patients from two sites, both equipped with 3‐tesla magnetic resonance imaging (MRI) systems from the same vendor. T2H2O value was defined as higher or lower than the median in each muscle bilaterally. The degree of deterioration on four functional tests over 3 years was assessed in a linear model against covariates of high or low T2H2O at baseline, age, disease duration, and baseline function. Results A higher T2H2O at baseline significantly correlated with a greater decline on functional tests in 21 out of 35 muscles and was never associated with slower decline. Higher baseline T2H2O in adductor magnus, vastus intermedius, vastus lateralis, and vastus medialis were the most sensitive, being associated bilaterally with greater decline in multiple timed tests. Patients with a higher than median baseline T2H2O (>40.6 ms) in the right vastus medialis deteriorated 11 points more on the North Star Ambulatory Assessment for Dysferlinopathy and lost an additional 86 m on the 6‐min walk than those with a lower T2H2O (<40.6 ms). Optimum sensitivity and specificity thresholds for predicting decline were 39.0 ms in adductor magnus and vastus intermedius, 40.0 ms in vastus medialis, and 40.5 ms in vastus lateralis from different sites equipped with different MRI systems. Conclusions In dysferlinopathy, T2H2O did not correlate with current functional ability. However, T2H2O at baseline was higher in patients who worsened more rapidly on functional tests. This suggests that inter‐patient differences in functional decline over time may be, in part, explained by different severities of the active muscle damage, assessed by T2H2O measure at baseline. Significant challenges remain in standardizing T2H2O values across sites to allow determining globally applicable thresholds. The results from the present work are encouraging and suggest that T2H2O could be used to improve prognostication, patient selection, and disease modelling for clinical trials.

Background Limb–girdle muscular dystrophy (MD) type R2 (LGMDR2, formerly LGMD2B) is an autosomal recessive form of MD caused by variants in the dysferlin gene, DYSF. It leads to slow proximal and distal muscle weakening that generally results in loss of ambulation around early adulthood but without the lethal cardiorespiratory dysfunction observed in the more severe Duchenne MD. How loss of dysferlin causes muscle fibre death is poorly understood, but recent evidence suggests a link between muscle wasting and loss of muscle cholesterol homeostasis with circulating lipoprotein abnormalities in many forms of MD. Methods Cross‐sectional circulating total cholesterol (CHOL), high‐density lipoprotein‐associated cholesterol (HDL‐C), non‐HDL‐C, creatine kinase (CK), transaminase levels and bilirubin were collected as part of the Jain Clinical Outcomes Study of Dysferlinopathy, a large multicentre LGMDR2 patient cohort (N = 188), along with ambulatory function values. Results We report that 43%, 49% and 50% of male patients were found to have abnormal circulating CHOL, HDL‐C and non‐HDL‐C levels, respectively, whereas in female patients 39%, 37% and 30% of values were in the abnormal range. Overall, 68% of the total cohort had at least one abnormal cholesterol value (78% of males and 60% of females) and 89% of male CHOL/HDL‐C ratios were in the suboptimal range (above 3.5). Although most patients were ambulant, the severity of circulating lipid abnormalities did not correlate with early loss of ambulation. Transaminase levels were lower in late‐stage LGMDR2 samples, whereas bilirubin remained unchanged, suggesting a low muscular mass rather than hepatic origin and the absence of major liver damage. Conclusions Data from the largest natural history cohort of LGMDR2 patients support the concept that dyslipidemia is a comorbidity of LGMDR2, and the causal role of cholesterol abnormalities in muscle death should be further investigated.

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.

Becker muscular dystrophy (BMD) is caused by specific mutations in the DMD gene that causes progressive muscle weakness and primarily affects skeletal and cardiac muscle. Although cardiac involvement is a significant cause of mortality in BMD, the genetic–phenotype correlation for skeletal and cardiac muscles has not been elucidated. Here, we described a 39-year-old man with BMD, who presented with subtle skeletal muscle weakness in the right leg in his 20s and underwent left ventricular restoration for severe dilated cardiomyopathy at the age of 29. He had difficulty climbing stairs after the age of 35. Neither duplication nor deletion of exons was detected by multiplex ligation-dependent probe amplification. A hemizygous c.264 + 1G>A mutation in intron 4 of the DMD was identified by next-generation sequencing. Furthermore, exon 4 skipping of the DMD was confirmed in both skeletal and cardiac muscles evaluated by reverse transcriptase PCR. Endomyocardial and skeletal muscle biopsies revealed dystrophic pathology characterized by muscle fiber atrophy and hypertrophy with a mild degree of interstitial fibrosis. Interestingly, dystrophin immunohistochemistry demonstrated patchy and faint staining of the skeletal muscle membranes but almost normal staining of the cardiac muscle membranes. Western blot analysis revealed a decreased amount of truncated dystrophin in skeletal muscle but surprisingly almost normal amount in cardiac muscle. This case indicates that BMD patients may have severe cardiac dysfunction despite preserved cardiac truncated dystrophin expression.

GNE myopathy is an autosomal recessive distal myopathy caused by loss-of-function mutations in the GNE gene, which encodes UDP-GlcNAc 2-epimerase/ManNAc kinase (GNE), a key enzyme in sialic-acid biosynthesis. By comprehensive screening of manifesting patients using a fine-mapped targeted next-generation sequencing (NGS), we identified copy number variations (CNVs) in 13 patients from 11 unrelated families. The nine unique CNVs largely vary in size from 0.3 to 72 kb. Over half of the cases carry different deletions spanning merely exon 2, which contains the 5[variant prime] untranslated region (5[variant prime]UTR) of the muscle major transcript hGNE1. Of most unique CNVs, either the telomeric or the centromeric breakpoint locates within intron 2, indicating rearrangement hotspots. Haplotype analysis suggested the existence of a founder allele with exon 2 deletion. The breakpoints for all CNVs were determined by long-range PCR and sequencing. All of the breakpoints of gross deletion/duplications reside within directly oriented pairs of Alu repeats. The results of this study firstly widen the spectra of mutations to CNVs encompassing 5[variant prime]UTR, underscoring the pivotal role of the hGNE1 transcript. Alu-mediated non-recurrent CNVs may have been overlooked in a wide variety of recessive phenotypes, especially in those associated with genomic Alu-rich genes such as GNE.

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.

Background Little is known about the social difficulties and health care needs of adult Duchenne muscular dystrophy (DMD) patients in Japan, as well as the financial and physical stress experienced by their caregivers. This study aimed to clarify the social circumstances surrounding adult DMD patients and assess the degree of involvement of family members in their care and the associated economic burden of the disorder in Japan. Methods Adult DMD patients were identified through the Registry of Muscular Dystrophy (Remudy) in Japan and invited to complete a questionnaire together with a caregiver. Data on health care use, quality of life, work status, informal care, and household expenses were collected to estimate the costs associated with DMD from social and caregiver household perspectives. Results In total, 234 (63.7%) of 367 adult DMD patients (mean age, 27.4 ± 6.0; range, 20–48 years) completed the questionnaire. Of these, 38 (21%) had developmental disorders (mental retardation, autism, and learning disorders), 57 (33%) experienced bullying in school, and 44 (77%) indicated the reason for bullying to be their physical handicap. Employment histories were noted by 72 (31%), although 23 (10%) lost their jobs mainly due to physical difficulties. Of the 234 patients, 164 (74%) lived with their relatives, and 78% of care time was supplied by family members, in particular, their mothers. The mean rate of care work provided by family members was 81%. Household income of families with an adult DMD patient was lower, whereas the rate of living with parent(s) and grandparent(s) was higher, in comparison with the general Japanese population. Conclusions Adult DMD patients in Japan experience many social difficulties from childhood up to adulthood. As adults, many DMD patients experience bullying and workplace difficulties. Families were found to provide most of the care and financial support for DMD patients. Our results suggest the need to improve public patient care systems, including financial support, to address the physical and economic burdens of care for adult DMD patients in Japan.