Screening for late-onset Pompe disease in western Denmark.

OBJECTIVE: Late-onset Pompe disease (LOPD) is a rare autosomal recessively inherited metabolic myopathy caused by reduced activity of the lysosomal enzyme alpha-glucosidase. In a previous screening study at two large neuromuscular university clinics in Denmark, three patients with LOPD were identified out of 103 patients screened. No systematic screening has been performed at the other neurological departments in the western part of Denmark. Thus, patients with a diagnosis of unspecified myopathy were screened for LOPD. MATERIALS AND METHODS: At seven neurological departments in the western part of Denmark, medical records were evaluated for all patients registered with myopathy diagnosis codes (ICD 10 codes: G 71.0-71.9 and G 72.0-72.9) during the period January 1, 2002, to December 31, 2012. If no specific diagnosis has been reached, patients were invited for screening. Dried blood spot (DBS) test was used to analyze the activity of the enzyme alpha-glucosidase. RESULT: A total of 654 patients were identified. From the medical records, information was obtained concerning symptoms, family history, electromyography, muscle biopsy results and creatine kinase levels. Eighty-seven patients (13.3%) (males 61%) at a mean age of 53.3 years (SD 16.5) fulfilled the criteria for screening. A DBS test was performed in 47 (54%) patients. In all patients, the enzyme activity was within reference values. CONCLUSION: None of the screened patients had a reduced activity of the enzyme alpha-glucosidase. Although the cohort studied was small, our findings do not suggest that LOPD is underdiagnosed in patients with unspecified myopathy in western Denmark.

PGM1 deficiency: Substrate use during exercise and effect of treatment with galactose.

Mutations in PGM1 (phosphoglucomutase 1) cause Glycogen Storage Disease type XIV, which is also a congenital disorder of protein N-glycosylation. It presents throughout life as myopathy with additional systemic symptoms. We report the effect of oral galactose treatment during five months in a patient with biochemically and genetically confirmed PGM1 deficiency. The 12-minute-walking distance increased by 225 m (65%) and transferrin glycosylation was restored to near-normal levels. The exercise assessments showed a severe exercise intolerance due to a block in skeletal muscle glycogenolytic capacity and that galactose treatment tended to normalize skeletal muscle substrate use from fat to carbohydrates during exercise.

Aerobic training in persons who have recovered from juvenile dermatomyositis.

A recent study has shown that 36 persons who had recovered from juvenile dermatomyositis (JDM) have on average an 18% decrease in maximal oxygen uptake. The objective of this study was to investigate the effect of a 12-week aerobic training program in this group, and assess whether aerobic training can normalize aerobic capacity to the expected level for age and gender. The patients participating in the study, one male and nine females (16-42 years of age), were in remission from JDM, defined as no clinical or biochemical evidence of disease activity and no medical treatment for 1 year. The patients had a median disease duration of 3.4 years (1.4-10.3), a median treatment duration of 2.4 years (0.4-9.3) and a median duration of remission of 7.0 years (1.2-30.0). Patients trained at home on a cycle ergometer for 12 weeks at a heart rate interval corresponding to 65% of their maximal oxygen uptake (VO(2max)). VO(2max) and maximal workload (W(max)) were determined before and after the 12-week training period through an incremental cycling test to exhaustion. The patients served as their own controls. Eight patients with JDM in remission completed the 12-week exercise program; one patient completed 9 weeks out of the 12-week program and one dropped out of the study. Training increased VO(2max) and W(max) by 26% and 30% (P < 0.001). Creatine kinase (CK) levels were normal pre-training and did not change with training, reflecting no muscle damage. We also found that at a given workload, heart rate was lowered significantly after the 12-week training period, indicating an improvement in cardiovascular fitness. This study shows that 12 weeks of moderate-intensity aerobic training is an effective and safe method to increase oxidative capacity and fitness in persons who have recovered from JDM. The results indicate that the low oxidative capacity in JDM patients in remission is reversible and can be improved. Thus, we recommend frequent aerobic training to be incorporated into supervised physiotherapy sessions in the treatment of JDM patients in remission.

Patients with medium-chain acyl-coenzyme a dehydrogenase deficiency have impaired oxidation of fat during exercise but no effect of L-carnitine supplementation.

BACKGROUND: It is not clear to what extent skeletal muscle is affected in patients with medium-chain acyl-coenzyme A dehydrogenase deficiency (MCADD). l-Carnitine is commonly used as a supplement in patients with MCADD, although its beneficial effect has not been verified. DESIGN: We investigated (1) fuel utilization during prolonged low-intensity exercise in patients with MCADD and (2) the influence of 4 weeks of oral l-carnitine supplementation on fuel utilization during exercise. METHODS: Four asymptomatic patients with MCADD and 11 untrained, healthy, age- and sex-matched control subjects were included. The subjects performed a 1-hour cycling test at a constant workload corresponding to 55% of Vo2max, while fat and carbohydrate metabolism was assessed, using the stable isotope technique and indirect calorimetry. The patients ingested 100 mg/kg/d of l-carnitine for 4 weeks, after which the cycling tests were repeated. RESULTS: At rest, palmitate oxidation and total fatty acid oxidation (FAO) rates were similar in patients and healthy control subjects. During constant workload cycling, palmitate oxidation and FAO rates increased in both groups, but increased 2 times as much in healthy control subjects as in patients (P = .007). Palmitate oxidation and FAO rates were unchanged by the l-carnitine supplementation. CONCLUSION: Our results indicate that patients with MCADD have an impaired ability to increase FAO during exercise but less so than that observed in patients with a number of other disorders of fat oxidation, which explains the milder skeletal muscle phenotype in MCADD. The use of carnitine supplementation in MCADD cannot be supported by the present findings.

Muscle phosphorylase kinase deficiency: a neutral metabolic variant or a disease?

OBJECTIVE: To examine metabolism during exercise in 2 patients with muscle phosphorylase kinase (PHK) deficiency and to further define the phenotype of this rare glycogen storage disease (GSD). METHODS: Patient 1 (39 years old) had mild exercise-induced forearm pain, and EMG showed a myopathic pattern. Patient 2 (69 years old) had raised levels of creatine kinase (CK) for more than 6 months after statin treatment. Both patients had increased glycogen levels in muscle and PHK activity <11% of normal. Two novel pathogenic nonsense mutations were found in the PHKA1 gene. The metabolic response to anaerobic forearm exercise and aerobic cycle exercise was studied in the patients and 5 healthy subjects. RESULTS: Ischemic exercise showed a normal 5-fold increase in plasma lactate (peak 5.7 and 6.9 mmol/L) but an exaggerated 5-fold increase in ammonia (peak 197 and 171 µmol/L; control peak range 60-113 µmol/L). An incremental exercise test to exhaustion revealed a blunted lactate response (5.4 and 4.8 mmol/L) vs that for control subjects (9.6 mmol/L; range 7.1-14.3 mmol/L). Fat and carbohydrate oxidation rates at 70% of peak oxygen consumption were normal. None of the patients developed a second wind phenomenon or improved their work capacity with an IV glucose infusion. CONCLUSION: Our findings demonstrate that muscle PHK deficiency may present as an almost asymptomatic condition, despite a mild impairment of muscle glycogenolysis, raised CK levels, and glycogen accumulation in muscle. The relative preservation of glycogenolysis is probably explained by an alternative activation of myophosphorylase by AMP and P(i) at high exercise intensities.

Fat metabolism during exercise in patients with McArdle disease.

OBJECTIVE: It is known that muscle phosphorylase deficiency restricts carbohydrate utilization, but the implications for muscle fat metabolism have not been studied. We questioned whether patients with McArdle disease can compensate for the blocked muscle glycogen breakdown by enhancing fat oxidation during exercise. METHODS: We studied total fat oxidation by indirect calorimetry and palmitate turnover by stable isotope methodology in 11 patients with McArdle disease and 11 healthy controls. Cycle exercise at a constant workload of 50% to 60% of maximal oxygen uptake capacity was used to evaluate fatty acid oxidation (FAO) in the patients. Healthy controls were exercised at the same absolute workload. RESULTS: We found that palmitate oxidation and disposal, total fat oxidation, and plasma levels of palmitate and total free fatty acids (FFAs) were significantly higher, whereas total carbohydrate oxidation was lower, during exercise in patients with McArdle disease vs healthy controls. We found augmented fat oxidation with the onset of a second wind, but further increases in FFA availability, as exercise continued, did not result in further increases in FAO. CONCLUSION: These results indicate that patients with McArdle disease have exaggerated fat oxidation during prolonged, low-intensity exercise and that increased fat oxidation may be an important mechanism of the spontaneous second wind. The fact that increasing availability of free fatty acids with more prolonged exercise did not increase fatty acid oxidation suggests that blocked glycogenolysis may limit the capacity of fat oxidation to compensate for the energy deficit in McArdle disease.

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 (Vo(2max)), maximal work capacity (W(max)), 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: W(max) increased by 18%, and CS activity increased by 35%. There was no significant change in Vo(2max) 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.