•We report a Japanese patient with myoglobinopathy, a rare myopathy.•First reported case of facial muscle weakness in a patient with myoglobinopathy.•Cardiopulmonary failure, dysarthria, and ...dysphagia associated with myoglobinopathy.•Our patient had muscle atrophy of the tongue, finger flexors (late onset), and legs.•Patient had older age at onset and slower course of myoglobinopathy.
Myoglobinopathy is a rare autosomal dominant myopathy that manifests in adulthood with proximal and axial weakness and variable respiratory and cardiac failure. Muscle pathology features associated with myoglobinopathy include characteristic sarcoplasmic bodies in skeletal and cardiac muscles. Here we present the first case of myoglobinopathy in an Asian individual. Although myoglobinopathy patients were reported not to have facial muscle weakness, our patient had orbicularis oculi muscle weakness, tongue weakness and atrophy, poor movement of the soft palate, and dysarthria. This is also the first reported case of tube feeding in a patient with myoglobinopathy. The patient started NPPV 18 years after onset, indicating that an older age of onset may have resulted in slow disease progression. Muscle selectivity, characteristic muscle pathology, and progressive cardiopulmonary dysfunction and dysphagia are hallmarks of this disease.
Epigenetic mechanisms regulate muscle mass and function in models of muscle dysfunction and atrophy. We assessed whether quadriceps muscle weakness and atrophy are associated with a differential ...expression profile of epigenetic events in patients with advanced COPD (chronic obstructive pulmonary disease). In vastus lateralis (VL) of sedentary severe COPD patients (n=41), who were further subdivided into those with (n=25) and without (n=16) muscle weakness and healthy controls (n=19), expression of muscle-enriched miRNAs, histone acetyltransferases (HATs) and deacetylases (HDACs), growth and atrophy signalling markers, total protein and histone acetylation, transcription factors, small ubiquitin-related modifier (SUMO) ligases and muscle structure were explored. All subjects were clinically evaluated. Compared with controls, in VL of all COPD together and in muscle-weakness patients, expression of miR-1, miR-206 and miR-27a, levels of lysine-acetylated proteins and histones and acetylated histone 3 were increased, whereas expression of HDAC3, HDAC4, sirtuin-1 (SIRT-1), IGF-1 (insulin-like growth factor-1) were decreased, Akt (v-akt murine thymoma viral oncogene homologue 1) expression did not differ, follistatin expression was greater, whereas myostatin expression was lower, serum reponse factor (SRF) expression was increased and fibre size of fast-twitch fibres was significantly reduced. In VL of severe COPD patients with muscle weakness and atrophy, epigenetic events regulate muscle differentiation rather than proliferation and muscle growth and atrophy signalling, probably as feedback mechanisms to prevent those muscles from undergoing further atrophy. Lysine-hyperacetylation of histones may drive enhanced protein catabolism in those muscles. These findings may help design novel therapeutic strategies (enhancers of miRNAs promoting myogenesis and acetylation inhibitors) to selectively target muscle weakness and atrophy in severe COPD.
Pseudoparalysis remains one of the most challenging conditions in shoulder surgery. Long thought of as an unsolvable problem, recent advances in surgical techniques offer potential return of overhead ...motion in the setting of massive irreparable rotator cuff tears. This article summarizes the available literature including existing definitions and the results of different treatment approaches regarding range of motion, outcome scores, and reversal.
In accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, a systematic review of the MEDLINE database, Cochrane database, Physiotherapy Evidence Database, and Google Scholar database was performed for studies that defined a preoperative shoulder group as having pseudoparalysis. A secondary search included preoperative active forward elevation less than 90°.
In 16 studies, the most consistent definition was a massive rotator cuff tear with active elevation less than 90°, but studies inconsistently included stiffness, external rotation loss, arthritic changes, neurologic status, and pain. There were 6 different techniques: nonoperative rehabilitation, rotator cuff repair, muscle transfer, hemiarthroplasty, reverse total shoulder arthroplasty, and reverse total shoulder arthroplasty with muscle transfer. Postoperatively, all approaches showed improvement.
Pseudoparalysis of the shoulder has a variable definition in the literature without consideration of degree or substratification of other confounders such as the presence of arthritis or pain. Thus the literature supports treating this condition with any variety of treatment. We propose that pseudoparalysis be more restrictively defined to allow comparisons. In addition, we propose an algorithm to serve as a treatment guideline to aid in surgical decision making for this condition.
Pathogenic alterations in the DPM2 gene have been previously described in patients with hypotonia, progressive muscle weakness, absent psychomotor development, intractable seizures, and early death. ...We identified biallelic DPM2 variants in a 23-year-old male with truncal hypotonia, hypertonicity, congenital heart defects, intellectual disability, and generalized muscle wasting. His clinical presentation was much less severe than that of the three previously described patients. This is the second report on this ultra-rare disorder. Here we review the characteristics of previously reported individuals with a defect in the DPM complex while expanding the clinical phenotype of DPM2-Congenital Disorders of Glycosylation. In addition, we offer further insights into the pathomechanism of DPM2-CDG disorder by introducing glycomics and lipidomics analysis.
We describe a long-term observational study of a large cohort of patients with sporadic inclusion body myositis and propose a sporadic inclusion body myositis weakness composite index that is easy to ...perform during a clinic. Data collection from two groups of patients (Paris and Oxford) was completed either during a clinic visit (52%), or by extraction from previous medical records (48%). One hundred and thirty-six patients 57% males, 61 (interquartile range 55-69) years at onset were included. At the last visit all patients had muscle weakness (proximal British Medical Research Council scale <3/5 in 48%, distal British Medical Research Council scale <3/5 in 40%, swallowing problems in 46%). During their follow-up, 75% of patients had significant walking difficulties and 37% used a wheelchair (after a median duration from onset of 14 years). The sporadic inclusion body myositis weakness composite index, which correlated with grip strength (correlation coefficient: 0.47; P < 0.001) and Rivermead Mobility Index (correlation coefficient: 0.85; P < 0.001), decreased significantly with disease duration (correlation coefficient: −0.47; P < 0.001). The risk of death was only influenced by older age at onset of first symptoms. Seventy-one (52%) patients received immunosuppressive treatments prednisone in 91.5%, associated (in 64.8%) with other immunomodulatory drugs (intravenous immunoglobulins, methotrexate or azathioprine) for a median duration of 40.8 months. At the last assessment, patients who had been treated were more severely affected on disability scales (Walton P = 0.007, Rivermead Mobility Index P = 0.004) and on the sporadic inclusion body myositis weakness composite index (P = 0.04). The first stage of disease progression towards handicap for walking was more rapid among patients receiving immunosuppressive treatments (hazard ratio = 2.0, P = 0.002). This study confirms that sporadic inclusion body myositis is slowly progressive but not lethal and that immunosuppressive treatments do not ameliorate its natural course, thus confirming findings from smaller studies. Furthermore, our findings suggest that immunosuppressant drug therapy could have modestly exacerbated progression of disability. The sporadic inclusion body myositis weakness composite index might be a valuable outcome measure for future clinical trials, but requires further assessment and validation.
Distal hereditary motor neuropathies (HMNs) and axonal Charcot-Marie-Tooth neuropathy (CMT2) are clinically and genetically heterogeneous diseases characterized primarily by motor neuron degeneration ...and distal weakness. The genetic cause for about half of the individuals affected by HMN/CMT2 remains unknown. Here, we report the identification of pathogenic variants in GBF1 (Golgi brefeldin A-resistant guanine nucleotide exchange factor 1) in four unrelated families with individuals affected by sporadic or dominant HMN/CMT2. Genomic sequencing analyses in seven affected individuals uncovered four distinct heterozygous GBF1 variants, two of which occurred de novo. Other known HMN/CMT2-implicated genes were excluded. Affected individuals show HMN/CMT2 with slowly progressive distal muscle weakness and musculoskeletal deformities. Electrophysiological studies confirmed axonal damage with chronic neurogenic changes. Three individuals had additional distal sensory loss. GBF1 encodes a guanine-nucleotide exchange factor that facilitates the activation of members of the ARF (ADP-ribosylation factor) family of small GTPases. GBF1 is mainly involved in the formation of coatomer protein complex (COPI) vesicles, maintenance and function of the Golgi apparatus, and mitochondria migration and positioning. We demonstrate that GBF1 is present in mouse spinal cord and muscle tissues and is particularly abundant in neuropathologically relevant sites, such as the motor neuron and the growth cone. Consistent with the described role of GBF1 in Golgi function and maintenance, we observed marked increase in Golgi fragmentation in primary fibroblasts derived from all affected individuals in this study. Our results not only reinforce the existing link between Golgi fragmentation and neurodegeneration but also demonstrate that pathogenic variants in GBF1 are associated with HMN/CMT2.
ICU-acquired weakness (ICUAW) occurs with reported incidence rates from 25% to 100%. Risk factors include immobility, sepsis, persistent systemic inflammation, multiorgan system failure, ...hyperglycemia, glucocorticoids, and neuromuscular blocking agents. The pathophysiology remains unknown. Clinical features may be neuropathic, myopathic, or a combination of both. Although manual muscle testing is more practical in diagnosing ICUAW, the "gold standard" for the diagnosis of ICUAW remains electromyography and nerve conduction studies. The only potential interventions known to date to prevent ICUAW include insulin therapy and early rehabilitation, but patients still may develop activity limitations in the acute care hospital. For these patients, rehabilitation may continue in long-term care hospitals, inpatient rehabilitation facilities, or skilled nursing facilities. ICUAW is a catastrophic and debilitating condition that potentially leaves patients with permanent residual activity limitations and participation restrictions. Further research on ICUAW needs to better understand its pathophysiology so that more definitive preventive and therapeutic interventions may be developed.
Dermatomyositis (DM) is an autoimmune disease associated with enhanced type I interferon (IFN) signalling in skeletal muscle, but the mechanisms underlying muscle dysfunction and inflammation ...perpetuation remain unknown. Transcriptomic analysis of early untreated DM muscles revealed that the main cluster of down-regulated genes was mitochondria-related. Histochemical, electron microscopy, and in situ oxygraphy analysis showed mitochondrial abnormalities, including increased reactive oxygen species (ROS) production and decreased respiration, which was correlated with low exercise capacities and a type I IFN signature. Moreover, IFN-β induced ROS production in human myotubes was found to contribute to mitochondrial malfunctions. Importantly, the ROS scavenger
N
-acetyl cysteine (NAC) prevented mitochondrial dysfunctions, type I IFN-stimulated transcript levels, inflammatory cell infiltrate, and muscle weakness in an experimental autoimmune myositis mouse model. Thus, these data highlight a central role of mitochondria and ROS in DM. Mitochondrial dysfunctions, mediated by IFN-β induced-ROS, contribute to poor exercise capacity. In addition, mitochondrial dysfunctions increase ROS production that drive type I IFN-inducible gene expression and muscle inflammation, and may thus self-sustain the disease. Given that current DM treatments only induce partial recovery and expose to serious adverse events (including muscular toxicity), protecting mitochondria from dysfunctions may open new therapeutic avenues for DM.
Respiratory muscle dysfunction may develop rapidly in critically ill ventilated patients and is associated with increased morbidity, length of intensive care unit stay, costs, and mortality. This ...review briefly discusses the pathophysiology of respiratory muscle dysfunction in intensive care unit patients and then focuses on strategies that prevent the development of muscle weakness or, if weakness has developed, how respiratory muscle function may be improved. We propose a simple strategy for how these can be implemented in clinical care.
The purpose of this paper is to review the incidence of upper-body morbidity (arm and breast symptoms, impairments, and lymphedema), methods for diagnosis, and prevention and treatment strategies. It ...was also the purpose to highlight the evidence base for integration of prospective surveillance for upper-body morbidity within standard clinical care of women with breast cancer. Between 10% and 64% of women report upper-body symptoms between 6 months and 3 years after breast cancer, and approximately 20% develop lymphedema. Symptoms remain common into longer-term survivorship, and although lymphedema may be transient for some, those who present with mild lymphedema are at increased risk of developing moderate to severe lymphedema. The etiology of morbidity seems to be multifactorial, with the most consistent risk factors being those associated with extent of treatment. However, known risk factors cannot reliably distinguish between those who will and will not develop upper-body morbidity. Upper-body morbidity may be treatable with physical therapy. There is also evidence in support of integrating regular surveillance for upper-body morbidity into the routine care provided to women with breast cancer, with early diagnosis potentially contributing to more effective management and prevention of progression of these conditions.
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