- Imaging Patterns of Muscle Atrophy. [Journal Article]
- SMSemin Musculoskelet Radiol 2018; 22(3):299-306
- The role of muscle imaging in the diagnosis of inherited and acquired muscle diseases has gained clinical relevance. In particular, magnetic resonance imaging (MRI) is increasingly being used for dia...
The role of muscle imaging in the diagnosis of inherited and acquired muscle diseases has gained clinical relevance. In particular, magnetic resonance imaging (MRI) is increasingly being used for diagnostic purposes, especially with its capability of whole-body musculature assessment. The assessment and quantification of muscle involvement in muscle diseases can be of diagnostic value by identifying a certain involvement pattern and thus narrowing the differential diagnosis and supporting the clinical diagnosis. In addition, more recently the role of imaging has gone beyond diagnostic purposes and includes disease as well as treatment monitoring. Conventional and quantitative muscle MRI techniques allow for the detection of subclinical disease progression (e.g., in muscular dystrophies) and is a powerful surrogate outcome measure in clinical trials. We present and discuss recent data on the role of conventional and quantitative MRI in the diagnosis and monitoring of inherited dystrophic muscle diseases as well as muscle denervation.
- Inflammatory myopathy in the context of an unusual overlapping laminopathy. [Journal Article]
- AEArch Endocrinol Metab 2018 May 17
- Laminopathies are genetic disorders associated with alterations in nuclear envelope proteins, known as lamins. The LMNA gene encodes lamins A and C, and LMNA mutations have been linked to diseases in...
Laminopathies are genetic disorders associated with alterations in nuclear envelope proteins, known as lamins. The LMNA gene encodes lamins A and C, and LMNA mutations have been linked to diseases involving fat (type 2 familial partial lipodystrophy [FPLD2]), muscle (type 2 Emery-Dreifuss muscular dystrophy [EDMD2], type 1B limb-girdle muscular dystrophy [LGMD1B], and dilated cardiomyopathy), nerves (type 2B1 Charcot-Marie-Tooth disease), and premature aging syndromes. Moreover, overlapping syndromes have been reported. This study aimed to determine the genetic basis of an overlapping syndrome in a patient with heart disease, myopathy, and features of lipodystrophy, combined with severe metabolic syndrome. We evaluated a 54-year-old woman with rheumatoid arthritis, chronic hypercortisolism (endogenous and exogenous), and a history of cured adrenal Cushing syndrome. The patient presented with a complex disorder, including metabolic syndrome associated with mild partial lipodystrophy (Köbberling-like); mild hypertrophic cardiomyopathy, with Wolff-Parkinson- White syndrome and atrial fibrillation; and limb-girdle inflammatory myopathy. Mutational analysis of the LMNA gene showed a heterozygous c.1634G>A (p.R545H) variant in exon 10 of LMNA. This variant has previously been independently associated with FPLD2, EDMD2, LGMD1B, and heart disease. We describe a new, LMNA-associated, complex overlapping syndrome in which fat, muscle, and cardiac disturbances are related to a p.R545H variant.
- Development of muscular dystrophy in a CRISPR-engineered mutant rabbit model with frame-disrupting ANO5 mutations. [Journal Article]
- CDCell Death Dis 2018 May 22; 9(6):609
- Limb girdle muscular dystrophy type 2L (LGMD2L) and Miyoshi myopathy type 3 (MMD3) are autosomal recessive muscular dystrophy caused by mutations in the gene encoding anoctamin-5 (ANO5), which belong...
Limb girdle muscular dystrophy type 2L (LGMD2L) and Miyoshi myopathy type 3 (MMD3) are autosomal recessive muscular dystrophy caused by mutations in the gene encoding anoctamin-5 (ANO5), which belongs to the anoctamin protein family. Two independent lines of mice with complete disruption of ANO5 transcripts did not exhibit overt muscular dystrophy phenotypes; instead, one of these mice was observed to present with some abnormality in sperm motility. In contrast, a third line of ANO5-knockout (KO) mice with residual expression of truncated ANO5 expression was reported to display defective membrane repair and very mild muscle pathology. Many of the ANO5-related patients carry point mutations or small insertions/deletions (indels) in the ANO5 gene. To more closely mimic the human ANO5 mutations, we engineered mutant ANO5 rabbits via co-injection of Cas9 mRNA and sgRNA into the zygotes. CRISPR-mediated small indels in the exon 12 and/or 13 in the mutant rabbits lead to the development of typical signs of muscular dystrophy with increased serum creatine kinase (CK), muscle necrosis, regeneration, fatty replacement and fibrosis. This novel ANO5 mutant rabbit model would be useful in studying the disease pathogenesis and therapeutic treatments for ANO5-deficient muscular dystrophy.
- Optogenetic activation of colon epithelium of the mouse produces high frequency bursting in extrinsic colon afferents and engages visceromotor responses. [Journal Article]
- JNJ Neurosci 2018 May 22
- Epithelial cells of the colon provide a vital interface between the internal environment (lumen of the colon) and colon parenchyma. To examine epithelial-neuronal signaling at this interface, we anal...
Epithelial cells of the colon provide a vital interface between the internal environment (lumen of the colon) and colon parenchyma. To examine epithelial-neuronal signaling at this interface, we analyzed mice in which channelrhodopsin (ChR2) was targeted to either TRPV1-positive afferents or to villin expressing colon epithelial cells. Expression of a ChR2-EYFP fusion protein was directed to either primary sensory neurons or to colon epithelial cells by crossing Ai32 mice with TRPV1-Cre or villin-Cre mice, respectively. An ex vivo preparation of the colon was used for single fiber analysis of colon sensory afferents of the pelvic nerve. Afferents were characterized using previously described criteria as mucosal, muscular, muscular-mucosal or serosal and then tested for blue light-induced activation. Light activation of colon epithelial cells produced robust firing of action potentials, similar to that elicited by physiologic stimulation (e.g., circumferential stretch), in 50.5% of colon afferents of mice homozygous for ChR2 expression. Light-induced activity could be reduced or abolished in most fibers using a cocktail of purinergic receptor blockers suggesting ATP release by the epithelium contributed to generation of sensory neuron action potentials. Using electromyographic (EMG) recording of visceromotor responses (VMR) we found that light stimulation of the colon epithelium evoked behavioral responses in Vil-ChR2 mice that was similar to that seen with balloon distension of the colon. These ex vivo and in vivo data indicate that light stimulation of colon epithelial cells alone, without added mechanical or chemical stimuli, can directly activate colon afferents and elicit behavioral responses.SIGNIFICANCE STATEMENTAbdominal pain that accompanies inflammatory diseases of the bowel is particularly vexing since it can occur without obvious changes in the structure or inflammatory condition of the colon. Pain reflects abnormal sensory neuron activity that may be controlled in part by release of substances from lining epithelial cells. In support of this mechanism we determined that blue light stimulation of channelrhodopsin-expressing colon epithelial cells could evoke action potential firing in sensory neurons and produce changes in measures of behavioral sensitivity. Thus, activity of colon epithelial cells alone, without added mechanical or chemical stimuli, is sufficient to activate pain-sensing neurons.
- Enzyme replacement therapy reduces the risk for wheelchair dependency in adult Pompe patients. [Journal Article]
- OJOrphanet J Rare Dis 2018 May 22; 13(1):82
- CONCLUSIONS: Our study found that ERT reduced the risk for wheelchair dependency. We could not demonstrate an effect on respiratory support.
- Genetic determinants of statin-associated myopathy. [Journal Article]
- PMPer Med 2008; 5(5):481-494
- Lipid-lowering drugs, especially 3-hydroxy-3-methylglutaryl coenzyme A inhibitors (statins), are widely used in the treatment of patients with increased risk of cardiovascular disease, with well-docu...
Lipid-lowering drugs, especially 3-hydroxy-3-methylglutaryl coenzyme A inhibitors (statins), are widely used in the treatment of patients with increased risk of cardiovascular disease, with well-documented benefits. However, in rare cases, lipid-lowering drugs may cause myopathy or rhabdomyolysis, the risk of which is increased by certain drug-drug interactions. Polymorphisms of metabolizing pathways, including CYP, and efflux transporters, such as MDR1 and SLCO1B1, may cause intersubject variability in plasma statin levels and therefore may be responsible for susceptibility to myopathy. The aim of this review is to summarize selected genetic polymorphisms that predispose to statin-related myopathy (including combined studies of myopathy and myalgia). Genome-wide studies suggest that there is a strong candidate variant within the SLCO1B1 gene (rs4149056) for statin-associated myopathy in a UK (European) population. An enhanced understanding of statin-related myopathy may lead to safer drug development and use.
- Pediatric transplantation: opportunities for pharmacogenomics and genomics. [Journal Article]
- PMPer Med 2013; 10(4):397-404
- Heterogeneity is the rule among pediatric heart transplant recipients. Patients vary in age, size, organ maturity, immune system maturity and underlying disease etiology, which can all influence post...
Heterogeneity is the rule among pediatric heart transplant recipients. Patients vary in age, size, organ maturity, immune system maturity and underlying disease etiology, which can all influence post-transplant outcomes. Overall, the survival of pediatric transplant recipients continues to improve and the goal remains long-term survival of the primary graft and mitigation of long-term complications and adverse events. The evolving fields of pharmacogenomics and genomics have the potential to revolutionize and personalize the care of pediatric transplant recipients, and although clinical validation in a pediatric cohort is lacking, many of these technologies are becoming more readily available. We discuss genotype-guided dosing of immunosuppressant medications and other commonly used medications after transplantation, the influence of donor and recipient genotype on risk of post-transplant complications, genotype-guided selection of therapies to treat complications, and the use of next-generation sequencing for noninvasive detection of graft rejection.
- S-25OHD is Associated with Hand Grip Strength and Myopathy at Five Years in Girls: An Odense Child Cohort Study. [Journal Article]
- JCJ Clin Endocrinol Metab 2018 May 16
- CONCLUSIONS: Five-year s-25OHD was independently associated with HGS and myopathy in girls, but not in boys. Muscle strength may be dependent on vitamin D status even in the higher range in preschool girls. The sex difference remains unexplained.
- A comprehensive review and meta-analysis of risk factors for statin-induced myopathy. [Review]
- EJEur J Clin Pharmacol 2018 May 22
- CONCLUSIONS: This comprehensive assessment of risk factors can help support clinicians in reducing the incidence of SIM in their patient population on statins.
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- Myopathy due to HMGCR antibodies in adult mimicking muscular dystrophy associated with cancer and statin exposure - narrative review of the literature - case report. [Journal Article]
- TCTher Clin Risk Manag 2018; 14:903-907
- Necrotizing autoimmune myopathy is characterized by predominant muscle fiber necrosis and regeneration with little or no inflammation. We describe a 58-year-old woman with previous breast cancer and ...
Necrotizing autoimmune myopathy is characterized by predominant muscle fiber necrosis and regeneration with little or no inflammation. We describe a 58-year-old woman with previous breast cancer and statin use who complained of rapidly progressive weakness of lower limbs without pain, making walking, running and climbing stairs difficult. The creatine kinase level was 2,843 U/L, and muscle biopsy showed a dystrophic pattern. The genetic test for muscular dystrophies was negative and for anti-3-hydroxy-3-methylglutaryl coenzyme A reductase was positive. Intravenous immunoglobulin was administered, which showed mild improvement. Unfortunately, she took a step and collapsed to the floor, which led to the fracture of right femur delaying her improvement. The diagnosis of necrotizing autoimmune myopathy is sometimes delayed due to the atypical pathologic findings on muscle biopsy. As the disease is a severe condition, prompt recognition can lead to a successful outcome. We advise to consider this entity as a differential diagnosis among muscular dystrophies.