The potential of a ketogenic diet to minimize effects of the metabolic fault in glycogen storage disease V and VII.

PURPOSE OF REVIEW: To explore the potential of a low carbohydrate ketogenic diet (LCKD) to counter physical activity intolerance, pain and muscle damage for glycogen storage disease (GSD) V and VII, and highlight the realistic possibility that nutrition could be key. RECENT FINDINGS: Carbohydrate (CHO) ingestion during physical activity in GSDV and a LCKD for GSDVII is common. For the latter, a long-term study demonstrated improvement in physiological markers while on a LCKD. This included improvement in aerobic power and activity tolerance. In GSDV, preliminary research on a LCKD suggest a diet of 75% fat, 15% protein, 10% CHO, is best for improved function and compliance. Ketones provide immediate fuel for acute physical activity, and have an epigenetic role, improving ketone and lipid use. Evidence from elite athletes found a LCKD can increase fat oxidation and is optimal at 70% VO2max. This suggests the need to also improve conditioning via exercise to maximize the benefit of a LCKD. SUMMARY: A high CHO diet in GSDV and VII comes with a restricted physical activity capacity alongside significant pain, muscle damage and risk of renal failure. Mounting evidence suggests a LCKD is efficacious for both disorders providing an immediate fuel source which may negate the need for a 'warm-up' prior to every activity and restore 'normal' function.

Titrating a modified ketogenic diet for patients with McArdle disease: A pilot study.

Glycogen storage disease type V (GSDV) is a rare inborn error of carbohydrate metabolism. Patients present with exercise intolerance due to blocked glycogen breakdown in skeletal muscle. Introducing alternative fuel substrates, such as ketone bodies (KBs), could potentially alleviate muscle symptoms. This pilot study investigates which of three different modified ketogenic diet regimes is optimal for GSDV-patients to follow in a future large-scale study. Participants were randomised to follow one of three diet regimes for 3 weeks (#1: 65%/15%/20%; #2: 75%/15%/10%, or #3: 80%/15%/5%, fat/protein/carbohydrate). The primary outcome was exercise tolerance assessed by heart rate (HR) changes during constant load cycling. Secondary outcomes included levels of ketosis, and changes in perceived exertion and indirect calorimetry measures during exercise. Ten GSDV-patients were included. Eight completed the study. The other two were excluded. Diet #3 showed the highest average KB level (1.1 mmol/L) vs #2 (0.5 mmol/L) and #1 (0.3 mmol/L). Five patients reported subjective symptom relief, all of whom were on diets #2 and #3. All diet regimes seemed to improve fatty acid oxidation rates and exercise capacity as indicated by a small decrease in HR and perceived exertion. The results of this open-label pilot study show that diets #2 and #3 induce ketosis and improve symptoms and exercise capacity in GSDV-patients. Diet #2 had the highest acceptability score and was superior or equal to diet #3 in all other parameters, except level of ketosis. Based on this, we suggest testing diet #2 in a large-scale, placebo-controlled study in GSDV.

No effect of triheptanoin on exercise performance in McArdle disease.

OBJECTIVE: To study if treatment with triheptanoin, a 7-carbon triglyceride, improves exercise tolerance in patients with McArdle disease. McArdle patients have a complete block in glycogenolysis and glycogen-dependent expansion of tricarboxylic acid cycle (TCA), which may restrict fat oxidation. We hypothesized that triheptanoin metabolism generates substrates for the TCA, which potentially boosts fat oxidation and improves exercise tolerance in McArdle disease. METHODS: Double-blind, placebo-controlled, crossover study in patients with McArdle disease completing two treatment periods of 14 days each with a triheptanoin or placebo diet (1 g/kg/day). Primary outcome was change in mean heart rate during 20 min submaximal exercise on a cycle ergometer. Secondary outcomes were change in peak workload and oxygen uptake along with changes in blood metabolites and respiratory quotients. RESULTS: Nineteen of 22 patients completed the trial. Malate levels rose on triheptanoin treatment versus placebo (8.0 ± SD2.3 vs. 5.5 ± SD1.8 µmol/L, P < 0.001), but dropped from rest to exercise (P < 0.001). There was no difference in exercise heart rates between triheptanoin (120 ± SD16 bpm) and placebo (121 ± SD16 bpm) treatments. Compared with placebo, triheptanoin did not change the submaximal respiratory quotient (0.82 ± SD0.05 vs. 0.84 ± SD0.03), peak workload (105 ± SD38 vs. 102 ± SD31 Watts), or peak oxygen uptake (1938 ± SD499 vs. 1977 ± SD380 mL/min). INTERPRETATION: Despite increased resting plasma malate with triheptanoin, the increase was insufficient to generate a normal TCA turnover during exercise and the treatment has no effect on exercise capacity or oxidative metabolism in patients with McArdle disease.

Beneficios de la dieta cetogénica en la enfermedad de McArdle: empoderando a un paciente / Benefits of ketogenic diet on McArdle disease: empowering a patient

La enfermedad de almacenamiento de glucógeno tipo V o enfermedad de McArdle, con una prevalencia de 1 entre 167 mil personas, se caracteriza por una incapacidad para la degradación del glucógeno muscular. El síntoma cardinal es la intolerancia al ejercicio, manifestado por fatiga, debilidad muscular, mialgias, disnea y taquicardia, con posible rabdomiolisis. Los pacientes afectos por esta enfermedad presentan un fenómeno patognomónico denominado "segundo aliento". Existe poca evidencia respecto al tratamiento de la enfermedad. Algunos estudios apuntan el posible beneficio de la dieta cetogénica (DC). Se presenta un caso clínico de un varón de 38 años diagnosticado de enfermedad de McArdle que decide, por cuenta propia, llevar a cabo una DC durante un mes. Se realizó la valoración enfermera según las 14 Necesidades de Virginia Henderson y se identificaron los diagnósticos enfermeros: disposición para mejorar la gestión de la propia salud y fatiga, así como las complicaciones potenciales: rabdomiolisis y alteración perfil hepático Se objetivaron una disminución sustancial en los valores enzimas musculares y la desaparición por completo del fenómeno del "segundo aliento", lo que apoya el efecto beneficioso de la DC en estos sujetos. En este caso, el paciente tuvo que tomar una decisión al margen de las recomendaciones terapéuticas. El empoderamiento del paciente lo capacita para escoger de manera adecuada entre las distintas opciones terapéuticas a su alcance

Glycogen storage disease type V or McArdle disease has a prevalence of 1 per 167 thousand persons; it is characterized by the inability to break down muscle glycogen. The main symptom is exercise intolerance, shown by fatigue, muscle weakness, myalgia, dyspnea and tachycardia, with potential rhabdomyolisis. Patients affected by this disease present a pathognomonic phenomenon called "second wind". There is little evidence regarding the treatment of this disease. Some studies point at the potential benefit of ketogenic diet (KD). We present a case report of a 38-year-old male patient diagnosed with McArdle disease who decided on his own to follow a KD during one month. Nursing assessment was conducted according to the 14 Needs by Virginia Henderson, and the nursing diagnoses Willingness to improve the management of his own health and Fatigue were identified, as well as potential complications: rhabdomyolisis and hepatic profile alteration. It was objectively observed that there was a significant reduction in the values of muscle enzymes, and the "second wind" phenomenon disappeared completely; this supports the beneficial effect of KD in these subjects. In this case, the patient had to make a decision outside treatment recommendations. Patient empowerment enables them to choose adequately among the different treatment options available

Enfermedad de McArdle: presentación de 2 casos clínicos / McArdle disease: 2 case reports

El estudio del incremento de la creatinina fosfoquinasa (CPK) constituye un motivo de consulta frecuente en diversas especialidades médicas. Entre las enfermedades que cursan con CPK alta se encuentran las miopatías metabólicas siendo la enfermedad de McArdle la glucogenosis muscular más frecuente. Presentamos 2 casos clínicos de pacientes derivados a nuestro servicio de reumatología para estudio de CPK elevada cuyo diagnóstico final fue enfermedad de McArdle: un hombre de 72 años, asintomático desde el punto de vista muscular, en el que se objetivó de manera casual elevación importante de CPK en una analítica de rutina y una mujer de 30 años con síntomas musculares muy leves. El electromiograma (EMG) fue normal en ambos pacientes. En ninguno de los 2 casos existía actividad de la miofosforilasa en la biopsia muscular, siendo diagnosticados de enfermedad de McArdle (AU)

A high serum level of creatine kinase (CK) is a common reason for referring to medical specialities. Myopathies are one of the causes of elevated levels of CK. McArdle disease is the most common disorder of skeletal muscle carbohydrate metabolism. The cases are presented on 2 patients who were referred to our medical consultation to study the cause of their increased CK levels: a 72 year old asymptomatic man with high levels of CK detected by chance in a routine analysis, and a 30 year old woman with very few symptoms, apart from slight muscle pain and tiredness. Electromyography was normal in both patients. There was null activity of myophosphorylase in muscle biopsy of both cases, so a diagnosis of McArdle disease was made (AU)

Confirmation of the efficacy of vitamin B6 supplementation for McArdle disease by follow-up muscle biopsy.

No effective treatment for McArdle disease exists.We report a Japanese patient with McArdle disease who was treated with vitamin B(6) supplementation (60-90 mg/day). After treatment, increased muscle phosphorylase activity was confirmed by follow-up muscle biopsy (3.8 times higher than pretreatment levels). Increased lactate levels were seen on the forearm exercise test, and regular work activities could be resumed. Vitamin B(6) supplementation can enhance residual phosphorylase activity and improve insufficient anaerobic glycolysis of skeletal muscle.

Therapeutic options in other metabolic myopathies.

Adult patients with metabolic myopathies typically present with exercise-induced pain, cramps, fatigue, and myoglobinuria. The current therapeutic options of glycogen and lipid storage myopathies include dietary treatments, excersise training, and pharmacological supplementations. Herein is a review of evidence from randomized controlled trials in McArdle disease (glycogen storage disease type V, muscle phosphorylase deficiency) and carnitine palmitoyltransferase (CPT) 2 deficiency. A brief overview on current treatment options in rhabdomyolysis is also included because patients with McArdle disease and CPT 2 often experience such potentially life-threatening complications.

Carbohydrate- and protein-rich diets in McArdle disease: effects on exercise capacity.

BACKGROUND: Two single case studies suggest that a protein-rich diet may be beneficial for patients with McArdle disease, based on improvements in either endurance or muscle energetics, as assessed by phosphorous MR spectroscopy. In healthy subjects, proteins contribute very little to energy metabolism during exercise, which questions the effect of protein in McArdle disease. METHODS: In a crossover, open design, we studied seven patients with McArdle disease, who were randomised to follow either a carbohydrate- or protein-rich diet for 3 days before testing. Calorific intake on each diet was identical, and was adjusted to the subject's weight, age and sex. After each diet, exercise tolerance and maximal work capacity were tested on a bicycle ergometer, using a constant workload for 15 minutes followed by an incremental workload to exhaustion. RESULTS: During the constant workload, heart rate and perceived exertion were consistently lower (p<0.0005) on the carbohydrate- versus protein-rich diet. Patients also had a 25% improvement in maximal oxidative work capacity on the carbohydrate versus the protein diet. CONCLUSIONS: This study shows that patients with McArdle disease can improve their maximal work capacity and exercise tolerance to submaximal workloads by maintaining a diet high in carbohydrate instead of protein. The carbohydrate diet not only improves tolerance to everyday activities, but will probably also help to prevent exercise-induced episodes of muscle injury in McArdle disease.

One-year follow-up in a child with McArdle disease: exercise is medicine.

A 9-year-old boy with McArdle disease, who demonstrated remarkable recovery of objectively measured exercise tolerance after 1 year of follow-up, during which he pursued age-appropriate physical activities. The patient presented 1 year previously with severe myalgia, muscle weakness, proteinuria, hematuria, hyperthermia, and elevated creatine kinase levels after noncompetitive swimming. At that time, he reported a 3-year history of general myalgia and poor exercise tolerance. He was diagnosed with McArdle disease by both biochemical and genetic methods. Subsequently he performed a maximal exercise test and was prescribed a return to age-appropriate physical activity (protected by a pre-exercise dietary consumption of approximately 20 g carbohydrate). At 1-year follow up, he reported no subsequent acute clinical episodes, no general problems with exercise either at school or in ordinary activities, a virtual normalization of serum creatine kinase levels, and a 14% increase in body mass-adjusted peak oxygen uptake (from 18.8 to 21.8 mL O2/kg/min). The results suggest that, with protection by increasing pre-exercise blood glucose with carbohydrate ingestion, a substantially normal lifestyle may be possible in some children with McArdle disease.

Pharmacological and nutritional treatment trials in McArdle disease.

A systematic review of evidence for randomised controlled trials using pharmacologic and nutritional therapies in McArdle disease was undertaken. Primary outcome measures included any objective assessment of exercise endurance. Secondary outcome measures included changes in metabolic parameters, subjective measures such as quality of life scores and adverse outcomes. Ten randomised controlled trials were identified. Two trials low dose creatine (60 mg/kg/day) and oral sucrose 75 g prior to exercise demonstrated a positive effect.

Treatment of glycogenosys type V (McArdle disease) with creatine and ketogenic diet with clinical scores and with 31P-MRS on working leg muscle.

McArdle's disease is caused by genetic defects of the muscle-specific isozyme of glycogen phosphorylase, which block ATP formation from glycogen in skeletal muscle. Creatine supplementation and ketogenic diet have been tested as potential supplements for muscle energy metabolism which may improve muscle symptomatic. Outcome measures were clinical scores describing muscle symptomatic and parameters derived from 31P-MRS examinations on working muscle. In two placebo controlled cross-over studies low dose creatine showed beneficial effects on muscle symptoms and performance whereas high dose creatine distinctly worsened muscle symptomatic in patients. In both studies, however, the absence of an elevation in phosphocreatine indicated the absence of a creatine uptake by the muscle fibre. The effects of creatine on muscle symptomatic may be independent from energy metabolism in muscle. In a case study, ketogenic diet improved muscle symptomatic and performance. However, these effects again did not result in 31P-MRS visible changes in muscle energy metabolism.

[McArdle's disease. Apropos of a case]. / Enfermedad de McArdle. A propósito de un caso.

McArdle's disease (glycogenosis type V) is a metabolic disorder of hydrocarbons, inherited with autosomic recessive pattern. Biochemically is defined by a myophosphorylase deficiency; clinically it is characterized by exercise intolerance, due to the impossibility of providing energetic substrate to the muscle, myalgias and stiffness. We present a case report of a patient with McArdle's disease and we comment the diagnostic procedures and current therapeutic options.

Improved energy kinetics following high protein diet in McArdle's syndrome. A 31P magnetic resonance spectroscopy study.

A patient with McArdle's syndrome was examined using bicycle ergometry and 31P NMR spectroscopy during exercise. The patients working capacity was approximately half the expected capacity of controls. Muscle energy kinetics improved significantly during intravenous glucose infusion and after 6 weeks of high protein diet. During intravenous infusion of amino acids, no changes in working capacity could be detected. No decrease was seen in intracellular muscle pH during aerobic exercise. A significant decrease in muscle pH during aerobic exercise was detected in all controls.

[Muscular diseases: epidemiology of progressive muscular dystrophies]. / Malattie muscolari: l'epidemiologia delle distrofie muscolari progressive.

Epidemiology of muscular dystrophies has been important in the prevention of these diseases. In fact the genetic counselling, after a preliminary epidemiological investigation, reduced the incidence rate of Duchenne muscular dystrophy in the Veneto Region. Furthermore the new biochemical data on dismetabolic muscular diseases revealed a future strategy in the early identification of muscular dystrophies for their epidemiology and genetic prevention as well as for the new systems of research used in the field of muscular dystrophies.

McArdle's syndrome: the reaction to a fat-rich diet.

The effect of a diet enriched with fats on the muscle performance of a patient with McArdle's syndrome was studied. The tolerance to physical activity was studied during exercise (ergometric examination) and by sustained abduction to 90 degrees of the deltoid muscle, both after a three-day period on a normal diet and after a three-day period on a fat-rich diet. After the first period a woody spasm of the deltoid muscle was found which lasted several days. After a period on fat-rich diet the patient's physical fitness was increased and the recovery period after the acute load was shorter. Moreover, no induration of the deltoid muscle was observed after the sustained abduction to 90 degrees. It is argued that maximal strength is not improved by a fat-rich diet but tolerance to submaximal loads is increased by such treatment and recovery from non-lactate-produced muscle discomfort is hastened.