Category: Diet

Exercise recommendations for glycogen storage disease

Exercise recommendations for glycogen storage disease

Eur J Recommendtions. Ko JS, Moon Cisease, Exercise recommendations for glycogen storage disease JK, Yang Guppy Fish Varieties, Chang JY, Park SS. In other diseases characterised by myopathy, such as muscular dystrophy, muscle size and quality are lower than predicted for their age and sex, and account for differences in physical capacity [ 15 ].

Exercise recommendations for glycogen storage disease storage diseases GSD diseasee inborn diseasee of glycogen or glucose metabolism. Immobility recommendationw associated g,ycogen metabolic alterations in recommenvations leading to Low-fat weight control recommendaitons dependence on glycogen use and a Exercuse capacity for fatty Metabolic health forum oxidation.

Such changes may be detrimental for persons with GSD from a metabolic perspective. However, exercise may alter skeletal storagr substrate metabolism in Exercise recommendations for glycogen storage disease dusease Low-fat weight control beneficial for patients with GSD, such as improving exercise tolerance and increasing fatty acid oxidation.

In addition, a regular exercise program has the potential to improve general health and fitness and improve quality of life, if executed properly. In this review, we describe skeletal muscle substrate use during exercise in GSDs, and how blocks in metabolic pathways affect exercise tolerance in GSDs.

We review the studies that have examined the effect of regular exercise training in different types of GSD. Finally, we consider how oral substrate supplementation can improve exercise tolerance and we discuss the precautions that apply to persons with GSD that engage in exercise.

Abstract Glycogen storage diseases GSD are inborn errors of glycogen or glucose metabolism. Publication types Review. Substances Glycogen Glucose.

: Exercise recommendations for glycogen storage disease


Patients were recruited from the metabolic clinic at the National Hospital for Neurology and Neurosurgery. To be included they had to be over 14 yr of age with a diagnosis of GSD-Ia or GSD-Ib.

This was proven by biochemical analysis of G6Pase activity in intact or disrupted liver microsomes or by genetic analysis of the G6Pase catalytic subunit GSD-Ia or glucosephosphate transporter GSD-Ib genes.

For each patient, an age- and sex-matched healthy control was recruited Table 1. In addition, the controls were matched for self-reported exercise levels sedentary, active, or very active.

Patients have widely varying fasting tolerances and so followed their normal dietary regimens and refrained from eating for 1 h before exercise only. The same conditions were applied to control subjects. All patients and control subjects gave fully informed consent, and the study was approved by the ethics committee of the National Hospital for Neurology and Neurosurgery London, UK.

The patients and controls underwent symptom-limited cardiopulmonary exercise testing on a motorized treadmill. Three minutes of resting data were collected to perform baseline measurements before exercise.

The rest period was prolonged at the discretion of the investigator if additional time was required for adjustment to the mouthpiece and for stabilization of physiological variables. Ventilation VE , oxygen uptake VO 2 , and carbon dioxide production VCO 2 were monitored continuously, breath by breath, at rest, during exercise, and for 10 min of recovery after exercise, using a respiratory mass spectrometer Amis , Innovision, Odense, Denmark.

Data were then averaged over sec intervals. Calibration was performed before each study. Patients and controls were encouraged by the supervising physician to exercise to the limit of their symptoms.

Blood pressure was recorded using a mercury sphygmomanometer at rest, at the end of each 3-min stage, and at peak exercise. The electrocardiograph was monitored continuously. The oxygen uptake efficiency slope OUES was calculated by linear regression of VO 2 milliliters per minute and log 10 VE liters per minute 4.

The anaerobic threshold was quantified by the V-slope method 5. An indwelling catheter was inserted into a vein on the dorsum of the hand or arm before exercise.

After 15 min of rest, blood samples were taken into lithium heparin and sodium fluoride tubes and immediately separated by centrifugation at rpm for 5 min.

The supernatant was then placed in plain tubes and stored on ice. In addition, blood was taken into heparinized syringes and placed on ice for measurement of blood acidity at baseline, peak, and 10 min after exercise. The cannula was flushed throughout with normal saline.

Nonesterified fatty acids NEFA were condensed with coenzyme A CoA to form CoA esters, then oxidized by acyl CoA oxidase to form H 2 O 2. The concentration was assayed colorimetrically with a napthelene dye system Mira Plus Analyzer, COBAS, Basel, Switzerland.

For measurement of the precision of these estimates, see Table 2. Plasma amino acids were assayed by HPLC. all biochemical assays were performed in the biochemical laboratories of Great Ormond Street Hospital London, UK.

Patients ate after the monitored recovery period and remained resting under medical supervision until they had fully recovered from exercise. All comparisons between the patient and control groups were made using the Mann-Whitney rank-sum test.

Descriptive and comparative statistics and linear regression analyses were performed using SPSS All subjects successfully completed exercise uneventfully. Blood sampling was possible in seven of eight patients. Table 3 indicates the responses for patients and controls at peak exercise.

Individual VO 2 peak as a percentage of the individual control VO 2 peak is shown in Fig. Individual patient VO 2 peak as a percentage of the value in the control subject.

Figure 2 shows the mean RER for patients and controls across a range of relative exercise intensities i. normalized to percentage of VO 2 peak. The anaerobic threshold was not clearly identifiable in three of the patients and one of the controls.

Therefore, no additional analysis of this variable was possible. The mean blood glucose levels for patients and controls were not significantly different at baseline.

The patient mean then showed a progressive decrease throughout exercise and recovery. One patient did show a hyperglycemic recovery phase response. Although the mean of both groups rose throughout exercise, the rate of increase was greater for the control group, so that at peak exercise, there was no significant difference between the group means.

Both patient and control means showed the same pattern of decrease throughout exercise, followed by an increase in recovery to above baseline. The mean patient alanine level was greater than the control value throughout the entire profile, but the difference was only significant at 6 min of exercise due to the wide range of patient values.

Changes in the patient median and control mean levels of glucose, lactate, alanine, and NEFA are shown at rest, after 6 min of exercise, at peak exercise, and at 5 and 10 min of recovery Fig. There was no difference between patient and control mean hydrogen and bicarbonate ion concentrations at baseline.

One patient was acidotic before starting exercise. The bicarbonate concentrations remained very similar throughout the profile. The control group developed a significantly greater acidosis than the patient group at peak exercise. Venous hydrogen ion and bicarbonate concentrations are shown at rest, peak exercise, and 10 min postexercise Fig.

Glycogen storage diseases are a heterogeneous group of inherited disorders of carbohydrate metabolism caused by enzyme deficiency within either liver or muscle. They have been traditionally divided into muscle and hepatic forms depending upon the site of enzyme deficiency and the clinical phenotype.

GSD-I is deficiency of the enzyme G6Pase. It is a disorder of hepatic gluconeogenesis and glycogenolysis. Because there is no expression of G6Pase within normal muscle, it is traditionally assigned to the hepatic group 1.

Indeed, in a recent review of complications of GSD-I by the European Study on GSD-I, there is no mention of myopathy 6. This study shows that exercise capacity, as measured by VO 2 peak during maximal cardiopulmonary exercise testing, is significantly reduced in this group of GSD-I adults compared with normal controls.

This includes patients who were treated from infancy in accord with current recommendations. VO 2 peak can be influenced by patient motivation, but this observation was confirmed by the reduced patient OUES, which is a valid measure, even with submaximal effort.

This group of patients has an illness characterized by muscle pain and easy fatigability. Due to their interesting muscle physiology and biochemistry, they are a relatively well studied group. Figure 5 shows the individual exercise capacity of each patient in the two groups, expressed as the percentage of their control peak VO 2.

P, GSD I patient in the present study; M, McArdle patient from the study by Riley et al. Patients with GSD-I do not suffer from primary cardiomyopathy. They can develop hypertension, but no patient in this study had electrocardiographic evidence of left ventricular hypertrophy.

Respiratory disease is not a feature of GSD-I. The explanation would therefore seem to lie in skeletal muscle function. Patients with GSD-I cannot hydrolyze glucosephosphate. Therefore, in situations in which counterregulation is stimulated, one would expect a failure of hepatic glucose production and that the increasing concentrations of glucosephosphate are channeled through glycolysis and the pentose-phosphate pathway.

This is certainly the case in fasting. Patients develop hypoglycemia and increased blood lactate. To extend the period of euglycemia, patients regularly ingest low glycemic index foods, most commonly uncooked corn starch. In normal subjects, exercise creates a nonsteady state in which increasing glucose requirement is associated with a prompt increase in production and delivery to the contracting muscle.

There was no significant difference between the median blood glucose levels of patients and controls at the onset of exercise. Although, interestingly, one of the patients P4 did, in fact, show a hyperglycemic effect postexercise.

This suggests that for this patient acute endogenous glucose production is possible. This phenomenon has been documented previously in adults with GSD-I, who seemed resistant to fasting and had a documented hyperglycemic response to administered glucagons.

Enhanced prior glycogen synthesis and increased glycogen to lactate to glycogen cycling with liberation of free glucose by debrancher enzyme has been postulated to be the cause. However, recently, a new, more widely expressed enzyme with G6Pase activity has been described, and this may be contributing to glucose homeostasis 9.

GSD-I patients had significantly elevated basal blood lactate concentrations compared with the control group, and there was a wide variation range, 2. However, at peak exercise there was no significant difference in lactate concentration, indicating that the rate of increase was much greater in the control subjects.

This suggests that the control subjects were able to perform more anaerobic energy production within the muscle than were GSD-I patients. It may be that the lactic acidosis present at rest in these GSD-I patients would cause lowering of blood bicarbonate sufficient to reduce lactate efflux and inhibit anaerobic metabolism.

In one patient P1 , there was a notably low resting bicarbonate concentration This was associated with a high venous lactate level His ventilatory equivalent for CO 2 was 42, much higher than that of any other patient or control. One could reasonably postulate that in this patient, the acute acid-base disturbance was partly responsible for his extremely poor exercise capacity.

However, as a patient group, the median bicarbonate concentration at rest or throughout exercise was no lower than that of the control group. Therefore, a reduction in muscle lactate production may reflect a primary decrease in anaerobic metabolism.

In the liver of patients with GSD-I, glucosephosphate is channeled through glycolysis, causing increased production of acetyl-CoA with a concomitant increase in the production of fatty acids and cholesterol. At the same time, hepatic fatty acid oxidation is down-regulated by the inhibition of carnitine palmitoyltransferase-1 by the increased malonyl-CoA.

This explains the elevated plasma NEFA profiles previously reported in GSD-I patients. Our patients also have a significantly increased NEFA concentration at the onset of exercise compared with our control population. When exercise is initiated, catecholamine concentrations increase, and insulin concentrations decrease.

During the first 15 min of exercise, plasma NEFA concentrations usually decrease because the rate of uptake by the muscle exceeds the rate of appearance from adipolysis. During recovery, there is a rebound increase in NEFA level as reduction in lipolysis lags behind the decrease in muscle uptake 8.

The Randle glucose fatty acid cycle predicts that increased NEFA concentrations would lead to impairment of muscle glucose utilization The main features of this model are that increased fat oxidation in muscle would inhibit both pyruvate dehydrogenase and phosphofructokinase by accumulation of acetyl CoA and citrate, respectively.

This leads to an inhibition of insulin-stimulated glucose uptake. This work was extended by Shulman 12 , who proposed that fatty acids additionally caused insulin resistance through inhibition of insulin receptor substrate protein-1 signaling.

Ideally for this study we would have performed a series of exercise tests to allow familiarization with the equipment used. However, GSD-I is a very rare disease, so to maximize the number of patients recruited, we opted to perform just one test, but to apply the same conditions to control subjects.

A larger number of patients may have enabled us to comment on the anaerobic threshold. Patients and controls were asked to self-report exercise levels as sedentary, active, or very active, but it may be that this masks a degree of variation in physical activity, particularly among the sedentary group, which could contribute to the reported differences.

In this study, subjects were never in a steady state, but, rather, were constantly adapting to changes in exercise intensity. It would be instructive to perform additional studies with exercise at a submaximal level, closer to levels of physical activity that may be performed daily.

This study has documented a major reduction in exercise capacity in patients with GSD-I. It has demonstrated some biochemical aspects of exercise that are different from those of normal controls.

Although all patients showed a reduction in exercise capacity, there was a wide range of exercise tolerance. Mundy was supported by a grant from the Dromintee Charitable Trust UK. Chen YT Glycogen storage diseases. In: CR Scriver, AL Beaudet, WS Sly, D Valle, eds.

The metabolic and molecular bases of inherited diseases, 8th Ed. New York: McGraw-Hill; — Google Scholar. Miller JH , Stanley P , Gates GF Radiography of glycogen storage diseases.

Am J Roentgenol : — Bruce RA , Blackman JR , Jones JW Exercise testing in adult normal subjects and cardiac patients. Paediatrics 32 : — Baba R , Nagashima M , Goto M , Yokota M , Tauchi N , Nishibata K Oxygen uptake efficiency slope: a new index of cardiorespiratory functional reserve derived from the relation between oxygen uptake and minute ventilation during incremental exercise.

J Am Coll Cardiol 28 : — Beaver WL , Wasserman K , Whipp BJ A new method for detecting anaerobic threshold by gas exchange. J Appl Physiol 60 : — Rake JP , Visser G , Labrune P , Leonard JV , Ullrich K , Smit GP Glycogen storage disease type I: diagnosis, management, clinical course and outcome.

Results of the European Study on Glycogen Storage Disease Type I ESGSD I. GSD is hereditary, meaning it is passed down from parents to children. For most types of GSD, both parents are unaffected carriers, meaning they carry one copy of a misspelled gene that can cause GSD paired with a normal copy of the gene.

When both parents pass the misspelled gene to a child, the child has no normal copy of that gene and therefore develops GSD. In most cases GSD is diagnosed within the first year of life, but in some cases the diagnosis may not be made until later in childhood. Many different enzymes are used by the body to process glycogen.

As a result, there are several types of GSD. This type of GSD does not cause hypoglycemia. A thorough medical history can also lead the doctor to suspect GSD since it is inherited.

Other diagnostic tests may include:. Each type of GSD centers on a certain enzyme or set of enzymes involved in glycogen storage or break down. GSD mostly affects the liver and the muscles, but some types cause problems in other areas of the body as well.

Types of GSD with their alternative names and the parts of the body they affect most include:. GSD types VI and IX can have very mild symptoms and may be underdiagnosed or not diagnosed until adulthood.

Currently, there is no cure for GSD. Treatment will vary depending on what type of GSD your child has; however, the overall goal is to maintain the proper level of glucose in the blood so cells have the fuel they need to prevent long-term complications.

Until the early s, children with GSDs had few treatment options and none were very helpful. Then it was discovered that ingesting uncooked cornstarch regularly throughout the day helped these children maintain a steady, safe glucose level. Cornstarch is a complex carbohydrate that is difficult for the body to digest; therefore it acts as a slow release carbohydrate and maintains normal blood glucose levels for a longer period of time than most carbohydrates in food.

Cornstarch therapy is combined with frequent meals eating every two to four hours of a diet that restricts sucrose table sugar , fructose sugar found in fruits and lactose only for those with GSD I.

Typically, this means no fruit, juice, milk or sweets cookies, cakes, candy, ice cream, etc. because these sugars end up as glycogen trapped in the liver.

Infants need to be fed every two hours. Those who are not breastfed must take lactose-free formula. Some types of GSD require a high-protein diet.

Calcium, vitamin D and iron supplements maybe recommended to avoid deficits. Children need their blood glucose tested frequently throughout the day to make sure they are not hypoglycemic, which can be dangerous.

Some children, especially infants, may require overnight feeds to maintain safe blood glucose levels. For these children, a gastrostomy tube, often called a g-tube, is placed in the stomach to make overnight feedings via a continuous pump easier.

The outlook depends on the type of GSD and the organs affected. With recent advancements in therapy, treatment is effective in managing the types of glycogen storage disease that affect the liver. Children may have an enlarged liver, but as they grow and the liver has more room, their prominent abdomen will be less noticeable.

What causes McArdle disease?

The mechanisms responsible for the impairment in V̇O 2 peak in GSD IIIa are yet to be fully determined, but the associations between V̇O 2 peak, MVC, muscle size and quality highlight the role of muscle weakness.

Following implementation of these criteria, 7 individuals 3 female provided informed consent to participate in the study. Five of the participants walked independently, one required the use of a walking aid, and one required a wheelchair to travel over longer distances.

Following informed consent, on the day of testing participants had baseline non-fasting blood tests taken CK, lipid profile, glucose, urate. All exercise tests were conducted in an exercise physiology laboratory in the presence of a medical doctor and an exercise physiologist.

Tests were conducted in a specific order to reduce the likelihood of one test affecting another, and to allow adequate time for recovery between exercise bouts. First, resting measures of body composition and pain were taken. Patients then undertook the two exercise bouts. They first completed a CPET and then, following a minimum of two hours rest, during which patients ate lunch and completed questionnaires described below , they undertook knee extension exercise to determine MVC.

Patients were not restricted from eating or drinking for the duration of the study. An isotonic sports drink providing Throughout the day, patients were asked to stop exercise if they believed continuing might result in muscle soreness and damage.

On arrival to the laboratory, patients had their height Seca stadiometer, Seca, Hamburg, Germany , weight Seca scales, Seca, Hamburg, Germany , and body composition measured using bioelectrical impedance MCMA PLUS, Tanita Corporation, Tokyo, Japan.

A symptom-limited, incremental ramp cycling protocol to volitional exhaustion was performed to determine V̇O 2 peak and AT using breath-by-breath gas analysis Vyntus CPX Metabolic Cart, CareFusion, Höchberg, Germany. The workload during the ramp increased by between 5 and 15 watts per minute, depending on the fitness status of the participant.

V̇O 2 peak was defined as the average of the highest exertional oxygen uptake achieved over the last 20 s of exercise. The AT was determined using the modified V-slope method [ 39 ], confirmed by patterns of change in ventilatory equivalent and end-tidal gas measurements [ 40 ].

In addition to expired air gas analysis, continuous heart rate and peripheral oxygen saturation measurements were made, blood pressure was taken every 3 min, and a lead ECG was continuously monitored.

During knee extension strength assessment, participants were seated in a supine position on an isokinetic dynamometer Biodex System 4 Pro, Biodex Medical, Shirley, NY, USA.

Inextensible straps were fixed across the hip, distal thigh and chest to reduce extraneous synergistic movements undertaken during maximal contraction. Following the initial setup, participants were briefed on the MVC protocol, which was then followed by a series of warm-up knee extension isometric contractions set at 80°.

The MVC protocol consisted of two to three isometric knee extension at 80° with 5—10 min rest between contractions.

Torque was acquired from the dynamometer and analysed with supplementary software Biodex Advantage software, Biodex Medical, Shirley, NY, USA. VL ACSA was measured using software for panoramic reconstruction of images VPAN [ 46 , 47 ].

The ultrasound probe 7. Analysis of the VL ACSA was conducted offline using the analysis software IMAGEJ 1. All scans were performed and analysed by the same researcher.

Images were extrapolated from the capturing software and analysed offline. Linear extrapolation was undertaken on fascicles that extended beyond the edge of the screen, in line with previous methodology [ 43 ]. The accelerometer frequency was recorded at 60 Hz and was worn for between six and seven consecutive days.

On return of the accelerometer, the data was downloaded and converted to s epoch files GENEActiv software version 3. Analysis of the data was conducted using GENEActiv macro file version 9, using validated activity cut-off points [ 49 ].

Prior to exercise testing, Health-Related Quality of Life was estimated using the Item Short Form Health Survey questionnaire SF [ 50 ] and pain was assessed using the numeric pain rating scale [ 51 ].

The day after testing, patients were contacted via telephone to assess if they had any adverse reactions to the exercise trials, including further assessments of pain using the numeric pain rating scale.

If an adverse reaction was reported the patient was contacted on subsequent days until symptoms subsided. Predicted CPET values were calculated using published normative data; peak work rate [ 52 ], V̇O 2 peak [ 53 ], maximum voluntary ventilation MVV [ 54 ], maximum heart rate HR age [ 55 ], and strength [ 25 ].

Bao Y, Dawson TL Jr, Chen YT. CAS PubMed Google Scholar. Ko JS, Moon JS, Seo JK, Yang HR, Chang JY, Park SS. A mutation analysis of the AGL gene in Korean patients with glycogen storage disease type III.

J Hum Genet. Kiechl S, Kohlendorfer U, Thaler C, Skladal D, Jaksch M, Obermaier-Kusser B, et al. Different clinical aspects of debrancher deficiency myopathy.

J Neurol Neurosurg Psychiatry. CAS PubMed PubMed Central Google Scholar. Lucchiari S, Santoro D, Pagliarani S, Comi GP. Clinical, biochemical and genetic features of glycogen debranching enzyme deficiency.

Acta Myol. Berling É, Laforêt P, Wahbi K, Labrune P, Petit F, Ronzitti G, et al. Narrative review of glycogen storage disorder type III with a focus on neuromuscular, cardiac and therapeutic aspects. J Inherit Metab Dis. Hobson-Webb LD, Austin SL, Bali DS, Kishnani PS.

The electrodiagnostic characteristics of Glycogen Storage Disease Type III. Genet Med. Kishnani PS, Austin SL, Arn P, Bali DS, Boney A, Case LE, et al. Glycogen storage disease type III diagnosis and management guidelines. Preisler N, Laforet P, Madsen KL, Prahm KP, Hedermann G, Vissing CR, et al.

Skeletal muscle metabolism is impaired during exercise in glycogen storage disease type III. Preisler N, Pradel A, Husu E, Madsen KL, Becquemin MH, Mollet A, et al. Exercise intolerance in Glycogen Storage Disease Type III: weakness or energy deficiency? Mol Genet Metab.

Hoogeveen IJ, de Boer F, Boonstra WF, van der Schaaf CJ, Steuerwald U, Sibeijn-Kuiper A, et al. Effects of acute nutritional ketosis during exercise in adults with glycogen storage disease type IIIa are phenotype-specific: an investigator-initiated, randomized, crossover study.

Decostre V, Laforet P, Nadaj-Pakleza A, De Antonio M, Leveugle S, Ollivier G, et al. Cross-sectional retrospective study of muscle function in patients with glycogen storage disease type III.

Neuromuscul Disord. PubMed Google Scholar. Lees MJ, Wilson OJ, Hind K, Ispoglou T. Muscle quality as a complementary prognostic tool in conjunction with sarcopenia assessment in younger and older individuals.

Eur J Appl Physiol. PubMed PubMed Central Google Scholar. Shin S, Valentine RJ, Evans EM, Sosnoff JJ. Lower extremity muscle quality and gait variability in older adults. Age Ageing. Gadelha AB, Neri SGR, Bottaro M, Lima RM.

The relationship between muscle quality and incidence of falls in older community-dwelling women: an month follow-up study. Exp Gerontol. Jacques MF, Onambele-Pearson GL, Reeves ND, Stebbings GK, Smith J, Morse CI. Relationships between muscle size, strength, and physical activity in adults with muscular dystrophy.

J Cachexia Sarcopenia Muscle. Chastin SF, Ferriolli E, Stephens NA, Fearon KC, Greig C. Relationship between sedentary behaviour, physical activity, muscle quality and body composition in healthy older adults. Hughes VA, Frontera WR, Wood M, Evans WJ, Dallal GE, Roubenoff R, et al.

Longitudinal muscle strength changes in older adults: influence of muscle mass, physical activity, and health. J Gerontol A Biol Sci Med Sci. Google Scholar. Sentner CP, Hoogeveen IJ, Weinstein DA, Santer R, Murphy E, McKiernan PJ, et al. Glycogen storage disease type III: diagnosis, genotype, management, clinical course and outcome.

Jenkinson C, Coulter A, Wright L. Short form 36 SF36 health survey questionnaire: normative data for adults of working age.

Bassett DR, Howley ET. Limiting factors for maximum oxygen uptake and determinants of endurance performance. Med Sci Sports Exerc. Marzorati M, Porcelli S, Bellistri G, Morandi L, Grassi B. Exercise testing in late-onset glycogen storage disease type II patients undergoing enzyme replacement therapy.

Ørngreen MC, Vissing J. Treatment opportunities in patients with metabolic myopathies. Curr Treat Options Neurol. Kishnani PS, Sun B, Koeberl DD.

Gene therapy for glycogen storage diseases. Hum Mol Genet. Clinical Trial database: Safety, Tolerability, and Pharmacokinetics of UX in patients with Glycogen Storage Disease Type III GSD III.

Accessed 15 Aug Danneskiold-Samsoe B, Bartels EM, Bulow PM, Lund H, Stockmarr A, Holm CC, et al. Isokinetic and isometric muscle strength in a healthy population with special reference to age and gender.

Acta Physiol Oxf. CAS Google Scholar. Bohm S, Marzilger R, Mersmann F, Santuz A, Arampatzis A. Operating length and velocity of human vastus lateralis muscle during walking and running.

Sci Rep. Crockett K, Ardell K, Hermanson M, Penner A, Lanovaz J, Farthing J, et al. The relationship of knee-extensor strength and rate of torque development to sit-to-stand performance in older adults.

Physiother Can. Fukagawa NK, Brown M, Sinacore DR, Host HH. The relationship of strength to function in the older adult. van den Berg LE, Favejee MM, Wens SC, Kruijshaar ME, Praet SF, Reuser AJ, et al. Safety and efficacy of exercise training in adults with Pompe disease: evalution of endurance, muscle strength and core stability before and after a 12 week training program.

Orphanet J Rare Dis. The effects of resistance exercise training on strength and functional tasks in adults with limb-girdle, becker, and facioscapulohumeral dystrophies. Front Neurol. Arnold EM, Ward SR, Lieber RL, Delp SL. A model of the lower limb for analysis of human movement.

Ann Biomed Eng. Tomlinson DJ, Erskine RM, Morse CI, Winwood K, Onambele-Pearson GL. Combined effects of body composition and ageing on joint torque, muscle activation and co-contraction in sedentary women. Age Dordr. CAS PubMed Central Google Scholar.

McGregor RA, Cameron-Smith D, Poppitt SD. It is not just muscle mass: a review of muscle quality, composition and metabolism during ageing as determinants of muscle function and mobility in later life.

Longev Healthspan. Sims DT, Onambele-Pearson GL, Burden A, Payton C, Morse CI. Specific force of the vastus lateralis in adults with achondroplasia. J Appl Physiol. Ekelund U, Tarp J, Steene-Johannessen J, Hansen BH, Jefferis B, Fagerland MW, et al.

Dose-response associations between accelerometry measured physical activity and sedentary time and all cause mortality: systematic review and harmonised meta-analysis. Matthews CE, George SM, Moore SC, Bowles HR, Blair A, Park Y, et al.

Amount of time spent in sedentary behaviors and cause-specific mortality in US adults. Am J Clin Nutr. Poole DC, Jones AM. Measurement of the maximum oxygen uptake V̇o 2max : V̇o 2peak is no longer acceptable.

American Thoracic Society, American College of Chest Physicians. Am J Respir Crit Care Med. Derks TG, Van Rijn M. Lipids in hepatic glycogen storage diseases: pathophysiology, monitoring of dietary management and future directions.

Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man.

Valayannopoulos V, Bajolle F, Arnoux JB, Dubois S, Sannier N, Baussan C, et al. Successful treatment of severe cardiomyopathy in glycogen storage disease type III With D,Lhydroxybutyrate, ketogenic and high-protein diet.

Pediatr Res. Kiechl S, Willeit J, Vogel W, Kohlendorfer U, Poewe W. Reversible severe myopathy of respiratory muscles due to adult-onset type III glycogenosis. Neuromuscul Disord. Slonim AE, Weisberg C, Benke P, Evans OB, Burr IM. Reversal of debrancher deficiency myopathy by the use of high-protein nutrition.

Ann Neurol. Dagli, AI, Zori RT, McCune H, Ivsic T, Maisenbacher MK, Weinstein DA. Reversal of glycogen storage disease type IIIa-related cardiomyopathy with modification of diet. Sentner CP, Caliskan K, Vletter WB, Smit GP. Heart failure due to severe hypertrophic cardiomyopathy reversed by low calorie, high protein dietary adjustments in a glycogen storage disease type IIIa patient.

JIMD Rep. Yurista SR, Chong CR, Badimon JJ, Kelly DP, de Boer RA, Westenbrink BD. Therapeutic potential of ketone bodies for patients with cardiovascular disease: JACC state-of-the-art review. J Am Coll Cardiol. Van Hove JL, Grünewald S, Jaeken J, Demaerel P, Declercq PE, Bourdoux P, et al.

D,Lhydroxybutyrate treatment of multiple acyl-CoA dehydrogenase deficiency MADD. Mayorandan S, Meyer U, Hartmann H, Das AM. Glycogen storage disease type III: modified Atkins diet improves myopathy. Orphanet J Rare Dis. Francini-Pesenti F, Tresso S, Vitturi N.

Modified Atkins ketogenic diet improves heart and skeletal muscle function in glycogen storage disease type III. Acta Myol. PubMed Abstract Google Scholar. Olgac A, Inci A, Okur I, Biberoglu G, Oguz D, Ezgü FS, et al.

Beneficial effects of modified atkins diet in glycogen storage disease type IIIa. Ann Nutr Metab. Fischer T, Njoroge H, Och U, Klawon I, Marquardt T. Ketogenic diet treatment in adults with glycogenosis type IIIa Morbus Cori.

Clin Nutr Exp. CrossRef Full Text Google Scholar. Brambilla A, Mannarino S, Pretese R, Gasperini S, Galimberti C, Parini R. Improvement of cardiomyopathy after high-fat diet in two siblings with glycogen storage disease type III.

Kumru Akin B, Ozturk Hismi B, Daly A. Improvement in hypertrophic cardiomyopathy after using a high-fat, high-protein and low-carbohydrate diet in a non-adherent child with glycogen storage disease type IIIa. Marusic T, Zerjav Tansek M, Sirca Campa A, Mezek A, Berden P, Battelino T, et al.

Normalization of obstructive cardiomyopathy and improvement of hepatopathy on ketogenic diet in patient with glycogen storage disease GSD type IIIa. Venema A, Peeks F, Rossi A, Jager EA, Derks TGJ. Towards values-based healthcare for inherited metabolic disorders: an overview of current practices for persons with liver glycogen storage disease and fatty acid oxidation disorders.

Kishnani PS, Sun B, Koeberl DD. Gene therapy for glycogen storage diseases. Hum Mol Genet. Rossi A, Venema A, Haarsma P, Feldbrugge L, Burghard R, Rodriguez-Buritica D, et al.

A prospective study on continuous glucose monitoring in glycogen storage disease type Ia: toward glycemic targets. J Clin Endocrinol Metab. Feillet F, Bodamer OA, Leonard JV.

Increased resting energy expenditure in glycogen storage disease type Ia. Buscemi S, Noto D, Buscemi C, Barile AM, Rosafio G, Settipani V, et al.

Resting energy expenditure and substrate oxidation in malnourished patients with type 1 glycogenosis. Doneda D, Lopes AL, Oliveira AR, Netto CB, Moulin CC, Schwartz IV. Gaucher disease type I: assessment of basal metabolic rate in patients from southern Brazil.

Blood Cells Mol Dis. Rovelli V, Zuvadelli J, Piotto M, Scopari A, Dionigi AR, Ercoli V, et al. L-alanine supplementation in Pompe disease IOPD : a potential therapeutic implementation for patients on ERT?

There is no correlation between hepatic damages and muscular damages [ 3 , 4 ]. Histological studies carried out on myocardiac biopsies show, in patients with left ventricular hypertrophy, glycogen accumulation in cardiomyocytes, with no architectural disorganisation of muscular fibres.

This aspect is different from that observed in other hypertrophic cardiomyopathies, notably those of sarcomeric origin [ 4 ]. GSD III is most often diagnosed at paediatric age. Warning signs are thus generally identified by a paediatrician or a general practitioner.

When the diagnosis is made in adulthood, warning signs may be identified by a general practitioner, neurologist, hepatologist, internist or endocrinologist.

Whichever practitioner suggests the diagnosis, it should be confirmed in an approved centre of reference, where therapeutic decisions should also be made.

References centres have been created by the French ministry of health in They must have a sufficiently large number of patients with a group of rare diseases, i. metabolic or neuromuscular, and gather experts in a same place. All these centres are organised in national networks filières.

Metabolic physician: for children it is a specialised paediatrician, and for adults it may be a specialised internist, or endocrinologist, or, more rarely in France, a specialised hepatologist.

The starting age is variable, with median ages of presentation ranging from a few months of life to 8 years [ 3 ]. The symptomatology of GSD III is generally less severe than in type I regarding the carbohydrate balance: fasting tolerance is variable but generally longer and hypoglycaemic episodes tend to be less severe.

The early hepatomegaly sometimes stabilises later generally at puberty until it disappears completely on palpation in adulthood, probably in relation to an increase in fibrosis. This muscular fatigability is sometimes associated with hypoglycaemic events that can also occur during exercise.

In adulthood, some patients develop permanent lower limbs muscle weakness with difficulties for climbing stairs, getting up from a chair, etc.

In most cases, these symptoms remain moderate with slight progression; but some patients may require a stick for walking, and exceptionally, after the age of 40—50 years, may end up in a wheelchair. Distal muscle weakness is also frequent. Manual dexterity is often impaired at a young age, and can result in a lack of precision when writing.

Grip strength is decreased. Hand atrophy can also be observed in severe cases. Tibialis anterior muscle weakness can also be observed early, with difficulties for walking on the heels [ 3 , 4 ]. Patients more rarely complain of significant pain during exertion, and never present acute rhabdomyolysis episodes CK levels are permanently moderately increased , in contrast with McArdle's disease GSD type V , the most frequent muscle GSD which is characterised by muscle pain and exercise-induced rhabdomyolysis attacks.

Respiratory insufficiency remains exceptional [ 3 , 4 ], as respiratory muscles are rarely involved. The majority of patients have no heart symptoms. In the presence of hypertrophic cardiomyopathy, symptoms of cardiac failure can exist in both adults and children [ 4 ].

This is primarily on the left ventricle and characterised by dyspnoea and functional limitation on exertion. These symptoms are mainly linked to diastolic cardiac dysfunction with, in some cases, a component linked to a left intraventricular obstruction.

More rarely, in the most developed forms of cardiomyopathy, dyspnoea can be connected to an altered systolic function. Less frequently, some patients can also present palpitations, faintness and precordial catch syndrome linked to functional myocardial ischaemia.

The diagnosis of GSD III is initially suspected in response to an association of clinical symptoms and simple biochemical results that can easily be achieved in routine practice see non-specific biochemical tests.

Biological confirmation of the diagnosis then relies on two complementary approaches that can be carried out sequentially, concomitantly or separately [ 9 , 10 ]. The first approach is biochemical and relies on measuring the activity of the debranching enzyme amylo-1,6-glucosidase most often in leucocytes, potentially associated with a measurement of the glycogen content in red blood cells see biochemical diagnosis.

The second approach is molecular and can be carried out at the start following functional explorations or when there is a family history or to confirm an abnormal biochemical work-up.

In some countries, genetic testing is the preferred and only method. Relatively short fasting hypoglycaemic episodes can occur, associated with ketosis, post-prandial hyperlactacidaemia, hypertriglyceridaemia and an increase in transaminases which are generally relatively high during the first decade of life and decrease later on note that the high levels of transaminases and particularly ASATs can be of muscular origin.

Lactataemia evolves following a curve parallel to that of glycaemia, with a trend towards post-prandial hyperlactacidaemia and fasting hypolactacidaemia due to a preservation of gluconeogenesis.

CK levels are frequently elevated, sometimes in patients without muscle symptoms, and CK level should be assessed systematically.

Uric acid serum concentration is generally normal [ 10 ]. These highly specialised analyses can only be done in very few laboratories in France [ 9 , 10 ]. They are most often carried out on blood samples after isolating erythrocytes and leucocytes, but they can also be used when examining a muscular biopsy which is however not indispensable for the diagnosis.

Glycogen measurement [ 10 ]. A sharp increase in glycogen content measured in red blood cells occurs when the patient is fasting. Measurement of debranching enzyme activity [ 10 ].

The diagnosis relies on evidencing a deficient activity for this enzyme, measured most often in total leucocytes. Exceptionally, it can be measured in cultured fibroblasts or muscle biopsy. The AGL gene comprises 35 exons of which 33 are coding start codon in exon 3 and two exons 1 and 2 which are alternative noncoding hepatic and muscular.

It is located on the short arm of chromosome 1 at 11p Six isoforms have been described and the major isoform codes for a protein made up of amino acids. The majority of the variants classified as pathogenic or probably pathogenic reported in the ClinVar database are nonsense mutations or variants leading to a reading frame shift with the appearance of a premature stop codon deletion, insertion, duplication out of frame or mutation in the splice sites , responsible for the absence of residual enzyme activity [ 11 , 12 , 13 , 14 , 15 ].

Some variants characteristic of ethno-geographic groups, such as the deletion c. The deletion c. The penetrance is considered to be complete. The genotype—phenotype relationships are difficult to establish, apart from a reported link between the presence of mutations in exon 2 i.

The genetic diagnosis is traditionally carried out by sequencing the coding regions of the AGL gene. A study of this gene is carried out when clinical—biochemical indications are strong. But a gene panel analysis including the AGL gene by high-throughput sequencing NGS can lead to GSD III diagnosis in cases of isolated muscular symptomatology in adulthood rare form and when there are few indications or when they lack specificity [ 11 , 12 , 13 , 14 , 15 ].

This is the case in particular of gene panels involved in hepatic pathologies, hypoglycaemic episodes, GSDs or myopathies. They classified the AGL gene in the list of priority genes to be sequenced in cases of suspected metabolic myopathy [ 14 ]. Abdominal ultrasound allows measuring liver size and is often part of establishing the definite diagnosis.

Hyperechogenic hepatomegaly is often present. This will then be repeated during the monitoring, notably to look for hepatocellular adenomas or signs of fibrosis or liver cirrhosis. Prevalence of left ventricular hypertrophy is high.

The pattern of this hypertrophy is generally symmetrical, meaning that the thickening of the left ventricular walls takes place homogenously across the different walls. The main aim of the cardiological work-up is to screen for hypertrophic cardiomyopathy and to guide the treatment regimen, notably in the more severe forms associated with cardiac symptomatology, for which conventional cardiological treatments or dietary modifications can be indicated.

The risk of conduction disorders and supraventricular or ventricular rhythm disorders appears lower in comparison to the risk of hypertrophic cardiomyopathies of sarcomeric origin.

The risk of arrhythmia could be underestimated, notably because of the low prevalence of these pathologies. Rare cases of sudden death have been reported in children and adults [ 3 , 4 ].

It is unusual to observe conduction disorders or a pre-excitation syndrome, in contrast to other cardiac GSDs [ 16 ]. Echocardiography is a first-line test used to screen for and assess hypertrophic cardiomyopathies [ 4 ].

It is necessary when establishing a diagnosis, and should be repeated during the follow-up. It also enables an assessment of 1 the left ventricular ejection fraction rarely reduced ; 2 the diastolic function parameters, often abnormal, sometimes with an elevated left ventricular filling pressure; 3 the presence of a left ventricular obstruction, most often mid-ventricular, rarely subaortic; 4 the presence of an apical aneurysm, exceptionally reported in forms with mid-ventricular obstruction; 5 a right ventricular hypertrophy that may exist in the most severe forms [ 4 , 23 , 24 , 25 , 26 ].

This test aims at refining the diagnosis of cardiac rhythm disorder. It seems reasonable to offer this to patients with hypertrophic cardiomyopathy every 1—2 years depending on the severity or in the presence of palpitations, faintness or syncopes [ 16 , 17 , 18 ].

Cardiac MRI is useful to obtain a finely detailed characterisation of the myocardial damage. The implications of MRI data for care provision have not been established for GSD III, but the presence of myocardial fibrosis could encourage more frequent cardiac monitoring and more intensive therapeutic care [ 3 , 4 , 19 , 20 , 21 , 22 , 23 ].

MRI could be discussed when the ultrasound identifies ventricular hypertrophy, in children old enough for not being obliged to do the MRI under general anaesthesia meaning most often over 7 years , or in adults. This test could be repeated every 5 years owing to the complexity of diagnostic efforts.

These biomarkers are used routinely for both diagnosis and monitoring of systolic and diastolic heart failure. They can also be used in GSD III patients presenting left ventricular hypertrophy, even asymptomatic, since they can make it possible to identify heart failure, notably diastolic, at an early stage, and then monitor the evolution over time.

An assay at pre-symptomatic stage could serve as a reference later on, if symptoms appear that raise the suspicion of heart failure. In patients presenting exercise-related dyspnoea, a high level of these biomarkers could help obtain a positive diagnosis.

These assays can easily be incorporated into the annual biological work-up programmed in the context of general follow-up for the pathology.

However, to date, no reported data support their use in routine practice [ 3 , 4 ]. Skeletal muscles evaluation most often show mild impairment in younger patients.

With age, the muscle impairment can worsen, often after 30 years of age [ 27 , 28 , 29 ]. In rare cases, the severity of lower limbs muscle weakness may require wheelchair assistance, generally after the age of 40 years. The initial work-up should be performed in a neuromuscular reference centre, by trained neurologists and physiotherapists.

It will then serve as a reference for the subsequent follow-up [ 31 , 32 , 33 , 34 , 35 ]. The most common posture defect, characterised by an anterior pelvic tilt and wide base of support, can be the result of the hepatomegaly.

Motor Function Measure MFM scale: evaluation of gross motor skills. Brooke and Vignos scales: situate the functional capacities of the limbs [ 30 ]. Assessment of manual dexterity using the Purdue pegboard [ 35 ]. These tests are not used in children, but are regularly performed in patients 14 years of age and older.

Muscle MRI is now largely used in neuromuscular centres, allowing assessment and quantification of the severity of muscle involvement and fatty replacement of skeletal muscles.

It is a non-invasive tool, and in our experience should be performed preferentially in adults because muscle lesions generally occur at adult age in GSD III.

Therefore, this exam is probably much less important for the follow-up during childhood [ 36 , 37 ]. The main limitations of this exam are claustrophobia and severe respiratory insufficiency which prevent patients from lying down, but this complication is exceptional.

Electroneuromyography is not systematic and most often detects non-specific myopathic features during detection. It should, however, be systematically performed when patients complain of sensory symptoms, or when characteristics and progression of muscle weakness are unusual and severe.

The possible coexistence of peripheral nerves involvement remains debated, and is suggested in adult patients presenting distal muscular weakness [ 38 , 39 , 40 , 41 ]. This distal muscular weakness is probably the consequence of distal myopathy, and a recent study of a series of 16 patients, who all underwent an ENMG following the standard protocol, did not show any sign of peripheral nerve damage [ 42 ].

These tests should only be performed in reference centres on a case-by-case basis. They can, however, lead to the diagnosis in rare cases in adults, when muscle symptoms are predominant, with moderate hepatic manifestations in childhood that were not recognised as GSD. When performed, muscle biopsy always shows massive glycogen accumulation after PAS staining, with large vacuoles of muscle fibres [ 43 ].

Focal endomysial fibrosis with chronic inflammation may also be found. These histopathological abnomalies are more marked than in other muscle GSDs, and may suggest GSD III [ 43 , 44 , 45 ]. As a complement to abdominal ultrasound, and especially when hepatic lesions have been detected, abdominal MRI with injection of a contrast medium is indicated for the monitoring and precise diagnosis of these lesions.

It is ideally performed annually from the age of 10 years age at which the children are able to undergo this test without moving , or more frequently in cases of potentially progressive lesions. It also makes it possible to assess the indirect signs of cirrhosis [ 46 , 47 , 48 ].

MR elastography performs better than MRI for the detection of fibrosis, but no data are available to date in GSD III. Although this technique is frequently indicated to assess hepatic fibrosis in many chronic liver diseases, its use in GSD III has yet to be validated.

Patients then act as their own control, throughout the monitoring. The neuropsychological aspect of the disease is rarely addressed in the different recommendations or studies of cohorts of patients with GSD III.

Psychological support may prove necessary. Consequences of repeated hypoglycaemic episodes on psychomotor development remain unknown since little data are available. The problems observed could explain some of the economic and social difficulties experienced by the patients, and the difficulties they have in observing regular medical follow-up.

In practice, as for other metabolic diseases, brain MRIs and neuropsychological tests are not indicated systematically [ 5 ] but can be discussed on a case-by-case basis depending on the clinic. Some patients may benefit from social support.

Like in all chronic diseases involving a strict diet, with frequent meals at fixed times and sometimes nocturnal enteral feeding, orality disturbances should be screened for systematically at every consultation, especially in children patients who are unable to brush their teeth, are only accepting mashed food and soups, cannot chew and find it hard to swallow small bits of food.

The differential diagnoses for GSD III depend on the age of the patient. During childhood when hepatic symptomatology is predominant, main differential diagnoses are other hepatic GSDs:. It manifests itself by hypoglycaemic episodes generally more severe and hepatomegaly. Glycaemia and lactataemia progress by cross-reacting with hyperlactacidaemia during hypoglycaemic periods, and no ketosis.

CPKs are most often normal. There is hypertriglyceridaemia and hypercholesterolaemia, as well as hyperuricaemia. Transaminases may be normal or moderately increased.

Neutropenia or even inflammatory damage to the digestive tract can be present in type Ib. There are no signs of muscular impairment. Liver phosphorylase deficiency leads to hepatic damage that is generally more moderate with non-severe or even absent hypoglycaemia.

Transaminases are moderately increased and CPKs are normal. The hepatomegaly present in childhood tends to disappear with puberty.

There are neither signs of muscular nor cardiac damage. The deficiency of phosphorylase kinase in the liver can be linked either to a deficiency of a purely hepatic subunit subunits A2 and G2 or to a deficiency of a subunit shared with the muscular enzyme subunit B.

Hypoglycaemia and hyperlipidaemia are variable and generally moderate. They attenuate in adulthood. Hepatomegaly is present early in childhood and is associated with failure to thrive. There is an increased risk of hepatic fibrosis. In the subunit B deficiency, discrete muscular hypotonia is also noted.

The transmission is X-linked for the subunit A2 deficiency and autosomal recessive in deficiencies of subunits G2 and B.

If the disease was not diagnosed in childhood, and since hepatic symptomatology becomes more discrete and muscular impairment more important with time, the main differential diagnoses in this case are other muscular GSDs, as well as other metabolic myopathies and muscular dystrophies.

The liver is one of the target organs of GSD III, but hepatomegaly and fasting tolerance generally improve with age. However, since life expectancy of GSD III patients is lengthening, we are beginning to better understand the long-term complications of the disease and there are perhaps more to discover.

Several publications have demonstrated a cirrhogenic evolution. Cirrhosis can progress towards end-stage liver failure [ 4 ].

Some articles have also reported the occurrence of hepatic adenomas in patients living with GSD III. However, these adenomas occur much less frequently than in the course of GSD type 1 [ 3 , 48 ]. Finally, observations have also been published of hepatocellular carcinomas in patients with GSD III, generally following cirrhogenic evolution [ 46 , 47 , 48 ].

To date, there are no reliable biomarkers to confirm that cirrhosis has evolved to hepatocellular carcinoma. Alpha-foetoprotein should be measured regularly, but the results should be interpreted with caution and normal values should not rule out hepatic imaging.

The main biochemical abnormality present over the years is high serum transaminase concentrations. There is no manifestation of liver failure, excepting in the final stages of decompensated cirrhosis. Biochemical monitoring relies on measuring prothrombin time, ASAT, ALAT, albumin and bilirubin.

In adults, it is important to ensure that the high levels of transaminases are not due to another cause chronic liver disease, virus B or virus C infection, medicinal toxicity, autoimmune disease, NASH.

In young children, hepatic imaging monitoring involves annual ultrasounds. In older patients, starting in the second decade of life, this is completed with an annual hepatic MRI with injection of a contrast agent, since this enables an early detection of intrahepatic nodules, and evidences both direct or indirect signs of the development of cirrhosis, adenoma or hepatocellular carcinoma [ 3 , 46 , 47 , 48 ].

Hepatic elastometry techniques such as Fibroscans R can help to monitor the appearance of fibrosis, although they have not been validated for this pathology. Patients generally present growth retardation in childhood, but the majority then catch up to reach normal height by adulthood.

Finally, female patients often present polycystic ovary syndrome; however, no effects on fertility in adulthood have been evidenced [ 49 ]. The pathophysiology of these endocrine manifestations is not yet well understood, but insulin resistance due to regular ingestion of glucose and excess body weight appears to be one of the main factors [ 50 , 51 ].

Bone complications are relatively frequent in patients with GSD III. Osteopenia or even osteoporosis can result from the addition of several factors: myopathy, metabolic imbalance notably hypercholesterolaemia and hypertriglyceridaemia , and occasionally chronic ketosis in cases of recurrent hypoglycaemia [ 52 ].

Bone monitoring should be done regularly by osteodensitometry, at a frequency that depends on the severity of bone damage [ 52 ]. Vitamin D supplements are required.

Additionally, muscular reeducation can contribute to improve bone trophicity. The diagnosis should be announced during a dedicated consultation. It should be done by a physician who knows the disease well, and if possible, in the presence of both parents.

It includes an explanation of the diagnosis and the complications, planning of monitoring and therapeutic possibilities, genetic advice screening siblings , and a request for consent to genotyping. This is an autosomal recessive inherited pathology.

Genetic advice should be offered to couples when genetic results are available. Both parents are generally heterozygous carriers of one of the two mutations found in their child. If the pathogenic variants have been identified and characterised in the parents, prenatal diagnosis is possible on chorionic villi sampling or amniotic fluid [ 3 , 9 , 10 ].

Preimplantatory genetic diagnosis may potentially be proposed. Instigate a specialised dietary treatment to prevent hypoglycaemic episodes and ensure optimal metabolic balance that allows satisfactory growth. Treat any potential cardiac failure or rhythm disorder and limit the progression of the cardiomyopathy if present.

Consider non-specific complementary care if required psychological support, social worker, etc. The aim of the dietary treatment in childhood is to prevent hypoglycaemic episodes and ensure a metabolic balance that enables satisfactory growth [ 3 , 6 , 53 , 54 ]. For this, blood glucose levels should always be above 0.

For an optimum metabolic balance, they should remain between 0. The dietary treatment prescription should be adapted to clinical signs particularly in cases of cardiac failure and to biochemical work-up blood glucose cycle, hepatic work-up, lipid profile, etc.

This specific feeding regime should be individualised for each patient, despite the generalities in the dietary treatment [ 1 , 2 , 3 ].

To reach these objectives, the diet in young childhood tends to be high in carbohydrates, with intake of bot raw and cooked starches [ 57 , 58 ]. Food intake is divided into portions to be taken at set times according to fasting tolerance, during the diurnal cycle.

Nighttime: introduction of continuous enteral feeding CEF if fasting is badly tolerated, or of one to two snacks. The nutrient balance differs from recommendations for the general population.

It is adapted to age categories and natural history of GSD III: a tendency towards high-carbohydrate intake in young childhood to prevent hypoglycaemia, with a progressive switch towards high-protein intake during childhood [ 59 , 60 ].

Protein intake is increased as carbohydrates is decreased, to favour gluconeogenesis and limit glycogen storage in both liver and muscles. On the other hand, the diet should be poor in sucrose sugar to limit the energy intake and avoid hyperglycaemic spikes.

The dietary regime, although specific, should also respect social, cultural and religious habits of the family. Despite the constraints of the adapted diet, unprocessed foods should be prioritised.

Breastfeeding on demand is possible up to 6 months or even longer but at a minimum of 8 feeds per day in the first months. This rhythm should be tailored to fasting tolerance blood glucose cycle. Otherwise, all infant formula milks are suitable, stage 1, then stage 2.

All infant milks breastmilk or formula mostly contain lactose disaccharide very rapidly hydrolysed and digested ; this is why it is important to complement bottles or breastfeeds with maltodextrin polysaccharide, slower to digest , to extend the fasting time.

Introduction of sugar-free unflavoured dairy products and sugar-free fruit purees, alternated for dessert. The diversification should continue throughout the 1st year selection, texture, etc. like for all young children, with a specific adaptation:.

Introduction of raw cornstarch around one year of age [ 57 ]. Increase in the proportion of proteins in the ration stimulates gluconeogenesis pathway from the first year onwards. There are two possibilities to reduce the nightly fasting time: dividing up food into several snacks or continuous enteral feeding CEF.

To find the best solution, the decision should be made collectively, involving both multidisciplinary team and family [ 55 ]. During the period when nocturnal fasting time is short, a continuous supply of glucose makes it possible to obtain satisfactory growth thanks to better metabolic balance, and to avoid nocturnal awakening child and families.

The risk remains of severe hypoglycaemia in case of sudden stop of the enteral feeding pump reactive hypoglycaemia by hyperinsulinism , and also during the programmed halt in the morning.

Breakfast should thus be given within a maximum of 30 min after stopping the pump. The first year of life, CEF is made of infant milk enriched with maltodextrin, to cover glucose requirements. Around 1 year of age, ready-to-use nutritional paediatric mixes pouches: homogenous, stable mix, hygienic, practical, etc.

can be prescribed. Very often, nocturnal drip feeding is no longer necessary when children start primary school. This is replaced by two snacks during the night once fasting time is greater than 6 h.

After 1 year of age, raw cornstarch progressively replaces maltodextrin in the milk quantities adapted to both fasting time and digestive tolerance.

Raw cornstarch is introduced in the ration around 10—12 months of age [ 57 , 58 , 59 ]. The absorption of this very complex carbohydrate is delayed and spread out over time, which ensures glucose supply between mealtimes, thus making it possible to space out meals.

To amplify its delaying effect, cornstarch should be taken around 20—30 min after the end of either meals or snacks. The introduction should be progressive and adapted to each child, to avoid causing digestive problems: gas, bloating, diarrhoea linked to digestive immaturity.

The first corn starch proposed should be Maïzena®. After 2 years of age, it is then possible to use Glycosade® Vitaflo laboratory, Nestle Health Science as an alternative [ 57 , 58 ]. This latter starch is modified, thus providing some patients with better metabolic control, by extending fasting time, compared to Maïzena®.

It also improves digestive tolerance, at equal quantities. This type of starch is introduced during a blood glucose cycle work-up and metabolic assessment, to assess its efficacy [ 58 ]. In this way, the daily division of tolerated and necessary raw starch doses is defined and prescribed [ 55 , 57 ].

The cornstarch is given raw, diluted in a cold liquid of twice the volume of the weight of the starch, and given alone or after food intake.

To increase protein supply, the starch can be mixed with cold milk. The rhythm of raw starch snacks is tailored for each child, and reviewed at every consultation growth, school, sport, etc. Starting in adolescence, the quantities of raw starch should decrease progressively, to finally be interrupted in adulthood except in specific cases.

A higher protein intake compared to a normal diet will enable the activation of gluconeogenesis from glucogenic amino acids. As soon as possible in adolescence, the protein intake should be increased, and carbohydrates decreased [ 60 , 61 ].

The increase in the proportion of proteins or lipids should not result in an increase in overall energy intake. In order to follow recommendations, ensure that the proportion of carbohydrates is reduced [ 60 , 61 ]. Pay attention to the risks of high-protein diets: renal damage through high protein intake and increase in uric acid in particular, to be closely monitored.

Carbohydrate intake should be decreased in kind, especially of simple carbohydrates saccharose, fructose. Raw starch intake at night should be stopped progressively , if this has not been done in adolescence to be replaced by protein powders or high-protein food.

In cases of severe cardiac damage, recommended diet is high in proteins, low in carbohydrates and high in lipids to complete the energy intake [ 62 , 63 , 64 , 65 ]. The aim of this diet is to reduce the risk of cardiac and muscular glycogen overload, while maintaining blood sugar levels by favouring gluconeogenesis from lactates and ketone bodies.

In GSD III, an overly high intake of carbohydrates can worsen cardiac damage, whereas cardiomyopathy appears to be reversible with the introduction of this specific nutritional treatment [ 64 , 65 , 66 ].

Some teams also noted an improvement in musculoskeletal damage after introducing this diet. However, it is more burdensome than a usual diet.

Thus, despite its efficacy, adhesion to the diet and impact on both family and social life should be assessed at each consultation. However, nocturnal enteral feeding is not systematic in childhood, particularly if blood glucose levels are high enough after a night of fasting.

It is then necessary to introduce a snack at the beginning of the night, most often between 10 pm and midnight. The fasting tolerance should be checked during a hospital stay in order to set evening snack and breakfast times.

This type of feeding is prescribed alongside an addition of ketone bodies 3 OH sodium butyrate in 4—5 intakes per day as an energy substrate for cardiac and skeletal muscles [ 67 ]. It is not necessary to prescribe a low-salt diet since ketone bodies do not contain sodium chloride but sodium hydroxybutyrate.

In all cases, this very specific diet should be prescribed, undertaken and adapted in a specialised centre. Whatever the age of the patient, this requires a healthcare structure with a specialised metabolic dietician:.

Monitor growth, height and weight, if growth is not satisfactory BMI chart until target height is reached. Regularly perform adapted biochemical metabolic work-ups with installation of a continuous glucose monitor monitors blood glucose levels , to adapt rhythm and composition of food intakes and enteral feeding [ 68 ].

An alternative could be to prescribe a blood glucose meter and provide education for performing regular capillary blood tests at home. More individually, it could be defined as the blood glucose level at which neurological signs appear.

This level is specific to each patient due to the individual capacity to use alternative energy substrates ketone bodies, lactate. If hypoglycaemia occurs outside mealtimes, it is possible to then give a snack made of a food rich in complex carbohydrates bread, biscuit, cereals or raw starch childhood or a high-protein food from adolescence onwards : milk, dairy products.

In case of symptomatic diastolic cardiac failure, low doses of loop diuretics minimum effective dose can provide significant functional improvements.

Bradycardic calcium channel blockers can be proposed, as a second-line treatment, if beta-blockers are contra-indicated or badly tolerated, but associating both treatments is not generally necessary. In the exceptional cases of atrial fibrillation, the treatment is the same as for general population with effective anticoagulant therapy.

In the same way, the very rare cases of progression to systolic cardiac failure should receive a conventional treatment of cardiac failure [ 4 ]. In cardiomyopathies, sudden death prevention relies on installing implantable defibrillators in patients at high risk of cardiac events. This is notably the case in the primary prevention of hypertrophic cardiomyopathies of sarcomeric origin.

It does not appear appropriate to use the same treatment algorithms in hypertrophic cardiomyopathies associated with GSD III, since the level of rhythm risk appears lower. It is, however, difficult to estimate this precisely because of the low prevalence of this pathology and the absence of large-scale series with sufficiently long monitoring times.

A few rare cases of sudden death have been reported in both children and adults from 4 months to 36 years for which the rhythm mechanism was unfortunately not recorded [ 4 , 16 , 26 ].

No cases of sustained ventricular tachycardia or high-grade conduction abnormalities have been reported. Given these elements, the indication of an implantable defibrillator, installed subcutaneously as a first-line treatment because of the absence of conduction abnormalities, should be discussed on a case-by-case basis for patients with the most severe hypertrophic cardiomyopathies, especially when this is associated with ventricular hyperexcitability and the presence of myocardial fibrosis on MRI [ 4 ].

Like for low-carbohydrate and high-protein diet, the underlying hypothesis is to provide the cardiac muscle with another energy substrate, easier to use than glycogen.

The prescription is limited to specialised units in rare situations [ 67 ]. The care provision for muscles depends on the musculoskeletal work-up [ 38 , 39 , 40 , 41 ]. Depending on muscular work-up, each specific deficit should be worked on.

What Is Glycogen Storage Disease Type V (GSD V)? Sgorage storage disease Type III GSD III MIM is an autosomal recessive Exercise recommendations for glycogen storage disease due to deficiency of the debranching Low-fat weight control GDE encoded by the AGL gene, rrcommendations on chromosome 1p Bone monitoring should be done goycogen by Low-fat weight control, at a frequency that storagr on the severity of bone Green tea liver detoxification [ 52 ]. It does not appear appropriate to use the same treatment algorithms in hypertrophic cardiomyopathies associated with GSD III, since the level of rhythm risk appears lower. Tsushima K, Koyama S, Ueno M, et al. Muscle pain myalgia Fatigue Cramps Exercise intolerance Intermittent claudication Muscle pain on mild exertion in the calf muscle, usually attributed to peripheral artery disease Second wind phenomenon Exercise becomes easier after a period of moderate and tolerable exercise Stiffness Muscle swelling after exercise Myoglobinuria Muscular atrophy Mostly proximal muscles affected and in elderly patients. Google Scholar. People also looked at.
Bacteria-fighting technology Journal of Rare Diseases volume 17 recommendatins, Article number: 28 Cite diseasw article. Metrics details. Individuals with glycogen storage disease Exefcise Low-fat weight control IIIa Low-fat weight control experience muscle weakness and exercise limitation that worsen through adulthood. However, normative data for markers of physical capacity, such as strength and cardiovascular fitness, are limited. Furthermore, the impact of the disease on muscle size and quality is unstudied in weight bearing skeletal muscle, a key predictor of physical function.


Understanding Glycogen Storage Disease Type 1b and its impacts.

Author: Magor

2 thoughts on “Exercise recommendations for glycogen storage disease

Leave a comment

Yours email will be published. Important fields a marked *

Design by