Immobility is associated with metabolic alterations in muscle leading to an increased dependence on glycogen use and a reduced capacity for fatty acid oxidation.

Such changes may be detrimental for persons with GSD from a metabolic perspective. However, exercise may alter skeletal muscle substrate metabolism in ways that are 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.

Cycle ergometry of patient F. The prognosis of McArdle disease is usually good, and life expectancy is normal although severe cases with muscle wasting and extreme weakness and death in childhood have been described [ 1 , 2 , 3 , 4 , 10 ]. At present there are no causal treatment options available.

Some symptomatic treatment options may reduce symptoms or enhance the amount physical activity that can be tolerated. These treatment options include oral sucrose before exercise [ 11 ], a low dose of oral creatine [ 12 ], vitamin B6 [ 2 , 10 ], and coenzyme Q10 [ 2 , 10 ].

Our study about the use of clenbuterol over a month period leads to a subjective improvement of exercise tolerance in three patients. Some relatives of the patients noted an improved exercise tolerance after clenbuterol intake over some weeks [ 2 ].

One patient from our study has used a low-dose clenbuterol 0. This patient used clenbuterol for some months with regular breaks of weeks up to months between the therapy cycles. A systematic Cochrane review on pharmacological and nutritional treatment options has been published by Quinlivian et al.

There do exist animal models for McArdle disease in sheep, cows, mice, and rats that may be used to test potential therapies in future studies [ 10 ]. Gene therapy of McArdle disease might be a future option, but its dangers outweigh the possible advantages at present [ 10 ].

Patients with McArdle disease are at risk of developing myoglobinuria and even kidney failure due to rhabdomyolysis after exercise or anesthesia [ 2 , 3 , 12 , 13 ]. Therefore, patients affected by McAd should learn how to accomplish daily activity with McAd and how to avoid major muscle damage and the risk for massive rhabdomyolysis and acute kidney failure.

Some cases with insulin resistance and a diabetes type II-like clinical picture in patients with McArdle have been described, but there is no known connection between type I diabetes and McArdle disease [ 10 ]. Increased glycogen storage in the muscle of McArdle patients has been suggested as a probable cause of insulin resistance in McArdle patients [ 10 ].

Overweight has been observed in many patients with McAd [ 14 ]. This might be a potential risk factor for developing type II diabetes as it is for other people without McArdle disease. Another potential problem is the possible risk of malignant hyperthermia which is a complication during general anesthesia associated with different muscular diseases.

Although no case of malignant hyperthermia during anesthesia has been described in McAd so far, it is a potential risk when patients with McAd have to undergo operations with the need for general anesthesia.

Therefore, precautions have to be taken by the anesthesiologist, and local or regional anesthesia may be preferred whenever feasible [ 6 , 13 ]. As described above patients with McAd might suffer from exercise intolerance and pain, fatigue, and cramps during exercise, typical clinical symptoms of McArdle disease.

Cases with extreme rhabdomyolysis and myoglobinuria have, e. The variation of creatine kinase CK levels in the blood has been investigated in a male with McAd over a period of several months by the author [ 2 ].

Figure 2 shows the results from this German doctor thesis from the year The results indicated that anaerobic exercise and physical activity demanding great strength or strenuous exercise lead to huge increases in creatine kinase activity, whereas aerobic exercise did not increase blood creatine kinase levels to a great extent.

Aerobic exercise was shown to be associated with lower creatine kinase levels after physical activity in a number of instances during the study period [ 2 , 20 ].

This finding was later proofed by other researchers [ 10 ]. Creatine kinase levels from a long-term follow-up over 5 months [modified from [ 2 ]]. Many patients with McArdle disease do experience this phenomenon that was first described by Pearson et al.

During exercise this phenomenon can lead to better endurance because patients are able to exercise for a longer period and experience physical activity as less painful in the long run.

Aerobic exercise is endurance exercise where oxygen is needed in energy production. Aerobic energy production takes some minutes to start but can help to supply energy for muscular activity over a longer period of time several minutes up to several hours. Due to the lack of glucose that cannot be released from the glycogen deposits in the muscle, patients with McArdle disease rely on fatty acids, amino acids, and glucose from the liver as energy source during exercise [ 2 , 10 ].

These mechanisms are based on aerobic metabolism. Patients with McAd can therefore tolerate longer periods of physical activity well if it is aerobic exercise of mild-to-moderate intensity.

The work intensity that patients with McAd do tolerate can show big variations between different patients. During the study period, different types of physical activity were recorded in a diary by the patient.

Different researchers have recommended aerobic training and aerobic conditioning in order to improve physical activity, oxygen uptake, cardiovascular fitness, and energy supply via the blood in McAd [ 2 , 10 , 23 , 24 , 25 , 26 ].

Especially walking and cycling with mild or moderate intensity can be recommended for all McAd patients to improve their physical capacity [ 2 , 10 , 25 , 26 , 27 ]. Aerobic metabolism usually starts after 7—10 min of exercising.

Therefore, patients with McAd should warm up with low intensity and may increase the intensity of physical work after 7—10 min. Some of the patients experience the above described second wind phenomenon. During anaerobic exercise within the first seconds and minutes or using great strength , energy is supplied by anaerobic mechanisms as anaerobic glycogenolysis without oxygen.

Short periods of activity with high intensity such as running, walking upstairs, and carrying or lifting heavy weights require anaerobic metabolism. Due to the deficiency of the myophosphorylase enzyme in the muscle of McAd patients, this is hampered.

Anaerobic physical activity can thus lead to muscular damage in patients with McAd and should be avoided as far as possible by patients with McAd [ 2 , 10 , 25 ]. Nevertheless supervised resistance training has been shown to improve muscle strength in patients with McAd [ 28 ].

Pietrusz et al. Sport is the most important therapeutical option for patients with McArdle disease. Aerobic conditioning can be recommended to all McAd patients, but anaerobic exercise may lead to muscular damage. It has been shown by different researchers that regular physical activity may lead to improved exercise capacity [ 2 , 10 , 23 , 24 , 25 , 26 ].

As we have learned from practical experience and the scientific literature, extensive physical and strenuous exercise may lead to muscle damage, myoglobinuria, and even acute kidney failure [ 15 , 16 , 17 , 18 , 19 ]. Nevertheless Santalla et al. and Pietrusz et al. have shown that resistance training under expert supervision is feasible and improves muscle strength in McArdle patients.

But it is important that this type of training is performed under supervision in order to avoid muscle damage [ 28 , 29 ]. On the other hand, a case study with a long-term follow-up of one patient with McAd has shown that mostly aerobic activity did not lead to an increase in the creatine kinase level.

Instead, moderate cycling or hiking led to a decrease in the creatine kinase [ 2 ]. In the same patient, anaerobic exercise lead to increased CK levels suggesting muscle damage after carrying heavy weights [ 2 ].

In order to avoid muscle damage by vigorous exercise or in a risky way, all patients with McAd should receive sport medical advice on an individualized training plan that meets their individual training needs.

In order to enhance patient compliance, common aims and routines for physical activity and sports should be established. In conclusion, regular activity and sport are paramount for patients with McArdle disease.

Patients benefit from regular physical activity. Sport should be based on aerobic conditioning such as walking and cycling, whereas anaerobic exercise of high intensity over short periods should be avoided in general.

Some case reports suggest that even resistance training might be feasible, effective, and safe for patients with McAd. Obviously there is individual variation of the intensity that is appropriate for different patients. Therefore, a cooperation with a doctor experienced on sports medicine, trainer, and physiotherapist can help to establish an individualized training plan in order to maintain and possibly to improve physical capacity without increasing the danger for undesirable effects of too much physical activity.

Probably a self-monitoring of the CK blood level like measuring blood-glucose in diabetes patients could help to guide training and individual response to exercise in the future.

More research on specially designed training programs for McAd is needed. The following general recommendations shown in Table 4 are based on personal experience of the author and the current state of the scientific literature [ 2 , 10 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 ].

Aerobic conditioning walking or cycling is the preferable training method for patients with McAd. Keep on doing physical activity on a regular basis three to five times a week using aerobic exercise, such as walking or cycling for about 30—40 min on each occasion.

Regular training of mild-to-moderate intensity will improve physical capacity and may postpone weakness and muscle wasting in elderly patients. As shown above, sport has therapeutic potential for people with McArdle disease.

Sport is used with reason and is therefore not a danger but a powerful medicine. Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution 3. Edited by Jesmine Khan. Open access peer-reviewed chapter Sports and McArdle Disease Glycogen Storage Disease Type V : Danger or Therapy?

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Impact of this chapter. Abstract McArdle disease glycogen storage disease type V is an inborn error of energy metabolism in the muscle. Keywords McArdle disease glycogen storage disease type V rhabdomyolysis endurance exercise muscle strength exercise aerobic exercise anaerobic exercise sports medicine.

bollig rsyd. Introduction and background 1. Are certain types of physical exercise better than others? Muscle cramps and tenderness Type VIII Phosphorylase b kinase deficiency X-linked recessive Liver, brain Ataxia, spasms, brain degeneration Type IX Phosphoglycerate kinase deficiency X-linked recessive Liver Mild hypoglycemia Type X Phosphoglycerate mutase deficiency Autosomal recessive Liver, muscle Exercise intolerance, muscle pain.

Table 1. 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.

Table 2. Clinical picture Elevated creatine kinase CK levels in the blood Absence of increased venous lactate during forearm ischemic exercise test or cycle ergometry Low or absent myophosphorylase activity on histochemical or biochemical examination of muscle biopsy Genetic testing the muscle phosphorylase gene is located on chromosome 11q13, and several mutations have been described—the most common mutation is called R50X.

Table 3. Do not be afraid of physical activity. Individualize your personal training goals. Compete with yourself and not with others. Preexercise nutrition may enhance physical performance. Table 4. Recommendations for physical activity for patients with McArdle disease. References 1. McArdle B.

Myopathy due to a defect in muscle glycogen breakdown. Clinical Science. Bollig G. Das McArdle-Syndrom Glykogenose Typ 5 unter sportmedizinischen Gesichtspunkten. Köln: Inaugural-Dissertation Universität zu Köln; 3.

DiMauro S, Tsujino S. Nonlysosomal glycogenoses. In: Engel AG, Franzini-Armstrong C, editors. New York: McGraw-Hill; Bartram C, Edwards RHT, Beynon RJ.

Biochimica et Biophysica Acta. Di Mauro S. Muscle glycogenoses: An overview. Acta Myologica. Pediatric Anesthesia. Kubisch C, Wicklein EM, Jentsch TJ. Molecular diagnosis of McArdle disease: Revised genomic structure of the myophosphorylase gene and identification of a novel mutation.

Human Mutation. Haller RG. Treatment of McArdle disease. Archives of Neurology. Vissing J, Haller RG. Annals of Neurology. Birch KE. Das McArdle-Handbuch.

Table 3. Chronological overview of clinical case reports of patients with GSD III treated with dietary manipulation. The hallmark of all these dietary programs is a reduction in CHO intake associated with an increase in protein and, more recently, in fat intake. The rationale being to avoid excessive glycemic elevation with consequent reactive hyperinsulinemia and tissue deposition of abnormal glycogen and, in the meanwhile, to provide alternative fuel for body needs.

More recently, a high fat diet has gained much attention following the evidence from cardiovascular research that ketone bodies are an efficient metabolic substrate for the failing heart since they require less oxygen per molecule of ATP generated In addition, the administration of D,Lhydroxybutyrate was found to be beneficial in patients with cardiomyopathy secondary to defects of fatty acid oxidation Finally, Valayannopoulus et al.

published the successful treatment of a 2-month-old infant with severe cardiomyopathy, by means of ketone bodies supplementation D, Lhydroxybutyrate , ketogenic and high protein diet 8. Overall, these data lent support to the hypothesis that a high-fat diet may help control myocardiopathy in patients with GSD III.

The results show the efficacy of these approaches in reducing muscle enzymes and improving cardiomyopathy, although some concern related to patient compliance and long- term effects of these diets on bone health and lipid profile remain to be addressed.

Indeed, the effect of nutritional modifications on traditional outcome parameters need to be carefully balanced against psychosocial wellbeing and quality of life in patients with hepatic GSDs The need for new therapies that can improve the quality of life of patients with GSD has prompted research toward innovative therapies such as the use of gene therapy or therapy using messenger RNA mRNA.

In principle, GSD patients would be no longer dependent on a strict dietary regimen. Early phase clinical studies are already available for GSD Ia and II and the approach appears promising also for other types of GSDs This improvement persisted throughout the COVID pandemic, during which the patient kept his diet constant for a year.

These findings highlight the concept that beyond restricting CHO and increasing fat intake, the quality of foods is of paramount importance. In fact, low glycemic index foods and whole grains help keep glucose levels more stable, thus limiting the risk of hypoglycemia, while increasing mono- and polyunsaturated fat consumption prevents atherogenic modifications of the lipid profile— a very important finding considering that the nutritional therapy is life-long.

Noteworthy, the number and duration of hypoglycemic episodes decreased during the dietary intervention despite the reduction in CHO intake. Although optimal TIR for patients with GSD III has not been defined yet, a glycemic target for TIR has been recently proposed for adult patients with GSD Ia.

Notably, the TIR observed in the present case was higher than that reported in GSD Ia patients i. CGM data from the present study support the opportunity to decrease CHO intake in older GSD III with no risk of precipitating hypoglycemia A possible explanation for the high REE value is that it may be related to an increased cell mass and, thus, to be an expression of organomegaly.

Elevated REE values have been documented also in patients with GSD Ia 25 , 26 and in patients with lysosomal storage disorders 27 , 28 , which are characterized by intra-organ accumulation of anomalous molecules. In addition to the low CHO intake, it is important to focus on macronutrient quality, favoring low-glycemic index food and unsaturated fats in order to preserve cardiometabolic health in the long-term.

Ethical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. EM and APA collected the clinical data, carried out the literature search, and wrote a first draft.

AR and RL reviewed the manuscript. BC took care of the patient, reviewed the manuscript, and provided relevant intellectual contribution. All authors have read and agreed to the published version of the manuscript. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers.

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This work was supported by the Association for Glycogen Storage Disease-UK AGSG-UK. Sport, Health and Performance Enhancement SHAPE Research Centre, Nottingham Trent University, Clifton Lane, Clifton, Nottingham, NG11 8NS, UK. Charles Dent Metabolic Unit, The National Hospital for Neurology and Neurosurgery, London, UK.

Elaine Murphy, Rick I. Section of Vascular Medicine, Department of Internal Medicine, Amsterdam UMC, Amsterdam, The Netherlands. Shackleton Department of Anaesthetics, Perioperative Medicine Team, University Hospital Southampton NHS Foundation Trust, Tremona Road, Southampton, SO16 6YD, UK.

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PJH conceived and ran the study, analysed and interpreted data and drafted the manuscript. EM conceived and ran the study, interpreted data and drafted the manuscript.

RIM health screened and recruited patients, acquired and analysed blood and diet data and substantively revised the manuscript. RHL health screened and recruited patients, acquired and analysed blood, diet and medical history data and substantively revised the manuscript.

RR health screened and recruited patients, acquired and analysed blood, diet and medical history data, and substantively revised the manuscript. CB analysed and interpreted data and substantively revised the manuscript.

GR performed tests of aerobic capacity VO 2 peak , interpreted data and substantively revised the manuscript. DJT performed tests of muscle architecture, strength and physical activity, analysed data and drafted the manuscript.

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Abstract Background Individuals with glycogen storage disease IIIa GSD IIIa OMIM experience muscle weakness and exercise limitation that worsen through adulthood.

Results Peak oxygen uptake V̇O 2 peak was lower in the individuals with GSD IIIa than predicted based on demographic data Conclusions V̇O 2 peak and knee extension strength are lower in individuals with GSD IIIa than predicted based on their demographic data.

Background Glycogen storage disease IIIa GSD IIIa OMIM is a rare inherited metabolic disorder caused by pathogenic variants in the AGL gene which spans 85 kb of DNA on chromosome 1p Purpose To produce normative reference values of aerobic capacity and strength in individuals with GSD III and to investigate the role of muscle size and quality on exercise impairment.

Results The demographic and clinical characteristics of the seven participants are shown in Table 1. Table 1 Participant characteristics, ordered by V̇O 2 peak from highest to lowest Full size table. Table 2 Cardio-respiratory properties, ordered by V̇O 2 peak Full size table.

Table 3 Descriptive skeletal muscle structural and functional characteristics, ordered by V̇O 2 peak from highest to lowest Full size table. Discussion This study demonstrates that V̇O 2 peak and knee extension strength are lower in individuals with GSD IIIa than predicted based on their demographic data.

Implications Expert guidelines highlight the need for regular assessments of strength and aerobic capacity in individuals with GSD IIIa to monitor status and guide exercise training [ 7 ]. Conclusion V̇O 2 peak and MVC are lower in individuals with GSD IIIa than would be expected.

Protocols Following informed consent, on the day of testing participants had baseline non-fasting blood tests taken CK, lipid profile, glucose, urate. Body composition 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.

Cardio-pulmonary exercise testing 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.

Maximum voluntary contraction assessment 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.

Quality of life and pain assessment 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 ].

Blood work is needed every six months. Once a year, they need a kidney and liver ultrasound. Research into enzyme replacement therapy and gene therapy is promising and may improve the outlook for the future.

CHOP will be a site for upcoming gene therapy clinical trials for types I and III. The GSD Clinic will have more information. Glycogen Storage Disease GSD. Contact Us Online.

Glycogen storage disorders occur in about one in 20, to 25, newborn babies. Manifestations of GSD often look like other health problems and may include: poor growth low blood glucose level hypoglycemia an enlarged liver may show as a bulging abdomen abnormal blood tests low muscle tone muscle pain and cramping during exercise too much acid in the blood acidosis fatigue A thorough medical history can also lead the doctor to suspect GSD since it is inherited.

Other diagnostic tests may include: blood tests to check blood glucose levels and how the liver, kidneys and muscles are functioning abdominal ultrasound to see if the liver is enlarged tissue biopsy to test a sample of tissue from muscle or liver to measure the level of glycogen or enzymes genetic testing, which can confirm a GSD.

Children may be prescribed medicines to manage side effects of GSD. These include: Allopurinol, a drug capable of reducing the level of uric acid in the blood, may be useful to control the symptoms of gout-like arthritis during the adolescent years in patients with GSD I.

Human granulocyte colony stimulating factor GCSF may be used to treat recurrent infections in GSD type Ib patients. In certain types of GSD, children must limit their amount of exercise to reduce muscle cramps.

Genetic counseling is recommended for affected individuals and their families. Next Steps Contact Us. Congenital Hyperinsulinism Center. Buerger Center for Advanced Pediatric Care. Stay in Touch. Subscribe to HI Hope, our e-newsletter for families.

Your Child's HI Appointment. doi: PubMed Abstract CrossRef Full Text Google Scholar. Schreuder AB, Rossi A, Grünert SC, Derks TGJ. GeneReviews ® [Internet]. Seattle WA : University of Washington, Seattle, p. Google Scholar. Hijazi G, Paschall A, Young SP, Smith B, Case LE, Boggs T, et al.

A retrospective longitudinal study and comprehensive review of adult patients with glycogen storage disease type III. Mol Genet Metab Rep.

Kishnani PS, Austin SL, Arn P, Bali DS, Boney A, Case LE, et al. Glycogen storage disease type III diagnosis and management guidelines. Genet Med. Rossi A, Hoogeveen IJ, Bastek VB, de Boer F, Montanari C, Meyer U, et al.

Dietary lipids in glycogen storage disease type III: a systematic literature study, case studies, and future recommendations. 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. Abstract Glycogen storage diseases GSD are inborn errors of glycogen or glucose metabolism. Publication types Review. Substances Glycogen Glucose.

Cardiac ultrasound evidenced an improvement in geometry and LV function as evidenced by a significant reduction in LV mass and an increase in global longitudinal strain GLS. Liver enzymes remained substantially stable and a trend toward a reduction in liver size was found at ultrasound examination.

Unfortunately, the analysis of the available literature does not lead to firm conclusions due to a large variation in patients' ages from 2 months to 47 years 8 , 9 , duration of follow-up from 4 months to 5 years , types of nutritional intervention—which are often not sufficiently detailed in terms of bromatological composition and, finally, the clinical outcomes heart, muscle, liver.

Table 3. Chronological overview of clinical case reports of patients with GSD III treated with dietary manipulation. The hallmark of all these dietary programs is a reduction in CHO intake associated with an increase in protein and, more recently, in fat intake.

The rationale being to avoid excessive glycemic elevation with consequent reactive hyperinsulinemia and tissue deposition of abnormal glycogen and, in the meanwhile, to provide alternative fuel for body needs. More recently, a high fat diet has gained much attention following the evidence from cardiovascular research that ketone bodies are an efficient metabolic substrate for the failing heart since they require less oxygen per molecule of ATP generated In addition, the administration of D,Lhydroxybutyrate was found to be beneficial in patients with cardiomyopathy secondary to defects of fatty acid oxidation Finally, Valayannopoulus et al.

published the successful treatment of a 2-month-old infant with severe cardiomyopathy, by means of ketone bodies supplementation D, Lhydroxybutyrate , ketogenic and high protein diet 8. Overall, these data lent support to the hypothesis that a high-fat diet may help control myocardiopathy in patients with GSD III.

The results show the efficacy of these approaches in reducing muscle enzymes and improving cardiomyopathy, although some concern related to patient compliance and long- term effects of these diets on bone health and lipid profile remain to be addressed.

Indeed, the effect of nutritional modifications on traditional outcome parameters need to be carefully balanced against psychosocial wellbeing and quality of life in patients with hepatic GSDs The need for new therapies that can improve the quality of life of patients with GSD has prompted research toward innovative therapies such as the use of gene therapy or therapy using messenger RNA mRNA.

In principle, GSD patients would be no longer dependent on a strict dietary regimen. Early phase clinical studies are already available for GSD Ia and II and the approach appears promising also for other types of GSDs This improvement persisted throughout the COVID pandemic, during which the patient kept his diet constant for a year.

These findings highlight the concept that beyond restricting CHO and increasing fat intake, the quality of foods is of paramount importance. In fact, low glycemic index foods and whole grains help keep glucose levels more stable, thus limiting the risk of hypoglycemia, while increasing mono- and polyunsaturated fat consumption prevents atherogenic modifications of the lipid profile— a very important finding considering that the nutritional therapy is life-long.

Noteworthy, the number and duration of hypoglycemic episodes decreased during the dietary intervention despite the reduction in CHO intake.

Although optimal TIR for patients with GSD III has not been defined yet, a glycemic target for TIR has been recently proposed for adult patients with GSD Ia.

Notably, the TIR observed in the present case was higher than that reported in GSD Ia patients i. CGM data from the present study support the opportunity to decrease CHO intake in older GSD III with no risk of precipitating hypoglycemia A possible explanation for the high REE value is that it may be related to an increased cell mass and, thus, to be an expression of organomegaly.

Elevated REE values have been documented also in patients with GSD Ia 25 , 26 and in patients with lysosomal storage disorders 27 , 28 , which are characterized by intra-organ accumulation of anomalous molecules.

In addition to the low CHO intake, it is important to focus on macronutrient quality, favoring low-glycemic index food and unsaturated fats in order to preserve cardiometabolic health in the long-term. Ethical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements.

EM and APA collected the clinical data, carried out the literature search, and wrote a first draft. AR and RL reviewed the manuscript. BC took care of the patient, reviewed the manuscript, and provided relevant intellectual contribution. All authors have read and agreed to the published version of the manuscript.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers.

Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher. 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.

J Inherit Metab Dis. doi: PubMed Abstract CrossRef Full Text Google Scholar. Schreuder AB, Rossi A, Grünert SC, Derks TGJ. GeneReviews ® [Internet]. Seattle WA : University of Washington, Seattle, p. Google Scholar. Hijazi G, Paschall A, Young SP, Smith B, Case LE, Boggs T, et al. A retrospective longitudinal study and comprehensive review of adult patients with glycogen storage disease type III.

Mol Genet Metab Rep. Kishnani PS, Austin SL, Arn P, Bali DS, Boney A, Case LE, et al. Glycogen storage disease type III diagnosis and management guidelines.

Genet Med. Rossi A, Hoogeveen IJ, Bastek VB, de Boer F, Montanari C, Meyer U, et al. Dietary lipids in glycogen storage disease type III: a systematic literature study, case studies, and future recommendations. 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. 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.

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Journal Article. Exercise Capacity and Biochemical Profile during Exercise in Patients with Glycogen Storage Disease Type I. Mundy , H.

Helen Mundy, Charles Dent Metabolic Unit, National Hospital for Neurology and Neurosurgery, Queen Square, London WC1N 3BG, United Kingdom. Oxford Academic. PDF Split View Views. Cite Cite H.