Guidelines for management of glycogen storage disease type I—European study on glycogen storage disease type I (ESGSD I)

Life-expectancy in glycogen storage disease type I (GSD I) has improved considerably. Its relative rarity implies that no metabolic centre has experience of large series of patients and experience with long-term management and follow-up at each centre is limited. There is wide variation in methods of dietary and pharmacological treatment. Based on the data of the European Study on Glycogen Storage Disease Type I, discussions within this study group, discussions with the participants of the international SHS-symposium ‘Glycogen Storage Disease Type I and II: Recent Developments, Management and Outcome’ (Fulda, Germany; 22–25th November 2000) and on data from the literature, guidelines are presented concerning: (1) diagnosis, prenatal diagnosis and carrier detection; (2) (biomedical) targets; (3) recommendations for dietary treatment; (4) recommendations for pharmacological treatment; (5) metabolic derangement/intercurrent infections/emergency treatment/preparation elective surgery; and (6) management of complications (directly) related to metabolic disturbances and complications which may develop with ageing and their follow-up.Conclusion: In this paper guidelines for the management of GSD I are presented.     

Consensus guidelines for management of glycogen storage disease type 1b—European study on glycogen storage disease type 1

Life expectancy in glycogen storage disease type 1 (GSD-1) has improved considerably. Its relative rarity implies that no metabolic centre has experience of large series of patients and therefore experience with long-term management and follow-up at each centre is limited. There is wide variation in methods of dietary and pharmacological treatment. Based on data from the European Study on Glycogen Storage Disease Type 1, discussions within this study group together with those at the International SHS Symposium ‘Glycogen Storage Disease Type I and II: Recent Developments, Management and Outcome’, Fulda, Germany (2000) and on data from the literature, a series of guidelines were drawn up.Conclusions: the following guidelines for the management of patients with glycogen storage disease type 1b are in addition to those general guidelines for glycogen storage disease type 1 and address specific problems related to neutropenia and neutrophil dysfunction. Published online: 13 September 2002     

More questions: 10 years later from glycogen storage disease patient support groups in Europe

In 1990 the first Fulda Workshop on Glycogen Storage Disease (GSD) type I was held in November. Eight adult representatives from Patient groups in the UK, USA, Germany and the Netherlands were invited to come and set up an information table of posters, leaflets etc. We were also asked to present a short list of questions that can occur to parents after the initial shock of diagnosis and treatment of GSD has been made. These “Questions of Parents” were presented on the final day. Ten years later, patient representatives from Europe were invited to present “More Questions: 10 Years Later”. On both occasions the questions centred around six broad areas: (1) treatments, (2) specific problems, (3) family planning, (4) long-term effects of having GSD type Ia and Ib, (5) research and (6) general questions.Conclusion: As representatives of GSD support groups, we hope that firm decisions can be agreed for common dietary and pharmacological treatment and follow-up procedures within the boundaries of cultural differences and financial circumstances. We anticipate that if there is a third Fulda workshop in 2010, the answer to the question “Is there a common set of protocols and guidelines among doctors and hospitals as to the correct treatment for glycogen storage disease type I?” will be a firm “Yes”.     

Liver transplantation for glycogen storage disease types I, III, and IV

Glycogen storage disease (GSD) types I, III, and IV can be associated with severe liver disease. The possible development of hepatocellular carcinoma and/or hepatic failure make these GSDs potential candidates for liver transplantation. Early diagnosis and initiation of effective dietary therapy have dramatically improved the outcome of GSD type I by reducing the incidence of liver adenoma and renal insufficiency. Nine type I and 3 type III patients have received liver transplants because of poor metabolic control, multiple liver adenomas, or progressive liver failure. Metabolic abnormalities were corrected in all GSD type I and type III patients, while catch-up growth was reported only in two patients. Whether liver transplantation results in reversal and/or prevention of renal disease remains unclear. Neutropenia persisted in both GSDIb patients post liver transplantation necessitating continuous granulocyte colony stimulating factor treatment. Thirteen GSD type IV patients were liver transplanted because of progressive liver cirrhosis and failure. All but one patient have not had neuromuscular or cardiac complications during follow-up periods for as long as 13 years. Four have died within a week and 5 years after transplantation. Caution should be taken in selecting GSD type IV candidates for liver transplantation because of the variable phenotype, which may include life-limiting extrahepatic manifestations. It remains to be evaluated, whether a genotype-phenotype correlation exists for GSD type IV, which may aid in the decision making. Conclusion Liver transplantation should be considered for patients with glycogen storage disease who have developed liver malignancy or hepatic failure, and for type IV patients with the classical and progressive hepatic form.     

Hypercalcemia in glycogen storage disease type I patients of Turkish origin

Glycogen storage disease type I (GSD I) is an autosomal recessive disorder caused by defects in the glucose-6-phosphatase complex. Deficient activity in the glucose-6-phosphatase-a (G6Pase) catalytic unit characterizes GSD IA and defects in the glucose-6-phosphate transporter protein (G6PC) characterize GSD IB. The main clinical characteristics involve fasting hypoglycemia, hyperuricemia, hyperlactatemia, and hyperlipidemia. Hypercalcemia arose as an unknown problem in GSD I patients, especially in those with insufficient metabolic control. The aim of the present study was to obtain the prevalence of hypercalcemia and to draw attention to the metabolic complications of GSD I patients, including hypercalcemia in poor metabolic control. Hypercalcemia frequency and the affecting factors were studied cross-sectionally in 23 GSD I pediatric subjects. Clinical diagnosis of GSD I was confirmed in all patients either through documentation of deficient G6Pase enzyme activity levels on liver biopsy samples or through G6PC gene sequencing of DNA. Hypercalcemia was detected in 78.3% of patients with GSD I. Different from the previous report about hypercalcemia in a GSD IA patient who had R83H and 341delG mutations, we could not identify any genotype-phenotype correlation in our GSD I patients. Hyperlactatemia and hypertriglyceridemia correlated significantly with hypercalcemia. Furthermore, no differences in serum calcium concentrations could be demonstrated between patients with optimal metabolic control. We observed hypercalcemia in our series of GSD I patients during acute metabolic decompensation. Therefore, we speculate that hypercalcemia should be considered as one of the problems of GSD I patients during acute attacks. It may be related with prolonged lactic acidosis or may be a pseudohypercalcemia due to hyperlipidemia that can be seen in GSD I patients with poor metabolic control.     

Nutritional therapy for glycogen storage diseases

Glycogen storage diseases (GSDs) are a group of inherited disorders characterized by enzyme defects that affect the glycogen synthesis and degradation cycle, classified according to the enzyme deficiency and the affected tissue. The understanding of GSD has increased in recent decades, and nutritional management of some GSDs has allowed better control of hypoglycemia and metabolic complications. However, growth failure and liver, renal, and other complications are frequent problems in the long-term outcome. Hypoglycemia is the main biochemical consequence of GSD type I and some of the other GSDs. The basis of dietary therapy is nutritional manipulation to prevent hypoglycemia and improve metabolic dysfunction, with the use of continuous nocturnal intragastric feeding or cornstarch therapy at night and foods rich in starches with low concentrations of galactose and fructose during the day and to prevent hypoglycemia during the night.     

Management recommendations for metabolic complications associated with second-generation antipsychotic use in children and youth

BACKGROUND:

Second-generation antipsychotics are commonly associated with metabolic complications. These medications are being used more frequently for the treatment of mental health disorders in children, which has stimulated the need for creating formal guidelines on monitoring their safety and effectiveness. Previous guidelines have been developed for monitoring metabolic and neurological complications. To assist practitioners who perform these monitoring procedures, a complementary set of treatment recommendations have been created for situations in which abnormal measurements or results are encountered.

OBJECTIVE:

To create evidence-based recommendations to assist in managing metabolic complications in children being treated with second-generation antipsychotics.

METHODS:

A systematic review of the literature on metabolic complications of second-generation antipsychotic medications in children was conducted. Members of the consensus group evaluated the information gathered from the systematic review of the literature and used a nominal group process to reach a consensus on treatment recommendations. Wherever possible, references were made to existing guidelines on the evaluation and treatment of metabolic abnormalities in children.

RESULTS:

Evidence-based recommendations are presented to assist in managing metabolic complications including weight gain; increased waist circumference; elevation in prolactin, cholesterol, triglyceride and glucose levels; abnormal liver function tests and abnormal thyroid studies.

CONCLUSION:

The use of second-generation antipsychotics requires proper monitoring procedures. The present treatment guideline provides guidance to clinicians on the clinical management of metabolic complications if they occur.     

Liver transplantation for type I and type IV glycogen storage disease

Progressive liver failure or hepatic complications of the primary disease led to orthotopic liver transplantation in eight children with glycogen storage disease over a 9-year period. One patient had glycogen storage disease (GSD) type I (von Gierke disease) and seven patients had type IV GSD (Andersen disease). As previously reported [19], a 16.5-year-old-girl with GSD type I was successfully treated in 1982 by orthotopic liver transplantation under cyclosporine and steroid immunosuppression. The metabolic consequences of the disease have been eliminated, the renal function and size have remained normal, and the patient has lived a normal young adult life. A late portal venous thrombosis was treated successfully with a distal splenorenal shunt. Orthotopic liver transplantation was performed in seven children with type N GSD who had progressive hepatic failure. Two patients died early from technical complications. The other five have no evidence of recurrent hepatic amylopectinosis after 1.1–5.8 postoperative years. They have had good physical and intellectual maturation. Amylopectin was found in many extrahepatic tissues prior to surgery, but cardiopathy and skeletal myopathy have not developed after transplantation. Post-operative heart biopsies from patients showed either minimal amylopectin deposits as long as 4.5 years following transplantation or a dramatic reduction in sequential biopsies from one patient who initially had dense myocardial deposits. Serious hepatic derangement is seen most commonly in types I and IV GSD. Liver transplantation cures the hepatic manifestations of both types. The extrahepatic deposition of abnormal glycogen appears not to be problematic in type I disease, and while potentially more threatening in type IV disease, may actually exhibit signs of regression after hepatic allografting.     

Effective renal plasma flow in patients with glycogen storage disease type I

To evaluate effective renal plasma flow (ERPF) we performed renal scintigraphies with^99mTc-Mercaptoacetyl-triglycine (MAG₃) in ninepatients with glycogen storage disease I (GSD I) (age: 16±7 years). Two patients presented with proteinuria, none showed hyperaminoaciduria, disturbed tubular reabsorption of phosphate or hypertension.^99mTc-MAG₃ clearance values were elevated in eight out of nine patients (865±233 ml/min/1.73 m² body surface area) and exceeded the agedependent mean values by 21%–145%. ERPF values in patients with poor metabolic control were higher than in patients with long-term good metabolic control (988±186 vs. 619±55 ml/min/1.73 m²;P<0.05). We conclude that enhanced ERPF is a common finding in GSD I patients, which preceeds clinically overt nephropathy. Renal scientigraphy with^99mTc MAG₃ is a suitable method for the early detection and monitoring of kidney dysfunction in GSD I.     

Decreased urinary citrate excretion in type 1a glycogen storage disease

OBJECTIVES: To quantify urinary citrate and calcium excretion and systemic acid-base status in patients with type 1a glycogen storage disease (GSD1a) and to investigate their relationship to renal complications. STUDY DESIGN: Fifteen patients (7 male and 8 female; age range, 3--28 years) were studied during annual evaluations of metabolic control. All were treated with intermittent doses of uncooked cornstarch. Hourly blood sampling and a 24-hour urine collection were obtained while subjects followed their usual home dietary regimen. RESULTS: All but the youngest subject had low levels of citrate excretion (mean 2.4 +/- 1.8 mg/kg/d; 129 +/- 21 mg citrate/g creatinine). Normally, urinary citrate excretion increases with age; however, in patients with GSD1a, a strong inverse exponential relationship was found between age and citrate excretion (r = -0.84, P <.0001). Urinary citrate excretion was unrelated to markers of metabolic control. Hypercalciuria occurred in 9 of 15 patients (mean urinary calcium/creatinine ratio, 0.27 +/- 0.15) and was also inversely correlated with age (r = -0.62, P =.001). CONCLUSIONS: Hypocitraturia that worsens with age occurs in metabolically compensated patients with GSD1a. The combination of low citrate excretion and hypercalciuria appears to be important in the pathogenesis of nephrocalcinosis and nephrolithiasis. Citrate supplementation may be beneficial in preventing or ameliorating nephrocalcinosis and the development of urinary calculi in GSD1a.     

Glycogen storage disease type I: diagnosis and phenotype/genotype correlation

Glycogen storage disease type Ia (GSD Ia) is caused by mutations in theG6PC gene encoding the phosphatase of the microsomal glucose-6-phosphatase system. GSD Ia is characterized by hepatomegaly, hypoglycemia, lactic acidemia, hyperuricemia, hyperlipidemia and short stature. Other forms of GSD I (GSD I non-a) are characterized by the additional symptom of frequent infections caused by neutropenia and neutrophil dysfunction. GSD I non-a is caused by mutations in a gene encoding glucose-6-phosphatase translocase (G6PT1). We report on the molecular genetic analyses of G6PC and G6PT 1 in 130 GSD Ia patients and 15 GSD I non-a patients, respectively, and provide an overview of the current literature pertaining to the molecular genetics of GSD I. Among the GSD Ia patients, 34 different mutations were identified, two of which have not been described before (A65P; F117C). Seventeen different mutations were detected in the GSD I non-a patients. True common mutations were identified neither in GSD Ia nor in GSD I non-a patients,Conclusion: Glycogen storage disease type Ia and and type I non-a are genetically heterogenous disorders. For the diagnosis of the various forms of glycogen storage disease type I, molecular genetic analyses are reliable and convenient alternatives to the enzyme assays in liver biopsy specimens. Some genotype-phenotype correlations exist, for example, homozygosity for oneG6PC mutation, G188R, seems to be associated with a glycogen storage disease type I non-a phenotype and homozygosity for the 727G>T mutation may be associated with a milder phenotype but an increased risk for hepatocellular carcinoma. Published online: 27 July 2002     

Improved growth with growth hormone therapy in a child with glycogen storage disease Ib

In type Ib glycogen storage disease (GSD) growth is typically affected and short stature is a common feature. Reported use and effect of growth hormone (GH) therapy in children with GSD is limited. We report on the use of substitutive GH treatment in a poorly growing adolescent female with GSD type Ib. The patient's growth velocity increased from a baseline level of 2.5 cm/y to an average growth velocity during GH therapy of 8.7 cm/y. During GH therapy this patient did not demonstrate metabolic decompensation but increased levels of cholesterol and triglycerides were seen (A-1).

Conclusion: Patients with GSD may experience an improvement in growth response with GH treatment. Prior to GH therapy, treatment of hyperlipidemia associated with GSD should allow the therapy to be safely tolerated.     

Liver transplantation in children with glycogen storage disease: controversies and evaluation of the risk/benefit of this procedure

Abstract:  GSD-I, III, and IV are congenital disorders of glycogen metabolism that are commonly associated with severe liver disease. Liver transplantation has been proposed as a therapy for these disorders. While liver transplantation corrects the primary hepatic enzyme defect, the extrahepatic manifestations of GSD often complicate post-transplantation management. Upon review of the English-language literature, 42 children <19 yr of age were discovered to have undergone liver transplantation for complications associated with GSD (18 patients with GSD-Ia, six with GSD-Ib, one with GSD-III, 17 with GSD-IV). An additional two children followed at our institution have undergone liver transplantation for GSD complications (one with GSD-Ia and one with GSD-III) and are included in this review. The risks and benefits of liver transplantation should be considered prior to performing liver transplantation in these metabolic disorders, particularly in GSD-Ia. As liver pathology is not the major source of morbidity in GSD-Ib and GSD-IIIa, liver transplantation should only be performed when there is high risk for HCC or evidence of substantial cirrhosis or liver dysfunction. Liver transplantation remains the best option for treatment of GSD-IV.     

Contraception and pregnancy in women affected by glycogen storage diseases

During the last decades, better understanding of specific enzymatic deficiencies has led to improved dietary management of children suffering from glycogen storage disease (GSD). Normal growth and development of infants can be achieved by a diet of regular meals supplemented by glucose and cornstarch during the night, and by monitoring glucose blood levels. This has resulted in an increase in the number of patients reaching adulthood and reproduction age. Therefore, developing a strategy for an optimal management of contraception and pregnancy is crucial for young women affected by GSD. Contraception has to be adapted to the specific metabolic requirements of women with GSD. Hormonal contraception is classically based on the combination of various synthetic progestogens and ethinyloestradiol. Ethinyloestradiol should be avoided because of a link with hepatic adenomas and is contraindicated in patients with hypertriglyceridaemia and hypercholesterolaemia. Blockade of ovulation can be achieved using high doses of progestogen alone, administered from the 5th to the 25th day of the cycle. Another scheme of hormonal contraception is based on daily administration of low doses of progestogen, which usually acts on local parameters of fertility, and can also achieve blockade of ovulation for the most recent compound proposed. Mechanical contraception using intra-uterine device is controversial for nulliparous patients. Benefits and side-effects of these different proposals are discussed. During pregnancy, the maternal nutritional state is important and a healthy maternal response to feeding and fasting is modified to ensure a constant supply of glucose for the developing fetus. Women with GSD are at risk of frequent hypoglycaemia. Only a few cases of successful pregnancies have been reported for patients with GSD. The outcomes using different approaches of dietary and obstetric management are discussed.Conclusion: in the future, multidisciplinary management is necessary to improve obstetric outcome of pregnancy in females affected with glycogen storage disease. Published online: 4 September 2002     

How many forms of glycogen storage disease type I?

 Glucose-6-phosphatase is a multicomponent enzymatic system of the endoplasmic reticulum, which catalyses the terminal steps of gluconeogenesis and glycogenolysis by converting glucose-6-phosphate to glucose and inorganic phosphate. Glycogen storage diseases type I (GSD I) are a group of metabolic disorders arising from a defect in a component of this enzymatic system, i.e. the glucose-6-phosphate hydrolase (GSD Ia), the glucose-6-phosphate translocase (GSD Ib) and possibly also the translocases for inorganic phosphate (GSD Ic) or glucose (GSD Id). The genes encoding the glucose-6-phosphate hydrolase and the glucose-6-phosphate translocase have both been cloned and assigned to human chromosomes 17q21 and 11q23, respectively. Investigation of patients with GSD I shows that those with GSD Ia are mutated in the glucose-6-phosphate hydrolase gene, whereas those diagnosed as GSD Ib, GSD Ic or GSD Id are mutated in the glucose-6-phosphate translocase gene, and are therefore GSD Ib patients, in agreement with the fact that they all have neutropenia or neutrophil dysfunction. This suggests that the biochemical assays used to differentiate GSD Ic and GSD Id from GSD Ib are not reliable. Conclusion In practice therefore appears to be only two types of GSD I (Ia and Ib), which can be differentiated by (1) measurement of glucose-6-phosphatase activity in fresh and detergent-treated homogenates and (2) by mutation search in the genes encoding the glucose-6-phosphate hydrolase and the glucose-6-phosphate translocase. Received: 20 July 1999 and in revised form: 1 October 1999 / Accepted: 1 October 1999     

Type I glycogen storage disease: Nine years of management with cornstarch

Long-term effects of cornstarch (CS) therapy on biochemical values and physical growth in children with type I glycogen storage disease (GSD I) were compared to those of children receiving continuous nocturnal nasogastric glucose feedings (CNG). Only patients who had received more than 5 years of dietary therapy (either CS or CNG) were evaluated. Six patients (five female, age 13.5 years±1.3, range 11.7–16.5 years) received CS (1.75–2.5 g/kg, four times daily) and seven patients (five female, age 9.6±2.5 years, range 7.3–14.8 years) received CNG. Blood glucose, lactate, cholesterol and triglyceride levels were not significantly different between the two methods of treatment. All patients maintained linear growth rates normal for their age. The standard deviation score of height after 6.7±1.6 years (range 5–9 years) of CS treatment was –1.29±0.59 and after 8.8±2.4 years (range 7–14 years) of CNG was –1.24±0.63. These values did not differ significantly from each other or from the target height, an estimate of genetic potential for height as determined from parental heights. With the exceptions of diarrhea, increased flatulence and excess weight gain, there were no adverse effects of CS after 9 years of treatment. Our data suggests that cornstarch is a simple, effective and safe therapy for GSD I.     

Echogenic kidneys and medullary calcium deposition in a young child with Glycogen Storage Disease type 1a

We report the case of a young child with Glycogen Storage Disease (GSD) type-Ia who developed echogenic kidneys, medullary calcium deposition and disturbance of renal function. These severe renal abnormalities are seen in young adults whose GSD-I has been ineffectively treated. Renal disease can be considered a major problem in GSD-I.     

Glycogenosis type I

OBJECTIVE: To o present up-to-date knowledge about Glycogen storage disease type I (GSD-type I) - a disease caused by the deposit of glycogen resulting from the deficiency of the enzyme glucose-6- phosphatase - and to provide the pediatricians with the necessary information for a precocious diagnosis and an adequate conduct for those cases where this metabolic disturbance is present. METHODS: Through Medline, the most significant articles published during the last 20 years were selected from national and international journals of medicine, with special attention to dietary treatment of glycogen storage disease type I. RESULTS: The metabolism of glycogen and the metabolic consequences of glycogen storage disease type I were discussed, especially hypoglycemia, the principal metabolic disturbance of the disease. The clinical and laboratory findings are described together with the histopathology. The use of uncooked cornstarch and enteral carbohydrate infusion are the means used for the maintenance of normoglycemia. The control of hyperuricemia, hyperlipidemia and platelet disorders are other aspects of the treatment as well as the prevention of infections and the use of G-CSF for glycogen storage type Ib. Hepatic transplant and its principal indications are commented on. Hepatic adenomae, which always have the potential of malignant transformation, are the results of incomplete treatment. CONCLUSIONS: Although it occurs rarely, glycogen storage type I is an important cause of volumous hepatomegaly which is associated with hypoglycemia among the infants. The dietary treatment of this illness has significantly altered the clinical course and has improved the prognosis. Therefore it is indispensable that the general pediatrician should be familiar with the diagnosis of this clinical state so as to act rigorously in favor of the dietary control.     

Intragastric feeding in type I glycogen storage disease: factors affecting the control of lactic acidemia

Continuous nocturnal intragastric feeding, combined with frequent daytime feedings, has been reported to improve both linear growth and the metabolic abnormalities in patients with glucose-6-phosphatase deficiency (Type I Glycogen Storage Disease). However, elevated blood levels of lactate have persisted. The present studies explore the relationship between blood lactate concentrations in six patients with glucose-6-phosphatase deficiency and variations in the rate and composition of the intragastric feeding. Blood lactate and plasma glucose concentrations were determined at rates of dextrose administration ranging from 3-34 mg/kg/min. Dextrose infusion at 100-200% of estimated normal glucose production rates gave the best control of blood lactate concentrations. Lower rates of dextrose infusion resulted in significantly higher blood lactate levels; higher rates produced hyperglycemia, but no significant further reduction of blood lactate. At identical rates of glucose administration, a dextrose-containing infant formula and a high carbohydrate enteric feeding solution gave no significant improvement in control of blood lactate levels compared to dextrose alone. Plasma glucose levels fell more rapidly when intragastric feeding was stopped than after a mixed meal and hypoglycemia appeared to develop before counter-regulatory responses could be mobilized. These observations may account for the increased susceptibility to symptomatic hypoglycemia reported in patients treated with intragastric feeding.