Grete Andersen

Muscle glycogenosis due to phosphoglucomutase 1 deficiency.

To the Editor: Muscle glycogen storage diseases are rare inborn diseases caused by errors of metabolism associated with either dynamic, exercise-related symptoms or permanent muscle weakness. The m...

Effect of aerobic training in patients with spinal and bulbar muscular atrophy (Kennedy disease)

Objective: We examined the effect of aerobic exercise in patients with spinal and bulbar muscular atrophy (SBMA). SBMA is caused by a defect androgen receptor. This defect causes motor neuron death, but considering the important function of androgens in muscle, it is possible that muscle damage in SBMA also occurs independently of motor neuron damage. Methods: Eight patients with SBMA engaged in regular cycling exercise for 12 weeks. Maximum oxygen uptake (Vo2max), maximal work capacity (Wmax), muscle morphology, citrate synthase (CS) activity, body composition, EMG, static strength measurements, lung function, plasma proteins, and hormones were evaluated before and after training. Evaluation of improvements in activities of daily living (ADL) was conducted after training. Results: Wmax increased by 18%, and CS activity increased by 35%. There was no significant change in Vo2max or any of the other variables examined before and after training, and the patients with SBMA did not feel improvements in ADL. Conclusions: Frequent, moderate-intensity aerobic conditioning is of little beneficial effect in patients with spinal and bulbar muscular atrophy (SBMA). High levels of plasma creatine kinase and muscle regeneration indicate a primary myopathic affection, which, in parallel with the motor neuron deficiency, may attenuate the response to exercise training in patients with SBMA.

Bezafibrate in skeletal muscle fatty acid oxidation disorders A randomized clinical trial

Objective: To assess whether bezafibrate increases fatty acid oxidation (FAO) and lowers heart rate (HR) during exercise in patients with carnitine palmitoyltransferase (CPT) II and very long-chain acyl-CoA dehydrogenase (VLCAD) deficiencies. Methods: This was a 3-month, randomized, double-blind, crossover study of bezafibrate in patients with CPT II (n = 5) and VLCAD (n = 5) deficiencies. Primary outcome measures were changes in FAO, measured with stable-isotope methodology and indirect calorimetry, and changes in HR during exercise. Results: Bezafibrate lowered low-density lipoprotein, triglyceride, and free fatty acid concentrations; however, there were no changes in palmitate oxidation, FAO, or HR during exercise. Conclusion: Bezafibrate does not improve clinical symptoms or FAO during exercise in patients with CPT II and VLCAD deficiencies. These findings indicate that previous in vitro studies suggesting a therapeutic potential for fibrates in disorders of FAO do not translate into clinically meaningful effects in vivo. Classification of evidence: This study provides Class I evidence that bezafibrate 200 mg 3 times daily is ineffective in improving changes in FAO and HR during exercise in adults with CPT II and VLCAD deficiencies.

Aerobic training and postexercise protein in facioscapulohumeral muscular dystrophy RCT study

Objective: To investigate the effect of regular aerobic training and postexercise protein-carbohydrate supplementation in patients with facioscapulohumeral muscular dystrophy (FSHD). Methods: In this randomized, double-blind, placebo-controlled parallel study, we randomized untrained men (n = 21) and women (n = 20) with FSHD (age 19–65 years) to 2 training groups—training with protein supplement (n = 18) and training with placebo supplement (n = 13)—and a nonintervention control group (n = 10). We assessed fitness, walking speed, muscle strength, questionnaires, and daily activity levels before and after 12 weeks of interventions. Training involved 36 sessions of 30-minute cycle-ergometer training. After each session, patients drank either a protein-carbohydrate or placebo beverage. Results: In the trained participants, fitness, workload, and walking speed improved (10% [confidence interval (CI) 4%–15%], 18% [CI 10%–26%], 7% [CI 4%–11%], respectively, p < 0.001, number needed to treat = 2.1). Self-assessed physical capacity and health (Short Form–36) also improved. Muscle strength and daily activity levels did not change with training. Protein-carbohydrate supplementation did not result in further improvements in any tests compared to training alone. Conclusions: This randomized, controlled study showed that regular endurance training improves fitness, walking speed, and self-assessed health in patients with FSHD without causing muscle damage. Postexercise protein-carbohydrate supplementation does not add any further improvement to training effects alone. Classification of evidence: This study provides Class II evidence that regular aerobic training with or without postexercise protein-carbohydrate supplementation improves fitness and workload in patients with FSHD.

Muscle phenotype in patients with myotonic dystrophy type 1

Introduction: The pathogenesis of muscle involvement in patients with myotonic dystrophy type 1 (DM1) is not well understood. In this study, we characterized the muscle phenotype in patients with confirmed DM1. Methods: In 38 patients, muscle strength was tested by hand‐held dynamometry. Myotonia was evaluated by a handgrip test and by analyzing the decrement of the compound muscle action potential. Muscle biopsies were assessed for morphological changes and Na+‐K+ pump content. Results: Muscle strength correlated with a decline in Na+‐K+ pump content (r = 0.60, P < 0.001) and with CTG expansion. CTG expansion did not correlate with severity of myotonia, proximal histopathological changes, or Na+‐K+ pump content. Histopathologically, we found few centrally placed nuclei (range 0.2–6.9%). Conclusions: The main findings of this study are that muscle weakness correlated inversely with CTG expansion and that central nuclei are not a prominent feature of proximal muscles in DM1. Muscle Nerve 47:409‐415, 2013

Protein-carbohydrate supplements improve muscle protein balance in muscular dystrophy patients after endurance exercise: a placebo controlled crossover study

In healthy individuals, postexercise protein supplementation increases muscle protein anabolism. In patients with muscular dystrophies, aerobic exercise improves muscle function, but the effect of exercise on muscle protein balance is unknown. Therefore, we investigated 1) muscle protein balance before, during, and after exercise and 2) the effect of postexercise protein-carbohydrate supplementation on muscle protein balance in patients with muscular dystrophies. In 17 patients [7 women and 10 men, aged 33 ± 11 yr (18-52), body mass index: 22 ± 3 kg/m(2) (16-26)] and 8 healthy matched controls [3 women and 5 men, age 33 ± 13 years (19-54), body mass index: 23 ± 3 kg/m(2) (19-27)], muscle protein synthesis, breakdown, and fractional synthesis rates (FSR) were measured across the leg using tracer dilution methodology on two occasions, with and without oral postexercise protein-carbohydrate supplementation. In patients, muscle protein breakdown increased in the recovery period (11 ± 1 μmol phenylalanine/min) vs. rest (8 ± 1 μmol phenylalanine/min, P = 0.02), enhancing net muscle protein loss. In contrast, postexercise protein-carbohydrate supplementation reduced protein breakdown, abolished net muscle protein loss, and increased the muscle FSR in patients (0.04 to 0.06%/h; P = 0.03). In conclusion, postexercise protein-carbohydrate supplementation reduces skeletal mixed-muscle protein breakdown, enhances FSR, resulting in a reduced net muscle loss in patients with muscular dystrophies. The findings suggest that postexercise protein-carbohydrate supplementation could be an important add-on to exercise training therapy in muscular dystrophies, and long-term studies of postexercise protein-carbohydrate supplementation are warranted in these conditions.

The antimyotonic effect of lamotrigine in non-dystrophic myotonias: a double-blind randomized study

&NA; Mexiletine is the only drug with proven effect for treatment of non‐dystrophic myotonia, but mexiletine is expensive, has limited availability and several side effects. There is therefore a need to identify other pharmacological compounds that can alleviate myotonia in non‐dystrophic myotonias. Like mexiletine, lamotrigine is a sodium channel blocker, but unlike mexiletine, lamotrigine is available, inexpensive, and well tolerated. We investigated the potential of using lamotrigine for treatment of myotonia in patients with non‐dystrophic myotonias. In this, randomized double‐blind, placebo‐controlled, two‐period cross‐over study, we included adult outpatients recruited from all of Denmark with clinical myotonia and genetically confirmed myotonia congenita and paramyotonia congenita for investigation at the Copenhagen Neuromuscular Center. A pharmacy produced the medication and placebo, and randomized patients in blocks of 10. Participants and investigators were all blinded to treatment until the end of the trial. In two 8‐week periods, oral lamotrigine or placebo capsules were provided once daily, with increasing doses (from 25 mg, 50 mg, 150 mg to 300 mg) every second week. The primary outcome was a severity score of myotonia, the Myotonic Behaviour Scale ranging from asymptomatic (score 1) to invalidating myotonia (score 6), reported by the participants during Weeks 0 and 8 in each treatment period. Clinical myotonia was also measured and side effects were monitored. The study was registered at ClinicalTrials.gov (NCT02159963) and EudraCT (2013–003309–24). We included 26 patients (10 females, 16 males, age: 19–74 years) from 13 November 2013 to 6 July 2015. Twenty‐two completed the entire study. One patient withdrew due to an allergic reaction to lamotrigine. Three patients withdrew for reasons not related to the trial intervention. The Myotonic Behaviour Scale at baseline was 3.2 ± 1.1, which changed after treatment with lamotrigine by 1.3 ± 0.2 scores (P < 0.001), but not with placebo (0.2 ± 0.1 scores, P = 0.4). The estimated effect size was 1.0 ± 0.2 (95% confidence interval = 0.5–1.5, P < 0.001, n = 22). The standardized effect size of lamotrigine was 1.5 (confidence interval: 1.2–1.8). Number needed to treat was 2.6 (P = 0.006, n = 26). No adverse or unsuspected event occurred. Common side effects occurred in both treatment groups; number needed to harm was 5.2 (P = 0.11, n = 26). Lamotrigine effectively reduced myotonia, emphasized by consistency between effects on patient‐related outcomes and objective outcomes. The frequency of side effects was acceptable. Considering this and the high availability and low cost of the drug, we suggest that lamotrigine should be used as the first line of treatment for myotonia in treatment‐naive patients with non‐dystrophic myotonias.

Aerobic training in myotonia congenita: Effect on myotonia and fitness

Exercise has not been investigated in myotonia congenita (MC). We investigated whether regular aerobic training can reduce myotonia and improve fitness.

Mitochondrial DNA mutation load in a family with the m.8344A>G point mutation and lipomas: a case study

Studies have shown that difference in mtDNA mutation load among tissues is a result of postnatal modification. We present five family members with the m.8344A>G with variable phenotypes but uniform intrapersonal distribution of mutation load, indicating that there is no postnatal modification of mtDNA mutation load in this genotype.