Several other strategies directed at knocking down the mutated DMPK allele or splice correction are in development (eg, NCT06138743, NCT05481879). Since the discovery of the dystrophin gene (DMD) in ...1987, researchers have investigated gene therapy options for Duchenne muscular dystrophy. With hindsight, this disease was probably the most difficult with which to start gene therapy research, because the DMD gene is the largest gene in the human body, and it is impossible to package the gene into available viral vectors. The problem with such an approach is that it is difficult to engage the target and, thus, obtain exon skipping. ...only a few people with Duchenne muscular dystrophy are amenable to the treatment because it is mutation specific.
•A consensus was reached on an updated definition of LGMD, and current sub-types were evaluated by application of the updated definition.•Consensus was reached on the most useful LGMD classification ...system that also allowed space for further discoveries of new sub-types.•Potential ramifications of the new definition and classification of LGMD for patients were discussed and several action points around how to disseminate this proposal were identified.
Congenital myopathies (CM) often affect contractile proteins of the sarcomere, which could render patients susceptible to exercise-induced muscle damage. We investigated if exercise is safe and ...beneficial in patients with CM.
Patients exercised on a stationary bike for 30 minutes, three times weekly, for 10 weeks at 70% of their maximal oxygen uptake (VO2max). Creatine kinase (CK) was monitored as a marker of muscle damage. VO2max, functional tests, and questionnaires evaluated efficacy.
Sixteen patients with CM were included in a controlled study. VO2max increased by 14% (range, 6-25%; 95% CI 7-20; p < 0.001) in the seven patients who completed training, and tended to decrease in a non-intervention group (n = 7; change -3.5%; range, -11-3%, p = 0.083). CK levels were normal and remained stable during training. Baseline Fatigue Severity Scale scores were high, 4.9 (SE 1.9), and tended to decrease (to 4.4 (SE 1.7); p = 0.08) with training. Nine patients dropped out of the training program. Fatigue was the major single reason.
Ten weeks of endurance training is safe and improves fitness in patients with congenital myopathies. The training did not cause sarcomeric injury, even though sarcomeric function is affected by the genetic abnormalities in most patients with CM. Severe fatigue, which characterizes patients with CM, is a limiting factor for initiating training in CM, but tends to improve in those who train.
The Regional Committee on Health Research Ethics of the Capital Region of Denmark H-2-2013-066 and ClinicalTrials.gov H2-2013-066.
Congenital myasthenic syndromes (CMSs) are increasingly recognized as causes of muscle fatigue and weakness. However, treatment of individual syndromes has been described only in small case series.
...To analyze the information published thus far concerning the effect of pharmacologic treatment of one of the most common subtypes of CMS, downstream of tyrosine kinase 7 (DOK7) CMS.
In a search of the PubMed database, we found 16 publications describing the response to medication in 122 individuals with DOK7 deficiency. The last search was performed August 15, 2013. If more than 1 article had been published by the same group, a comparison of the participants in the studies was made, and data appearing more than once were excluded.
Positive effects were observed in 6 of 66 patients who received an acetylcholinesterase inhibitor, 65 of 69 patients who received ephedrine or salbutamol, 18 of 29 who were given 3,4-diaminopyridine, and 13 of 16 individuals who received a combination of these drugs. Our analysis found no evidence that age at disease onset, age at treatment start, drug dosage, or mutation type influenced treatment results. The magnitude of treatment effect with ephedrine or salbutamol seems to increase gradually, peaking after approximately 6 to 8 months. Treatment with acetylcholinesterase inhibitors resulted in worsened conditions for most patients.
This analysis suggests that (1) ephedrine or salbutamol is the first choice of treatment in DOK7 CMS; (2) 3,4-diaminopyridine may provide additional benefi; (3) it is never too late to initiate treatment; and (4) in contrast to acquired myasthenia gravis, treatment with acetylcholinesterase inhibitors should be avoided in DOK7 CMS.
The aim of the study was to describe the clinical spectrum of limb girdle muscular dystrophies (LGMDs), the pitfalls of the current classification system for LGMDs, and emerging therapies for these ...conditions.
Close to half of all LGMD subtypes have been discovered within the last 6 years of the 21-year-period in which the current classification system for LGMD has existed. The number of letters for annotation of new recessive LGMD conditions is exhausted, and multiple already classified LGMDs do not strictly fulfill diagnostic criteria for LGMD or are registered in other classification systems for muscle disease. On the contrary, diseases that fulfill classical criteria for LGMD have found no place in the LGMD classification system. These shortcomings call for revision/creation of a new classification system for LGMD. The rapidly expanding gene sequencing capabilities have helped to speed up new LGMD discoveries, and unveiled pheno-/genotype relations. Parallel to this progress in identifying new LGMD subtypes, emerging therapies for LGMDs are under way, but no disease-specific treatment is yet available for nonexperimental use.
The field of LGMD is rapidly developing from a diagnostic and therapeutic viewpoint, but a uniform and universally agreed classification system for LGMDs is needed.
Genetic diagnosis of muscular dystrophies (MDs) has classically been guided by clinical presentation, muscle biopsy, and muscle MRI data. Muscle MRI suggests diagnosis based on the pattern of muscle ...fatty replacement. However, patterns overlap between different disorders and knowledge about disease-specific patterns is limited. Our aim was to develop a software-based tool that can recognize muscle MRI patterns and thus aid diagnosis of MDs.
We collected 976 pelvic and lower limbs T1-weighted muscle MRIs from 10 different MDs. Fatty replacement was quantified using Mercuri score and files containing the numeric data were generated. Random forest supervised machine learning was applied to develop a model useful to identify the correct diagnosis. Two thousand different models were generated and the one with highest accuracy was selected. A new set of 20 MRIs was used to test the accuracy of the model, and the results were compared with diagnoses proposed by 4 specialists in the field.
A total of 976 lower limbs MRIs from 10 different MDs were used. The best model obtained had 95.7% accuracy, with 92.1% sensitivity and 99.4% specificity. When compared with experts on the field, the diagnostic accuracy of the model generated was significantly higher in a new set of 20 MRIs.
Machine learning can help doctors in the diagnosis of muscle dystrophies by analyzing patterns of muscle fatty replacement in muscle MRI. This tool can be helpful in daily clinics and in the interpretation of the results of next-generation sequencing tests.
This study provides Class II evidence that a muscle MRI-based artificial intelligence tool accurately diagnoses muscular dystrophies.
Generalized myasthenia gravis (gMG) is an autoimmune disorder in which pathogenic autoantibodies damage the neuromuscular junction, causing disabling or life-threatening muscle weakness. Most ...treatments nonspecifically inhibit aspects of the immune system, do not directly address the causal mechanisms of tissue damage, and often have side-effect profiles that negatively impact patients. Understanding of the central pathogenic role of the complement cascade in gMG is advancing, and a new complement-targeting treatment is under investigation.
We provide an overview of gMG etiology, the complement cascade, current treatments, and the investigational gMG therapy zilucoplan. Zilucoplan is a small, subcutaneously administered, macrocyclic peptide that inhibits cleavage of complement component C5 and the subsequent formation of the membrane attack complex.
In a randomized, double-blind, placebo-controlled, phase 2 clinical trial, zilucoplan demonstrated clinically meaningful complement inhibition in patients with acetylcholine receptor-positive gMG. Zilucoplan, a first-of-its-kind cyclic peptide targeting C5, appears to be a therapeutic option for the treatment of gMG based on available pharmacokinetic/pharmacodynamic data and phase 1 and 2 efficacy, safety, and tolerability data with limited long-term follow-up. Zilucoplan use earlier in the treatment paradigm would be suitable in this population should phase 3 efficacy and safety data be equally favorable.
Skeletal muscle sodium channel disorders give rise to episodic symptoms such as myotonia and/or periodic paralysis. Chronic symptoms with permanent weakness are not considered characteristic of the ...phenotypes. Muscle fat replacement represents irreversible damage that inevitably will impact on muscle strength. This study investigates muscle fat replacement and contractility in patients with pathogenic SCN4A variants compared to healthy controls. T1-weighted and 2-point Dixon MRI of the legs were conducted to assess fat replacement. Stationary dynamometry was used to assess muscle strength. Contractility was determined by maximal muscle contraction divided by cross-sectional muscle area. The average cross-sectional intramuscular fat fraction was greater in patients compared with controls by 2.5% in the calves (95% CI 0.74-4.29%, p = 0.007) and by 2.0% in the thighs (95% CI 0.75-3.2%, p = 0.003). Muscle contractility was less in patients vs. controls by 14-27% (p < 0.05). Despite greater fat fraction and less contractility, absolute strength was not significantly less. This study quantitatively documents greater fat fraction and additionally describes difference in muscle contractility in a large cohort of patients with skeletal muscle sodium channel disorders. The clinical impact of these abnormal findings is likely limited as muscle hypertrophy in the patients served to preserve absolute muscle strength. Subgroup analysis indicated significant difference in phenotype by genotype, however these findings lack statistical significance and serve as inspiration for future researchers to probe into the geno- phenotype relationship in these disorders.Trial registration: The study was registered at http://clinicaltrials.gov (identifier: NCT04808388).
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