J Inherit Metab Dis DOI 10.1007/s10545-014-9756-x
GLYCOGENOSES
Dietary management in glycogen storage disease type III: what is the evidence? Terry G. J. Derks & G. Peter A. Smit
Received: 2 June 2014 / Revised: 18 July 2014 / Accepted: 23 July 2014 # SSIEM 2014
Abstract In childhood, GSD type III causes relatively severe fasting intolerance, classically associated with ketotic hypoglycaemia. During follow up, history of (documented) hypoglycaemia, clinical parameters (growth, liver size, motor development, neuromuscular parameters), laboratory parameters (glucose, lactate, ALAT, cholesterol, triglycerides, creatine kinase and ketones) and cardiac parameters all need to be integrated in order to titrate dietary management, for which age-dependent requirements need to be taken into account. Evidence from case studies and small cohort studies in both children and adults with GSD III demonstrate that prevention of hypoglycaemia and maintenance of euglycemia is not sufficient to prevent complications. Moreover, overtreatment with carbohydrates may even be harmful. The ageing cohort of GSD III patients, including the non-traditional clinical presentations in adulthood, raises new questions.
Abbreviations EGP endogenous glucose production GSD III glycogen storage disease type III HCM hypertrophic cardiomyopathy IEM inborn error of metabolism UCCS uncooked cornstarch
Communicated by: John H. Walter Presented at “The changing spectrum of IMD: surviving longer and growing old with IMDs” Recordati Rare Diseases Academy Symposium in London, United Kingdom, 8 May 2014. T. G. J. Derks (*) : G. P. A. Smit Section of Metabolic Diseases, Beatrix Children’s Hospital, University of Groningen, University Medical Center Groningen, PO Box 30 001, 9700 RB Groningen, The Netherlands e-mail: [email protected]
Introduction Glucose is the major source of energy for the brain, although lactate, ketone bodies, and certain amino acids can be used additionally (Wahren et al 1999). There is an intimate relation between the fasting response and glucose homeostasis (Ruderman 1975). Both endogenous glucose production (EGP) and metabolic clearance rate of glucose determine blood glucose concentration during fasting. Impairment of EGP may be caused by decreased glycogenolysis, decreased gluconeogenesis or a combination. Many inborn errors of metabolism (IEMs) are associated with fasting intolerance and/or hypoglycaemia and these IEMs include enzyme deficiencies and transporter defects in metabolic processes like glycogen synthesis, glycogenolysis, gluconeogenesis, mitochondrial fatty acid oxidation, ketogenesis and ketolysis. At least four arguments illustrate the challenges of dietary management of young patients with IEMs that are associated with fasting intolerance. First, gastrointestinal capacity (both in size and oral-fecal transit time) in young children may limit the possibilities for gastrointestinal carbohydrate load to provide exogenous carbohydrates. The consequence is a delicate balance between over-treatment (and thereby potentially causing obesity) and under-treatment, causing poor metabolic control. Second, the developing brain is more susceptible to hypoglycaemia compared with the adult brain (Zijlmans et al 2009). Third, related to the ratio between brain weight and body weight, relative EGP is approximately 3–4 times higher in early infancy than in adulthood (Bier et al 1977). Fourth, intercurrent infections with (high) fever are more common in early childhood, which further increases energy demands.
Glycogen storage disease type III (GSD III) Glycogen storage disease type III (GSD III; OMIM # 232400), also known as Cori or Forbes disease), is an
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autosomal recessive IEM of glycogenolysis (Laforêt et al 2011; Dagli et al 2010). The disorder is caused by deficiency of the glycogen debranching enzyme. In this special issue of The Journal, Sentner et al present data on the genotypephenotype relations in a large cohort of GSD III patients before and after establishment of the diagnosis, based on the International Study on Glycogen Storage Diseases Type III (Sentner et al., In Preparation). According to the textbooks, patients present with fasting intolerance, severe hepatomegaly and failure to thrive, biochemically associated with ketotic hypoglycaemia. Other biochemical features are elevated transaminases and hyperlipidemia. Upon follow-up, short- and long-term complications include recurrent hypoglycaemia, liver adenomas, hepatocellular carcinoma, cardiomyopathy, myopathy, growth failure, osteoporosis and osteopenia. From the diagnosis, a written and clearly communicated emergency protocol should be established to avoid dangerous hypoglycaemia and/or ketoacidosis. This is not only important during incurrent infection in childhood, but also during certain high-risk events in adulthood, like the obstetric management and upon fasting before and during surgery (Kishnani et al 2010). GSD III is a monogenetic IEM causing storage of an intermediate glycogen molecular structure called “limit dextrin” in the affected organs. Either sequencing of the responsible AGL gene or testing of debranching enzyme activity in leukocytes are the recommended confirmatory tests, hence, invasive liver or muscle biopsies are nowadays considered obsolete. Phenotypically, GSD III can be further classified as either type IIIa or type IIIb. About 85 % of the patients display GSD type IIIa including symptoms and signs due to the enzyme deficiency in liver, skeletal muscle and heart, whereas the remaining patients with GSD type IIIb only display liverrelated complaints. AGL genotyping is helpful for classification purposes. GSD IIIb is strongly associated with specific mutations in exon 3 of the AGL gene (Shen et al 1996), although GSD IIIb patients have been described without exon 3 mutations (Okubo et al 1998). Increased blood creatine kinase concentrations may point into the direction of GSD IIIa, reflecting that children become more active (Talente et al 1994). In GSD IIIa patients, blood creatinine kinase concentrations may remain normal until adulthood. However, an increased creatine kinase may also indicate muscle damage due to endogenous proteolysis. Dietary management is the mainstay of treatment in GSD III, for which the fundaments originate from the 1960s and 1970s (Fernandes and van de Kamer 1968; Fernandes and Pikaar 1972). Traditionally, management focussed on the prevention of hypoglycaemia and maintenance of euglycemia in childhood, which is easy to understand given the earlier mentioned age-dependant physiology. In the late 1960s, Fernandes and van de Kamer reported their key-reference on oral carbohydrate and protein tolerance tests studies in five
GSD III patients (Fernandes and van de Kamer 1968). Their important observations were: (1) protein induced rise in blood glucose concentrations, (2) simple sugars caused fluctuating glucose curves and significant increase of blood lactate concentrations, and (3) wheat starch boiled in water caused more gradual increase and decrease of blood glucose concentrations. Based on these studies, Fig. 1 presents the model for dietary management and monitoring of GSD III patients.
The role of (complex) carbohydrates The mainstay of dietary management of GSD III patients is a nocturnal high-protein diet with uncooked cornstarch (UCCS) supplementation to maintain euglycemia (Dagli et al 2010). Unlike patients with GSD I, individuals with GSD III can utilize fructose and galactose, hence special formulas without these simple sugars are not required. Nevertheless, like patients with deficiencies in the phosphorylase (kinase) cascade (Fernandes et al 1974), GSD III patients display an abnormal blood lactate response after oral carbohydrate administration at a dose of 2 grams per kg body weight (Fernandes et al 1969). It is considered an overflow phenomenon because of increased glycolysis, and may also lead to increased storage of hepatic glycogen. Although these historical in vivo studies were originally performed for diagnostic purposes, they form the rationale behind dietary restrictions of these simple carbohydrates in GSD dietary management. In the early 1980s, UCCS was described for the first time as a good alternative nocturnal treatment for continuous nocturnal gastric drip-feeding in GSD type I patients (Chen et al 1984; Smit et al 1984). Although UCCS may be introduced from 6 months of age, it is recognized that the tolerance may be reduced as a consequence of deficient pancreatic amylase until 1 year of age (Hayde and Widhalm 1990). Later studies in GSD III patients merely report on UCCS loading doses for nocturnal management. The GeneReviews paper is most explicit about the practical advice on dosing UCCS in GSD III patients, stating: “Toward the end of the first year of life, one to three daily doses of 1 g/kg UCCS can be used to avoid hypoglycaemia” (Dagli et al 2010). At an estimated body weight of 10 kg at the age of 1 year, this maximum of 3 g/kg/d corresponds with ~28 % of the calculated EGP based on the formula derived from experimental data (Y=0.0014x3 – 0.214x2 +10.411x – 9.084, with [Y] = mg/min and [x] = body weight in kg) (Bier et al 1977). This UCCS dose would correct for the partial defect of glycogenolysis, whereas in GSD III patients theoretically there would still be some residual glycogenolysis flux due to in vivo phosphorylase (kinase) activity. Prescription of the similar dose of 3 g/kg/d to patients with body weights of 30 kg and 60 kg, corresponding with ~42 % and ~85 % of the estimated EGP, respectively, carries a potential risk of carbohydrate overtreatment. Age-dependent
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SIMPLE & COMPLEX CARBOHYDRATES
growth liversize ALAT CK
GLYCOGEN
GLUCOSE*
G6P
FFA
PYRUVATE ACETYL-CoA OAA CITRATE
KETONES* glucogenic
PROTEIN
ketogenic
AMINO ACIDS
Fig. 1 Model for dietary management and monitoring of GSD III patients. The figure has been published elsewhere (Fernandes and Pikaar 1972) and was edited for this presentation. The bar represents the metabolic block, indicating that gluconeogenesis is still available for maintaining EGP. Carbohydrates (simple and complex) and protein represent the major macronutrient dietary variables to achieve metabolic control. Besides the history of (nocturnal) hypoglycemias and exercise tolerance, growth parameters (height, body weight and related parameters) and liver size should be taken into account. The * represents the potential of the
combination of subcutaneous continuous glucose monitoring with preprandial measurement of blood ketones. In our experience this home monitoring of dietary management is an elegant alternate method for inhospital bedside monitoring. Blood concentrations (in black) of glucose and ketone bodies together with free fatty acids and amino acids reflect instantaneous intracellular metabolism (in grey). Alanineaminotransferase and creatinine kinase represent long-term metabolic control and involvement of the liver and skeletal muscle, respectively. Legend: G6P, glucose-6-phosphate; OAA, oxaloacetate
physiology in fasting response should be taken into account (Bonnefont et al 1990; van Veen et al 2011), emphasizing the need to individualize the dietary management in GSD III patients with regular check-up (Kishnani et al 2010). Last, the ability to maintain euglycemia additionally depends on the daily amount and distribution of dietary protein. More recently, the experimental heat-moisture processed high amylopectin cornstarch Glycosade® (Vitaflo Int. Ltd, Liverpool, UK) has been developed and characterized, mostly in GSD I patients (Bhattacharya et al 2007; Correia et al 2008) but also in two GSD III patients (Bhattacharya et al 2007). Both studies report biochemical data suggesting better metabolic control after Glycosade®, when compared to regular UCCS. In this special issue of The Journal, Nalin et al report studies on the in vitro digestion of different starches (including Glycosade®) in a dynamic gastrointestinal model simulating the human upper gastrointestinal tract (Nalin et al 2014). Small differences in digestibility were observed between different brands of UCCS, whereas sweet polvilho (a Brazilian cassava derived starch) displayed a superior digestibility pattern. Additional in vivo studies with clinically relevant endpoints are needed to confirm the potential to achieve good metabolic control, regardless of which starch is used during the different parts of the day.
The role of protein The role of dietary protein in dietary management of GSD III patients is currently still under-appreciated, despite the first reports from the 1960s. Increased dietary protein may be beneficial in at least three ways (Kishnani et al 2010). In GSD III gluconeogenesis is intact and exogenous gluconeogenic protein can be used as an additional source of carbohydrates during fasting. Theoretically, endogenous proteolysis by skeletal muscle breakdown would be reduced or perhaps even prevented. By replacing dietary carbohydrates, storage of “limited dextrin” could be reduced in the affected organs. Few small cohort studies and case reports present reversibility of (cardio)myopathy after increasing dietary protein intake in GSD III patients. Slonim et al reported increased exercise tolerance, muscle strength and growth in a 7 year old GSD III patient after increasing (nocturnal) dietary protein treatment (Slonim et al 1982). Relative daily protein intake expressed in energy percentages was increased from 18 % towards 25 %, continuous nocturnal caloric intake from 20 % towards 25 % of the daily amount. Later, additional results were reported in a small cohort study of seven GSD IIIa patients in whom the distribution of dietary carbohydrates
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mass in order to assess the natural history of HCM in this patient group (Vertilus et al 2010). In the last decade, three case reports from different groups described reversibility of HCM in GSD IIIa patients after initiation of a high protein diet (Dagli et al 2009; Valayannopoulos et al 2011; Sentner et al 2012). Although the three reports share the concept of a highprotein dietary management, they differ importantly with respect to the remaining dietary macronutrients and clinical o u t c o m e p a r a m e t e r s ( Ta b l e 1 ) . I n t e r e s t i n g l y, Valayannapoulos et al observed in their case that ketone bodies were capable to reverse HCM, when the dietary management remained constant (Valayannopoulos et al 2011). Given the character of the long-term muscular and cardiac complications in GSD III patients and the crucial role for mitochondrial fatty acid oxidation in these organs, dietary management with high fat (and thereby ketone bodies) has been underappreciated and deserves more attention. High protein diets have been prescribed in patients with other GSD subtypes in which gluconeogenesis is intact. Based on observations in eight adult GSD II patients, it was concluded that high-protein diets might stabilize the disease progression in skeletal muscle, but does not cause significant clinical improvements (Ravaglia et al 2006). According to the textbooks, the X-linked GSD IX due to PHKA2 mutations is considered a relatively benign condition with minimal complications. A recent case series reported significant clinical improvements after strict treatment with regular doses of UCCS and protein (2.5 g/kg/day) in two GSD IX patients who presented liver cirrhosis, prominent ketosis, laboratory abnormalities and failure to thrive (Tsilianidis et al 2013). Despite these advantages of high-protein diets, several items deserve both individual patient monitoring and
and protein was changed from 50–60 % to 40–50 % and 10– 13 % to 20–25 %, respectively (Slonim et al 1984). Between 1/3 and 1/4 of the caloric intake was given as continuous nocturnal drip-feeding. The patients with failure to thrive showed dramatic improvements of growth, next to improvements of physical activity, endurance and muscle strength. Moreover, there was reversal of myopathic electromyography patterns to normal in two patients and reversal of abnormal electrocardiography findings to normal in one patient. More recently, Kiechl et al reported a 47-year-old male GSD III patient presenting non-classically with severe myopathy of the respiratory muscles (Kiechl et al 1999). He could be successfully weaned from the ventilator after a period of 4 days on a high protein diet, i.e. 30–35 % of total energy intake, but the cardiomyopathy further deteriorated. In addition to these published data, interesting clinical observations come from the GSD IIIa founder population at the Faroe Islands. The local adult patient cohort with GSD IIIa was physically much fitter than the patients in childhood, because the paediatric patients were switched to a more carbohydrate based diet (to prevent hypoglycaemias, according to the traditional medical opinion at the time), whereas the adult patients had remained on their naturally protein-rich diet at the islands (personal communications by Ulrike Steuerwald). Skeletal myopathy and hypertrophic cardiomyopathy (HCM) are not correlated in GSD III patients (Labrune et al 1991). HCM is a common echocardiographic phenomenon in GSD IIIa patients, but rarely associated with severe clinical symptomatology of dysfunction, as determined by ejection fraction and/or shortening fraction (Lee et al 1997). There is one cohort study describing cross-sectional and longitudinal data of measurements of left ventricular wall thickness and
Table 1 Case reports describing reversibility of HCM in GSD IIIa patients after initiation of a high protein diet (Dagli et al 2009)
(Valayannopoulos et al 2011)
(Sentner et al 2012)
Patient AGL genotype
22 years old male n.r.
30 years old female c.753_756delCAGA homozygote
Cardiac findings
Cardiac murmur
2 month old male c.2157+1G>T homozygote Asymptomatic HCM, but positive family history
Prior diet
20 energy % protein suboptimal compliance 2.95 g/kg UCCS 3 times per day 30 energy % protein 1.36 g/kg UCCS twice daily
Outcome parameters
Echocardiography CK
65 energy % carbohydrates±23 energy % fat±12 energy % protein 15 energy % protein (3 g/kg/d) 20 energy % carbohydrates 65 energy % fat 3OHB Echocardiography CK
Follow-up
1 year
24 months
Dietary change
The prior diet is expressed as energy percentage, unless expressed otherwise Legend: BMI body mass index, NHYA New York Heart Association, n.r. not reported
BMI 30.3 NYHA 3+ echocardiography n.r. 900 cal+37 energy % protein for 4 months, thereafter 1,370 cal+43 energy % protein Echocardiography BMI 27.8 kg/m2 NYHA 2+ 3 years
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systematical study in the cohort of GSD III patients, i.e. costs, tolerability, micronutrient intake, renal function and other long-term complications.
Conclusions and future perspectives To summarize, based on expert opinions, case studies and small cohort studies, there is low-grade level of evidence for the role of UCCS and protein in current dietary management of GSD III patients. The evidence is mainly derived from paediatric GSD III patients in whom management generally focuses on the prevention of hypoglycaemia. The ageing cohort of GSD III patients demonstrates that maintenance of euglycemia may not be sufficient to prevent chronic, longterm. Over-treatment with carbohydrates may be even harmful and is intimately connected with protein under-treatment, when fat intake is constant. Although the reversibility of myopathy and cardiomyopathy upon dietary manipulations has been demonstrated, to date it is questionable whether prevention is possible. After the classical clinical presentations of GSD III in early childhood, the phenotype is changing in the ageing cohort of patients. Towards adulthood, EGP is declining, glucose homeostasis is controlled more easily and hypoglycaemia become uncommon. Special circumstances however, like pregnancy, diabetes and exercise, necessitate increased attention for dietary management to control glucose homeostasis in adulthood. Based on experimental data, during pregnancy EGP is increased by 16 % (Kalhan et al 1979), which increases the risk of hypoglycaemia and poor metabolic control in GSD III patients. There are several reports on the successful obstetric management (Confino et al 1984; Mendoza et al 1998; Lee 1999; Bhatti and Parry 2006; Ramachandran et al 2012; Bolton et al 2012), mostly on a UCCS-based dietary regimen. To date there is no general agreement on the dietary management under these circumstances. Several reports suggest an association between diabetes and GSD III, in either classically ascertained patients or patients with non-classical adult presentations (Moe et al 1972; Oki et al 2000; Spengos et al 2009; Ismail 2009; Sharma 2009). Dietary and pharmacological treatment of diabetes in GSD III carry the risk of hypoglycaemia in GSD III patients. Interestingly, Oki et al recommended the neutral alpha-glucosidase inhibitor voglibose for treatment in their GSD III patient (Oki et al 2000). Acid alpha-glucosidase and neutral alpha-glucosidase are ubiquitous expressed. It remains an open question whether α-glucosidase inhibitors may increase the risk of (cardio)myopathy (like observed in acid α-glucosidase deficiency, i.e. glycogen storage disease type II of Pompe’s disease) in the ageing GSD III cohort. Exercise tolerance was recently studied in six GSD IIIa patients (Preisler et al 2013). After glucose infusion, the authors observed improved work
capacity by lowering the heart rate, and increased peak work rate by 30 %. Deficient energy production in muscle was discussed as an explanation for exercise intolerance in GSD IIIa patients, next to the traditional explanation of muscle wasting. To conclude, dietary management in GSD (III) patients is challenging, should be patient tailored and can be therefore regarded precision management. Cohort studies on dietary management are complicated by the rarity of this IEM. More than ever before, new management strategies and changing phenotypes in adulthood emphasize the need for international patient registries in hepatic GSD, which is a work in progress.
Acknowledgments Taking care of GSD-patients is teamwork and the discussions with the colleagues in our department have been very stimulating while preparing the presentation and this subsequent manuscript. Therefore the authors are thankful to Rixt van der Ende, Cynthia van Amerongen, Irene Hoogeveen, Chris Peter Sentner, Esther van Dam, Foekje de Boer, Francjan van Spronsen and Margreet van Rijn, the latter who critically read an early version of the manuscript. Compliance with Ethics Guidelines Conflict of interest The authors received speaker’s fees from Recordati Rare Diseases for this study, which was presented orally at “The changing spectrum of IMD: surviving longer and growing old with IMDs” Recordati Rare Diseases Academy Symposium in London, United Kingdom, 8 May 2014. In addition to that, in the last 5 years, Terry GJ Derks had received speaker’s fees from Danone Nutricia and Vitaflo, research fees from Sigma Tau and Vitaflo, and training support from Sigma Tau and Genzyme. G Peter A Smit declares that he has no conflict of interest. This article does not contain any studies with human or animal subjects performed by the any of the authors.
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Okubo M, Horinishi A, Nakamura N, Aoyama Y, Hashimoto M, Endo Y, Murase T (1998) A novel point mutation in an acceptor splice site of intron 32 (IVS32 A-12–>G) but no exon 3 mutations in the glycogen debranching enzyme gene in a homozygous patient with glycogen storage disease type IIIb. Hum Genet 102:1–5 Preisler N, Pradel A, Husu E et al (2013) Exercise intolerance in glycogen storage disease type III: weakness or energy deficiency? Mol Genet Metab 109:14–20 Ramachandran R, Wedatilake Y, Coats C et al (2012) Pregnancy and its management in women with GSD type III—a single centre experience. J Inherit Metab Dis 35:245–251 Ravaglia S, Pichiecchio A, Rossi M et al (2006) Dietary treatment in adult-onset type II glycogenosis. J Inherit Metab Dis 29:590 Ruderman NB (1975) Muscle amino acid metabolism and gluconeogenesis. Annu Rev Med 26:245–258 Sentner CP, Caliskan K, Vletter WB, Smit GP (2012) 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 5:13–16 Sharma RWS (2009) Diabetes in patients with glycogen storage disease types I and III. Diabet Med J Br Diabet Assoc 26:102 Shen J, Bao Y, Liu HM, Lee P, Leonard JV, Chen YT (1996) Mutations in exon 3 of the glycogen debranching enzyme gene are associated with glycogen storage disease type III that is differentially expressed in liver and muscle. J Clin Invest 98:352–357 Slonim AE, Weisberg C, Benke P, Evans OB, Burr IM (1982) Reversal of debrancher deficiency myopathy by the use of high-protein nutrition. Ann Neurol 11:420–422 Slonim AE, Coleman RA, Moses WS (1984) Myopathy and growth failure in debrancher enzyme deficiency: improvement with highprotein nocturnal enteral therapy. J Pediatr 105:906–911 Smit GP, Berger R, Potasnick R, Moses SW, Fernandes J (1984) The dietary treatment of children with type I glycogen storage disease with slow release carbohydrate. Pediatr Res 18:879–881 Spengos K, Michelakakis H, Vontzalidis A, Zouvelou V, Manta P (2009) Diabetes mellitus associated with glycogen storage disease type III. Muscle Nerve 39:876–877 Talente GM, Coleman RA, Alter C et al (1994) Glycogen storage disease in adults. Ann Intern Med 120:218–226 Tsilianidis LA, Fiske LM, Siegel S et al (2013) Aggressive therapy improves cirrhosis in glycogen storage disease type IX. Mol Genet Metab 109:179–182 Valayannopoulos V, Bajolle F, Arnoux J et al (2011) Successful treatment of severe cardiomyopathy in glycogen storage disease type III With D, L-3-hydroxybutyrate, ketogenic and high-protein diet. Pediatr Res 70:638–641 van Veen MR, van Hasselt PM, de Sain-van der Velden MG, Verhoeven N, Hofstede FC, de Koning TJ, Visser G (2011) Metabolic profiles in children during fasting. Pediatrics 127:e1021–e1027 Vertilus SM, Austin SL, Foster KS et al (2010) Echocardiographic manifestations of glycogen storage disease III: increase in wall thickness and left ventricular mass over time. Genet Med 12:413– 423 Wahren J, Ekberg K, Fernqvist-Forbes E, Nair S (1999) Brain substrate utilisation during acute hypoglycaemia. Diabetologia 42:812–818 Zijlmans WC, van Kempen AA, Serlie MJ, Sauerwein HP (2009) Glucose metabolism in children: influence of age, fasting, and infectious diseases. Metabolism 58:1356–1365
GLYCOGENOSES
Dietary management in glycogen storage disease type III: what is the evidence? Terry G. J. Derks & G. Peter A. Smit
Received: 2 June 2014 / Revised: 18 July 2014 / Accepted: 23 July 2014 # SSIEM 2014
Abstract In childhood, GSD type III causes relatively severe fasting intolerance, classically associated with ketotic hypoglycaemia. During follow up, history of (documented) hypoglycaemia, clinical parameters (growth, liver size, motor development, neuromuscular parameters), laboratory parameters (glucose, lactate, ALAT, cholesterol, triglycerides, creatine kinase and ketones) and cardiac parameters all need to be integrated in order to titrate dietary management, for which age-dependent requirements need to be taken into account. Evidence from case studies and small cohort studies in both children and adults with GSD III demonstrate that prevention of hypoglycaemia and maintenance of euglycemia is not sufficient to prevent complications. Moreover, overtreatment with carbohydrates may even be harmful. The ageing cohort of GSD III patients, including the non-traditional clinical presentations in adulthood, raises new questions.
Abbreviations EGP endogenous glucose production GSD III glycogen storage disease type III HCM hypertrophic cardiomyopathy IEM inborn error of metabolism UCCS uncooked cornstarch
Communicated by: John H. Walter Presented at “The changing spectrum of IMD: surviving longer and growing old with IMDs” Recordati Rare Diseases Academy Symposium in London, United Kingdom, 8 May 2014. T. G. J. Derks (*) : G. P. A. Smit Section of Metabolic Diseases, Beatrix Children’s Hospital, University of Groningen, University Medical Center Groningen, PO Box 30 001, 9700 RB Groningen, The Netherlands e-mail: [email protected]
Introduction Glucose is the major source of energy for the brain, although lactate, ketone bodies, and certain amino acids can be used additionally (Wahren et al 1999). There is an intimate relation between the fasting response and glucose homeostasis (Ruderman 1975). Both endogenous glucose production (EGP) and metabolic clearance rate of glucose determine blood glucose concentration during fasting. Impairment of EGP may be caused by decreased glycogenolysis, decreased gluconeogenesis or a combination. Many inborn errors of metabolism (IEMs) are associated with fasting intolerance and/or hypoglycaemia and these IEMs include enzyme deficiencies and transporter defects in metabolic processes like glycogen synthesis, glycogenolysis, gluconeogenesis, mitochondrial fatty acid oxidation, ketogenesis and ketolysis. At least four arguments illustrate the challenges of dietary management of young patients with IEMs that are associated with fasting intolerance. First, gastrointestinal capacity (both in size and oral-fecal transit time) in young children may limit the possibilities for gastrointestinal carbohydrate load to provide exogenous carbohydrates. The consequence is a delicate balance between over-treatment (and thereby potentially causing obesity) and under-treatment, causing poor metabolic control. Second, the developing brain is more susceptible to hypoglycaemia compared with the adult brain (Zijlmans et al 2009). Third, related to the ratio between brain weight and body weight, relative EGP is approximately 3–4 times higher in early infancy than in adulthood (Bier et al 1977). Fourth, intercurrent infections with (high) fever are more common in early childhood, which further increases energy demands.
Glycogen storage disease type III (GSD III) Glycogen storage disease type III (GSD III; OMIM # 232400), also known as Cori or Forbes disease), is an
J Inherit Metab Dis
autosomal recessive IEM of glycogenolysis (Laforêt et al 2011; Dagli et al 2010). The disorder is caused by deficiency of the glycogen debranching enzyme. In this special issue of The Journal, Sentner et al present data on the genotypephenotype relations in a large cohort of GSD III patients before and after establishment of the diagnosis, based on the International Study on Glycogen Storage Diseases Type III (Sentner et al., In Preparation). According to the textbooks, patients present with fasting intolerance, severe hepatomegaly and failure to thrive, biochemically associated with ketotic hypoglycaemia. Other biochemical features are elevated transaminases and hyperlipidemia. Upon follow-up, short- and long-term complications include recurrent hypoglycaemia, liver adenomas, hepatocellular carcinoma, cardiomyopathy, myopathy, growth failure, osteoporosis and osteopenia. From the diagnosis, a written and clearly communicated emergency protocol should be established to avoid dangerous hypoglycaemia and/or ketoacidosis. This is not only important during incurrent infection in childhood, but also during certain high-risk events in adulthood, like the obstetric management and upon fasting before and during surgery (Kishnani et al 2010). GSD III is a monogenetic IEM causing storage of an intermediate glycogen molecular structure called “limit dextrin” in the affected organs. Either sequencing of the responsible AGL gene or testing of debranching enzyme activity in leukocytes are the recommended confirmatory tests, hence, invasive liver or muscle biopsies are nowadays considered obsolete. Phenotypically, GSD III can be further classified as either type IIIa or type IIIb. About 85 % of the patients display GSD type IIIa including symptoms and signs due to the enzyme deficiency in liver, skeletal muscle and heart, whereas the remaining patients with GSD type IIIb only display liverrelated complaints. AGL genotyping is helpful for classification purposes. GSD IIIb is strongly associated with specific mutations in exon 3 of the AGL gene (Shen et al 1996), although GSD IIIb patients have been described without exon 3 mutations (Okubo et al 1998). Increased blood creatine kinase concentrations may point into the direction of GSD IIIa, reflecting that children become more active (Talente et al 1994). In GSD IIIa patients, blood creatinine kinase concentrations may remain normal until adulthood. However, an increased creatine kinase may also indicate muscle damage due to endogenous proteolysis. Dietary management is the mainstay of treatment in GSD III, for which the fundaments originate from the 1960s and 1970s (Fernandes and van de Kamer 1968; Fernandes and Pikaar 1972). Traditionally, management focussed on the prevention of hypoglycaemia and maintenance of euglycemia in childhood, which is easy to understand given the earlier mentioned age-dependant physiology. In the late 1960s, Fernandes and van de Kamer reported their key-reference on oral carbohydrate and protein tolerance tests studies in five
GSD III patients (Fernandes and van de Kamer 1968). Their important observations were: (1) protein induced rise in blood glucose concentrations, (2) simple sugars caused fluctuating glucose curves and significant increase of blood lactate concentrations, and (3) wheat starch boiled in water caused more gradual increase and decrease of blood glucose concentrations. Based on these studies, Fig. 1 presents the model for dietary management and monitoring of GSD III patients.
The role of (complex) carbohydrates The mainstay of dietary management of GSD III patients is a nocturnal high-protein diet with uncooked cornstarch (UCCS) supplementation to maintain euglycemia (Dagli et al 2010). Unlike patients with GSD I, individuals with GSD III can utilize fructose and galactose, hence special formulas without these simple sugars are not required. Nevertheless, like patients with deficiencies in the phosphorylase (kinase) cascade (Fernandes et al 1974), GSD III patients display an abnormal blood lactate response after oral carbohydrate administration at a dose of 2 grams per kg body weight (Fernandes et al 1969). It is considered an overflow phenomenon because of increased glycolysis, and may also lead to increased storage of hepatic glycogen. Although these historical in vivo studies were originally performed for diagnostic purposes, they form the rationale behind dietary restrictions of these simple carbohydrates in GSD dietary management. In the early 1980s, UCCS was described for the first time as a good alternative nocturnal treatment for continuous nocturnal gastric drip-feeding in GSD type I patients (Chen et al 1984; Smit et al 1984). Although UCCS may be introduced from 6 months of age, it is recognized that the tolerance may be reduced as a consequence of deficient pancreatic amylase until 1 year of age (Hayde and Widhalm 1990). Later studies in GSD III patients merely report on UCCS loading doses for nocturnal management. The GeneReviews paper is most explicit about the practical advice on dosing UCCS in GSD III patients, stating: “Toward the end of the first year of life, one to three daily doses of 1 g/kg UCCS can be used to avoid hypoglycaemia” (Dagli et al 2010). At an estimated body weight of 10 kg at the age of 1 year, this maximum of 3 g/kg/d corresponds with ~28 % of the calculated EGP based on the formula derived from experimental data (Y=0.0014x3 – 0.214x2 +10.411x – 9.084, with [Y] = mg/min and [x] = body weight in kg) (Bier et al 1977). This UCCS dose would correct for the partial defect of glycogenolysis, whereas in GSD III patients theoretically there would still be some residual glycogenolysis flux due to in vivo phosphorylase (kinase) activity. Prescription of the similar dose of 3 g/kg/d to patients with body weights of 30 kg and 60 kg, corresponding with ~42 % and ~85 % of the estimated EGP, respectively, carries a potential risk of carbohydrate overtreatment. Age-dependent
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SIMPLE & COMPLEX CARBOHYDRATES
growth liversize ALAT CK
GLYCOGEN
GLUCOSE*
G6P
FFA
PYRUVATE ACETYL-CoA OAA CITRATE
KETONES* glucogenic
PROTEIN
ketogenic
AMINO ACIDS
Fig. 1 Model for dietary management and monitoring of GSD III patients. The figure has been published elsewhere (Fernandes and Pikaar 1972) and was edited for this presentation. The bar represents the metabolic block, indicating that gluconeogenesis is still available for maintaining EGP. Carbohydrates (simple and complex) and protein represent the major macronutrient dietary variables to achieve metabolic control. Besides the history of (nocturnal) hypoglycemias and exercise tolerance, growth parameters (height, body weight and related parameters) and liver size should be taken into account. The * represents the potential of the
combination of subcutaneous continuous glucose monitoring with preprandial measurement of blood ketones. In our experience this home monitoring of dietary management is an elegant alternate method for inhospital bedside monitoring. Blood concentrations (in black) of glucose and ketone bodies together with free fatty acids and amino acids reflect instantaneous intracellular metabolism (in grey). Alanineaminotransferase and creatinine kinase represent long-term metabolic control and involvement of the liver and skeletal muscle, respectively. Legend: G6P, glucose-6-phosphate; OAA, oxaloacetate
physiology in fasting response should be taken into account (Bonnefont et al 1990; van Veen et al 2011), emphasizing the need to individualize the dietary management in GSD III patients with regular check-up (Kishnani et al 2010). Last, the ability to maintain euglycemia additionally depends on the daily amount and distribution of dietary protein. More recently, the experimental heat-moisture processed high amylopectin cornstarch Glycosade® (Vitaflo Int. Ltd, Liverpool, UK) has been developed and characterized, mostly in GSD I patients (Bhattacharya et al 2007; Correia et al 2008) but also in two GSD III patients (Bhattacharya et al 2007). Both studies report biochemical data suggesting better metabolic control after Glycosade®, when compared to regular UCCS. In this special issue of The Journal, Nalin et al report studies on the in vitro digestion of different starches (including Glycosade®) in a dynamic gastrointestinal model simulating the human upper gastrointestinal tract (Nalin et al 2014). Small differences in digestibility were observed between different brands of UCCS, whereas sweet polvilho (a Brazilian cassava derived starch) displayed a superior digestibility pattern. Additional in vivo studies with clinically relevant endpoints are needed to confirm the potential to achieve good metabolic control, regardless of which starch is used during the different parts of the day.
The role of protein The role of dietary protein in dietary management of GSD III patients is currently still under-appreciated, despite the first reports from the 1960s. Increased dietary protein may be beneficial in at least three ways (Kishnani et al 2010). In GSD III gluconeogenesis is intact and exogenous gluconeogenic protein can be used as an additional source of carbohydrates during fasting. Theoretically, endogenous proteolysis by skeletal muscle breakdown would be reduced or perhaps even prevented. By replacing dietary carbohydrates, storage of “limited dextrin” could be reduced in the affected organs. Few small cohort studies and case reports present reversibility of (cardio)myopathy after increasing dietary protein intake in GSD III patients. Slonim et al reported increased exercise tolerance, muscle strength and growth in a 7 year old GSD III patient after increasing (nocturnal) dietary protein treatment (Slonim et al 1982). Relative daily protein intake expressed in energy percentages was increased from 18 % towards 25 %, continuous nocturnal caloric intake from 20 % towards 25 % of the daily amount. Later, additional results were reported in a small cohort study of seven GSD IIIa patients in whom the distribution of dietary carbohydrates
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mass in order to assess the natural history of HCM in this patient group (Vertilus et al 2010). In the last decade, three case reports from different groups described reversibility of HCM in GSD IIIa patients after initiation of a high protein diet (Dagli et al 2009; Valayannopoulos et al 2011; Sentner et al 2012). Although the three reports share the concept of a highprotein dietary management, they differ importantly with respect to the remaining dietary macronutrients and clinical o u t c o m e p a r a m e t e r s ( Ta b l e 1 ) . I n t e r e s t i n g l y, Valayannapoulos et al observed in their case that ketone bodies were capable to reverse HCM, when the dietary management remained constant (Valayannopoulos et al 2011). Given the character of the long-term muscular and cardiac complications in GSD III patients and the crucial role for mitochondrial fatty acid oxidation in these organs, dietary management with high fat (and thereby ketone bodies) has been underappreciated and deserves more attention. High protein diets have been prescribed in patients with other GSD subtypes in which gluconeogenesis is intact. Based on observations in eight adult GSD II patients, it was concluded that high-protein diets might stabilize the disease progression in skeletal muscle, but does not cause significant clinical improvements (Ravaglia et al 2006). According to the textbooks, the X-linked GSD IX due to PHKA2 mutations is considered a relatively benign condition with minimal complications. A recent case series reported significant clinical improvements after strict treatment with regular doses of UCCS and protein (2.5 g/kg/day) in two GSD IX patients who presented liver cirrhosis, prominent ketosis, laboratory abnormalities and failure to thrive (Tsilianidis et al 2013). Despite these advantages of high-protein diets, several items deserve both individual patient monitoring and
and protein was changed from 50–60 % to 40–50 % and 10– 13 % to 20–25 %, respectively (Slonim et al 1984). Between 1/3 and 1/4 of the caloric intake was given as continuous nocturnal drip-feeding. The patients with failure to thrive showed dramatic improvements of growth, next to improvements of physical activity, endurance and muscle strength. Moreover, there was reversal of myopathic electromyography patterns to normal in two patients and reversal of abnormal electrocardiography findings to normal in one patient. More recently, Kiechl et al reported a 47-year-old male GSD III patient presenting non-classically with severe myopathy of the respiratory muscles (Kiechl et al 1999). He could be successfully weaned from the ventilator after a period of 4 days on a high protein diet, i.e. 30–35 % of total energy intake, but the cardiomyopathy further deteriorated. In addition to these published data, interesting clinical observations come from the GSD IIIa founder population at the Faroe Islands. The local adult patient cohort with GSD IIIa was physically much fitter than the patients in childhood, because the paediatric patients were switched to a more carbohydrate based diet (to prevent hypoglycaemias, according to the traditional medical opinion at the time), whereas the adult patients had remained on their naturally protein-rich diet at the islands (personal communications by Ulrike Steuerwald). Skeletal myopathy and hypertrophic cardiomyopathy (HCM) are not correlated in GSD III patients (Labrune et al 1991). HCM is a common echocardiographic phenomenon in GSD IIIa patients, but rarely associated with severe clinical symptomatology of dysfunction, as determined by ejection fraction and/or shortening fraction (Lee et al 1997). There is one cohort study describing cross-sectional and longitudinal data of measurements of left ventricular wall thickness and
Table 1 Case reports describing reversibility of HCM in GSD IIIa patients after initiation of a high protein diet (Dagli et al 2009)
(Valayannopoulos et al 2011)
(Sentner et al 2012)
Patient AGL genotype
22 years old male n.r.
30 years old female c.753_756delCAGA homozygote
Cardiac findings
Cardiac murmur
2 month old male c.2157+1G>T homozygote Asymptomatic HCM, but positive family history
Prior diet
20 energy % protein suboptimal compliance 2.95 g/kg UCCS 3 times per day 30 energy % protein 1.36 g/kg UCCS twice daily
Outcome parameters
Echocardiography CK
65 energy % carbohydrates±23 energy % fat±12 energy % protein 15 energy % protein (3 g/kg/d) 20 energy % carbohydrates 65 energy % fat 3OHB Echocardiography CK
Follow-up
1 year
24 months
Dietary change
The prior diet is expressed as energy percentage, unless expressed otherwise Legend: BMI body mass index, NHYA New York Heart Association, n.r. not reported
BMI 30.3 NYHA 3+ echocardiography n.r. 900 cal+37 energy % protein for 4 months, thereafter 1,370 cal+43 energy % protein Echocardiography BMI 27.8 kg/m2 NYHA 2+ 3 years
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systematical study in the cohort of GSD III patients, i.e. costs, tolerability, micronutrient intake, renal function and other long-term complications.
Conclusions and future perspectives To summarize, based on expert opinions, case studies and small cohort studies, there is low-grade level of evidence for the role of UCCS and protein in current dietary management of GSD III patients. The evidence is mainly derived from paediatric GSD III patients in whom management generally focuses on the prevention of hypoglycaemia. The ageing cohort of GSD III patients demonstrates that maintenance of euglycemia may not be sufficient to prevent chronic, longterm. Over-treatment with carbohydrates may be even harmful and is intimately connected with protein under-treatment, when fat intake is constant. Although the reversibility of myopathy and cardiomyopathy upon dietary manipulations has been demonstrated, to date it is questionable whether prevention is possible. After the classical clinical presentations of GSD III in early childhood, the phenotype is changing in the ageing cohort of patients. Towards adulthood, EGP is declining, glucose homeostasis is controlled more easily and hypoglycaemia become uncommon. Special circumstances however, like pregnancy, diabetes and exercise, necessitate increased attention for dietary management to control glucose homeostasis in adulthood. Based on experimental data, during pregnancy EGP is increased by 16 % (Kalhan et al 1979), which increases the risk of hypoglycaemia and poor metabolic control in GSD III patients. There are several reports on the successful obstetric management (Confino et al 1984; Mendoza et al 1998; Lee 1999; Bhatti and Parry 2006; Ramachandran et al 2012; Bolton et al 2012), mostly on a UCCS-based dietary regimen. To date there is no general agreement on the dietary management under these circumstances. Several reports suggest an association between diabetes and GSD III, in either classically ascertained patients or patients with non-classical adult presentations (Moe et al 1972; Oki et al 2000; Spengos et al 2009; Ismail 2009; Sharma 2009). Dietary and pharmacological treatment of diabetes in GSD III carry the risk of hypoglycaemia in GSD III patients. Interestingly, Oki et al recommended the neutral alpha-glucosidase inhibitor voglibose for treatment in their GSD III patient (Oki et al 2000). Acid alpha-glucosidase and neutral alpha-glucosidase are ubiquitous expressed. It remains an open question whether α-glucosidase inhibitors may increase the risk of (cardio)myopathy (like observed in acid α-glucosidase deficiency, i.e. glycogen storage disease type II of Pompe’s disease) in the ageing GSD III cohort. Exercise tolerance was recently studied in six GSD IIIa patients (Preisler et al 2013). After glucose infusion, the authors observed improved work
capacity by lowering the heart rate, and increased peak work rate by 30 %. Deficient energy production in muscle was discussed as an explanation for exercise intolerance in GSD IIIa patients, next to the traditional explanation of muscle wasting. To conclude, dietary management in GSD (III) patients is challenging, should be patient tailored and can be therefore regarded precision management. Cohort studies on dietary management are complicated by the rarity of this IEM. More than ever before, new management strategies and changing phenotypes in adulthood emphasize the need for international patient registries in hepatic GSD, which is a work in progress.
Acknowledgments Taking care of GSD-patients is teamwork and the discussions with the colleagues in our department have been very stimulating while preparing the presentation and this subsequent manuscript. Therefore the authors are thankful to Rixt van der Ende, Cynthia van Amerongen, Irene Hoogeveen, Chris Peter Sentner, Esther van Dam, Foekje de Boer, Francjan van Spronsen and Margreet van Rijn, the latter who critically read an early version of the manuscript. Compliance with Ethics Guidelines Conflict of interest The authors received speaker’s fees from Recordati Rare Diseases for this study, which was presented orally at “The changing spectrum of IMD: surviving longer and growing old with IMDs” Recordati Rare Diseases Academy Symposium in London, United Kingdom, 8 May 2014. In addition to that, in the last 5 years, Terry GJ Derks had received speaker’s fees from Danone Nutricia and Vitaflo, research fees from Sigma Tau and Vitaflo, and training support from Sigma Tau and Genzyme. G Peter A Smit declares that he has no conflict of interest. This article does not contain any studies with human or animal subjects performed by the any of the authors.
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