No effect of oral sucrose or IV glucose during exercise in phosphorylase b kinase deficiency.

This case report investigated exercise metabolism and the effect of oral sucrose and intravenous glucose supplementation in a 30-year-old, mildly affected man with muscle phosphorylase b kinase (PHK) deficiency caused by a novel c.586G>A mutation in the PHKA1 gene. Only 12 patients with PHK deficiency have been reported and it is unclear to what extent patients exhibit symptoms during exercise. Carbohydrate and fat metabolism were measured during 30 min of exercise at ∼ 70% of peak oxidative capacity using stabile isotope technique and signaling proteins and enzymes in the energy pathway were analyzed by Western blot. Results were compared to four healthy subjects. These studies show that neither oral nor intravenous glucose improved exercise tolerance in this patient with PHK deficiency. Despite Western blots indicated affected metabolism on protein level, systemic substrate turnover studies showed that carbohydrate and fatty acid oxidations were normal.

Endocrine function over time in patients with myotonic dystrophy type 1.

BACKGROUND AND PURPOSE: Patients with myotonic dystrophy type 1 (DM1) have an increased incidence of endocrine dysfunction. In this study, the temporal evolution of endocrine dysfunction in patients with DM1 was investigated. METHODS: Endocrine function was assessed in 68 patients with DM1, in whom endocrine function had been followed, on average, for 8 years. The endocrine function was assessed by measuring the concentration of hormones and metabolites in blood and by validating libido with questionnaires. RESULTS: At baseline, 30 of the 68 patients presented with at least one hormonal dysfunction. When re-evaluated after 8 years, 57 of 68 patients had endocrine dysfunction. Diabetic patients had increased from one to four. At follow-up, hyperparathyroidism occurred in 25% and abnormal thyroid-stimulating hormone in 21%, compared with 14% and 9% at baseline. Sixteen of 33 men had increased luteinizing hormone levels compared with seven at baseline. CONCLUSIONS: Our findings show that endocrine abnormalities amongst patients with DM1 increase over time. Based on these findings it is suggested that correctable endocrine abnormalities should be monitored periodically in this patient group.

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 regeneration and inflammation in patients with facioscapulohumeral muscular dystrophy.

BACKGROUND AND OBJECTIVES: The aim of this study was to investigate whether inflammation and regeneration are prominent in mildly affected muscles of patients with facioscapulohumeral muscular dystrophy type 1A (FSHD1A). Inflammation in muscle has been suggested by MRI studies in patients with FSHD1A. METHODS: We analysed immunohistological and histological stains of muscle biopsies from 24 patients with FSHD1A, using 10 patients with Becker muscular dystrophy (BMD) for comparison. RESULTS: Internalized nuclei were more prevalent in BMD (23.7 ± 10.8%) vs FSHD1A (6.3 ± 6.8%; P < 0.001), indicating more past regenerating fibres in BMD. Recently regenerating fibres, expressing neonatal myosin heavy chain and vimentin, did not differ significantly between patients with FSHD1A (1.1 ± 2.9%) and patients with BMD (1.8 ± 1.9%). Regeneration was not correlated with the number of KpnI restriction fragment repeats, an FSHD1A-defining genotype property within the D4Z4 locus, or overall disease severity in patients with FSHD1A. Macrophages were more prevalent in FSHD1A (0.50 ± 0.63 per mm(2) ) vs BMD (0.07 ± 0.07 per mm(2) ), whereas inflammatory T cells were equally infrequent. CONCLUSIONS: Macrophages were more prevalent in patients with FSHD1A and could be an important pathogenic mechanism for the initiation of the dystrophic process. Furthermore, regeneration was unrelated to genotype and disease severity in FSHD1A.

Endocrine function in 97 patients with myotonic dystrophy type 1.

The aim of this study was to investigate the endocrine function and its association to number of CTG repeats in patients with myotonic dystrophy type 1 (DM1). Concentration of various hormones and metabolites in venous blood was used to assess the endocrine function in 97 patients with DM1. Correlation with CTG(n) expansion size was investigated with the Pearson correlation test. Eighteen percent of the DM1 patients had hyperparathyroidism with increased PTH compared with 0.5% in the background population. Of these, 16% had normocalcemia and 2% had hypercalcemia. An additional 3% had hypercalcemia without elevation of PTH; 7% had abnormal TSH values (2% subnormal and 5% elevated TSH levels); 5% of the patients had type 2 diabetes mellitus; 17% of the male DM1 patients had increased LH and low levels of plasma testosterone indicating absolute androgen insufficiency. Another 21% had increased LH, but normal testosterone levels, indicating relative insufficiency. Numbers of CTG repeats correlated directly with plasma PTH, phosphate, LH, and tended to correlate with plasma testosterone for males. This is the largest study of endocrine dysfunction in a cohort of Caucasian patients with DM1. We found that patients with DM1 have an increased risk of abnormal endocrine function, particularly calcium metabolism disorders. However, the endocrine dysfunction appears not to be of clinical significance in all of the cases. Finally, we found correlations between CTG(n) expansion size and plasma PTH, phosphate, and testosterone, and neck flexion strength.

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.

Is muscle glycogenolysis impaired in X-linked phosphorylase b kinase deficiency?

OBJECTIVE: It is unclear to what extent muscle phosphorylase b kinase (PHK) deficiency is associated with exercise-related symptoms and impaired muscle metabolism, because 1) only four patients have been characterized at the molecular level, 2) reported symptoms have been nonspecific, and 3) lactate responses to ischemic handgrip exercise have been normal. METHODS: We studied a 50-year-old man with X-linked PHK deficiency using ischemic forearm and cycle ergometry exercise tests to define the derangement of muscle metabolism. We compared our findings with those in patients with McArdle disease and in healthy subjects. RESULTS: Sequencing of PHKA1 showed a novel pathogenic mutation (c.831G>A) in exon 7. There was a normal increase of plasma lactate during forearm ischemic exercise, but lactate did not change during dynamic, submaximal exercise in contrast to the fourfold increase in healthy subjects. Constant workload elicited a second wind in all patients with McArdle disease, but not in the patient with PHK deficiency. IV glucose administration appeared to improve exercise tolerance in the patient with PHK deficiency, but not to the same extent as in the patients with McArdle disease. Lipolysis was higher in the patient with PHK deficiency than in controls. CONCLUSION: These findings demonstrate that X-linked PHK deficiency causes a mild metabolic myopathy with blunted muscle glycogen breakdown and impaired lactate production during dynamic exercise, which impairs oxidative capacity only marginally. The different response of lactate to submaximal and maximal exercise is likely related to differential activation mechanisms for myophosphorylase.

Impaired energy metabolism and abnormal muscle histology in mut- methylmalonic aciduria.

The authors report a 27-year-old man with B12-responsive mut- methylmalonic aciduria associated with pure muscle symptoms. Two mutations were found in the methylmalonyl-CoA mutase gene. An exercise test showed a reduced maximal workload and reduced oxygen uptake, and a muscle biopsy showed subsarcolemmal accumulation of mitochondria and normal respiratory chain enzyme activities. These findings may be caused by inhibition of mitochondrial energy metabolism by methylmalonate or its metabolites.

Patients with severe muscle wasting are prone to develop hypoglycemia during fasting.

The authors investigated whether hypoglycemia develops during 23 hours of fasting in patients with Duchenne dystrophy (7 patients), spinal muscular atrophy (4 patients), and congenital myopathy (2 patients), all with residual muscle mass <10% of body weight. All patients with spinal muscular atrophy and congenital myopathy and one patient with Duchenne dystrophy, but none of six healthy subjects, developed hypoglycemia. Skeletal muscle is an important source of gluconeogenic substrates during fasting. Hypoglycemia must be considered in patients with low muscle mass, especially during surgery and febrile episodes.