Deletion of exon 26 of the dystrophin gene is associated with a mild Becker muscular dystrophy phenotype

With the possible introduction of exon skipping therapy in Duchenne muscular dystrophy, it has become increasingly important to know the role of each exon of the dystrophin gene to protein expression, and thus the phenotype. In this report, we present two related men with an unusually mild BMD associated with an exon 26 deletion. The proband, a 23-year-old man, had slightly delayed motor milestones, walking 1½ years old. He had no complaints of muscle weakness, but had muscle pain. Clinical examination revealed no muscle wasting or loss of power, but his CK was 1500-7000 U/l. Muscle biopsy showed dystrophic changes. He had comorbidity with dystonia, slight mental retardation, low stature and neuropathy. The brother of the proband's mother came to medical attention when he was 43 years old. He complained about muscle pain. On examination, a MRC grade 4+ hip extention palsy and a discrete calf hypertrophy was noted. Creatine kinase was normal or raised maximally to 500U/l. The muscle biopsy was myopathic with increased fiber size variation and many internal nuclei, but no dystrophy. No comorbidity was found. In both cases, western blot showed a reduced dystrophin band. Genetic evaluation revealed a deletion of exon 26 of the dystrophin gene in both. This is the first description of patients with a exon 26 deletion of the dystrophin gene. Assuming the proband's comorbidity is unrelated, exon 26 deletion results in a very mild phenotype. This might be of interest in planning exon skipping therapy for Duchenne muscular dystrophy. This report also shows that BMD may present with a normal CK

Aerobic Training in Patients with Congenital Myopathy

INTRODUCTION: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. METHODS: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. RESULTS: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. CONCLUSIONS: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. TRIAL REGISTRATION:The Regional Committee on Health Research Ethics of the Capital Region of Denmark H-2-2013-066 and ClinicalTrials.gov H2-2013-066

Decreased Variability of the 6-Minute Walk Test by Heart Rate Correction in Patients with Neuromuscular Disease

OBJECTIVE: The 6-minute walk test is widely used to assess functional status in neurological disorders. However, the test is subject to great inter-test variability due to fluctuating motivation, fatigue and learning effects. We investigated whether inter-test variability of the 6MWT can be reduced by heart rate correction. METHODS: Sixteen patients with neuromuscular diseases, including Facioscapulohumeral muscular dystrophy, Limb-girdle muscular dystrophy, Charcot-Marie-Tooths, Dystrophia Myotonica and Congenital Myopathy and 12 healthy subjects were studied. Patients were excluded if they had cardiac arrhythmias, if they received drug treatment for hypertension or any other medical conditions that could interfere with the interpretation of the heart rate and walking capability. All completed three 6-minute walk tests on three different test-days. Heart rate was measured continuously. RESULTS: Successive standard 6-minute walk tests showed considerable learning effects between Tests 1 and 2 (4.9%; P = 0.026), and Tests 2 and 3 (4.5%; P = 0.020) in patients. The same was seen in controls between Tests 1 and 2 (8.1%; P = 0.039)). Heart rate correction abolished this learning effect. CONCLUSION: A modified 6-minute walk test, by correcting walking distance with average heart rate during walking, decreases the variability among repeated 6-minute walk tests, and should be considered as an alternative outcome measure to the standard 6-minute walk test in future clinical follow-up and treatment trials

Level of muscle regeneration in limb-girdle muscular dystrophy type 2I relates to genotype and clinical severity

<p>Abstract</p> <p>Background</p> <p>The balance between muscle regeneration and ongoing degeneration is a relationship that greatly influences the progression of muscular dystrophy. Numerous factors may influence the muscle regeneration, but more information about the relationship between genotype, clinical severity and the ability to regenerate is needed.</p> <p>Methods</p> <p>Muscle biopsies were obtained from the tibialis anterior muscle, and frozen sections were stained for general histopathological and immunohistological evaluation. Differences between groups were considered statistical significant at <it>P </it>< 0.05 using Student's unpaired <it>t</it>-test.</p> <p>Results</p> <p>We found that all patients with limb-girdle muscular dystrophy type 2I (LGMD2I) had a large number of internally nucleated fibers, a sign of previous regeneration. The level of expression of muscle-specific developmental proteins, such as neonatal myosin heavy chain (nMHC) and myogenin, was related to the clinical severity. Additionally, we found that the majority of nMHC-positive fibers did not stain positively for utrophin in patients who were compound heterozygous for the L276I mutation, suggesting that the predominant form of regeneration in these patients is fiber repair rather than formation of new fibers. Double staining showed that many smaller nMHC-positive fibers were positive for antibodies against the glycosylation on α-dystroglycan, suggesting that such glycosylation may be a result of muscle regeneration.</p> <p>Conclusion</p> <p>Severely affected patients with LGMD2I have a high level of muscle degeneration, which leads to a high rate of regeneration, but this is insufficient to change the imbalance between degeneration and regeneration, ultimately leading to progressive muscle wasting. Detailed information regarding the level and rate of muscle regeneration and potential obstructions of the regenerative pathway should be of use for future therapies involving satellite-cell activation.</p