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00019616-200211000-00010ReviewThe EndocrinologistThe Endocrinologist© 2002 Lippincott Williams & Wilkins, Inc.12November 2002 p 531-538Glycogen Storage Diseases: A Primer for CliniciansCME Review Articles: Genetics & MetabolismWeinstein, David A. M.D., M.M.Sc.*; Wolfsdorf, Joseph I. M.B., B.Ch.†*Assistant in Endocrinology, Children’s Hospital Boston, Instructor in Pediatrics, Harvard Medical School, Boston, Massachusetts.†Director, Diabetes Program, and Chief, Charles A. Janeway Medical Firm, Children’s Hospital Boston, Associate Professor of Pediatrics, Harvard Medical School, Boston, Massachusetts.CHIEF EDITOR’S NOTE: This article is the 36th of 36 that will be published in 2002 for which a total of up to 36 Category 1 CME credits can be earned. Instructions for how credits can be earned appear after the Table of Contents.DOI: 10.1097/01.ten.0000037854.88896.6cAddress correspondence to: David A. Weinstein, M.D., M.M.Sc., Division of Endocrinology, Children’s Hospital, 300 Longwood Avenue, Boston, MA 02115. Telephone: 617-355-2451; Fax: 617-734-1369; E-Mail: [email protected] authors have disclosed that they have no significant relationships with or financial interests in any commercial company pertaining to this educational activity.AbstractNormal glycogen synthesis and degradation are required for maintenance of blood glucose concentrations during periods of fasting. The hepatic glycogen storage diseases comprise several inherited diseases caused by abnormalities of the enzymes that regulate these pathways. Although hypoglycemia is the cardinal manifestation of all the hepatic glycogenoses, there is a wide spectrum of severity. In many patients the hypoglycemia is unrecognized leading to delayed diagnosis. Traditional fasting studies may not appropriately identify all the disorders of glycogen synthesis and degradation, and specific testing is often required. All the glycogen storage diseases are treated with continuous glucose delivery, either by intermittent administration of uncooked cornstarch or frequent feeds during the day and overnight intragastric feeding, in an attempt to maintain blood glucose concentrations above the threshold level for glucose counterregulation. During periods of stress, exposure to pharmacological doses of glucocorticoids, or both, severe lactic acidosis can occur in type I GSD despite maintenance of normal blood glucose concentrations. Patients with the glycogen storage disease are at risk for long-term complications that are type-specific, including hepatic adenomas, hepatocellular carcinoma, focal segmental glomerulosclerosis, anemia, and cardiac dysfunction. Minimizing the metabolic abnormalities of these disorders may decrease the risk for long-term complications. The achievement of optimal biochemical control continues to be a challenge and requires individualized treatment regimens. With modern management, good biochemical control can be achieved, and the prognosis for all the glycogen storage diseases has improved considerably.IntroductionDistinguish the major forms of glycogen storage disease (GSD) with regard to enzyme deficiency and ethnic/geographic distribution.Recall the clinical features of the respective GSDs and describe how best to diagnose these disorders.Outline the treatment of GSDs and its expected effect on long-term complications.The brain is dependent upon a continuous supply of glucose as it can neither synthesize glucose nor store more than a few minutes supply as glycogen. Despite the critical importance of glucose, the total amount of glucose in blood and the extracellular space is small (∼5% of a teaspoon of glucose per kg of body weight). For example, the total amount of glucose in the extracellular space of a person with a plasma glucose concentration of 90 mg/dL is 225 mg/kg of body weight. For an average 10-year-old child who weighs 30 kg, this is 6.75 grams of glucose, which could meet the basal glucose requirements for 45 minutes [1].After a meal, glucose is predominantly stored as glycogen, a complex, highly branched spherical structure, which allows efficient storage and release of glucose. The liver is freely permeable to glucose, which is rapidly phosphorylated by glucokinase to form glucose-6-phosphate. After conversion to glucose-1-phosphate, glycogen synthase catalyzes the formation of α-1,4-linkages that elongate into chains of glucose molecules. A branching enzyme leads to formation of α-1,6-linkages at approximately every 10 glucose units along the chain. This structure allows for compact storage of glucose and its slow release during periods of fasting. In between meals, a cascade of enzymatic reactions activates hepatic glycogen phosphorylase, the rate-limiting enzyme in glycogenolysis, which removes glucose from the outer branches of glycogen, and leads to formation of glucose-6-phosphate. Hydrolysis by glucose-6-phosphatase allows glucose to be released from the liver into the systemic circulation. Debranching enzyme is required for hydrolysis of α-1,6-linkages at branch points.The glycogen storage diseases (GSD) or glycogenoses comprise several inherited diseases caused by abnormalities of the enzymes that regulate glycogen synthesis and degradation. Glycogen is stored principally in the liver and muscle, but muscle lacks glucose-6-phosphatase and is, therefore, unable to release glucose for systemic use. Hypoglycemia is the primary manifestation of the hepatic glycogenoses, whereas weakness and muscle cramps are the predominant features of the muscle glycogenoses. This review will focus principally on clinical management of the glycogenoses with hepatic involvement, as these are the disorders most likely to be managed by endocrinologists.Hepatic Glycogen Synthase Deficiency (Glycogen Storage Disease Type 0)Type 0 glycogen storage disease (GSD0) is caused by a deficiency of the hepatic isoform of glycogen synthase leading to a marked decrease in liver glycogen content. After consumption of carbohydrate, the inability to store glucose as glycogen in the liver results in postprandial hyperglycemia and hyperlactatemia [2]. Fasting can cause severe ketotic hypoglycemia [3].GSD0 is inherited in an autosomal recessive manner and is caused by mutations in the GYS2 gene located on chromosome 12p12.2. Mutation analysis for this disorder has been limited. To date, 11 different mutations from 10 families have been reported with no dominant mutation found. Cases of GSD0 have been identified throughout Europe, North America, and South America, and no high-risk population has been identified [4].Clinical FeaturesGSD0 was initially described as a devastating disorder characterized by fasting hypoglycemia, seizures, and severe developmental delay. Only recently has it been appreciated that most children with GSD0 have milder symptoms. Recurrent ketotic hypoglycemia with illness may be the only manifestation, and some asymptomatic children have been reported [5]. The physical exam is usually normal and, unlike the other hepatic glycogenoses, hepatomegaly does not occur.Fasting ketotic hypoglycemia develops upon cessation of nighttime feeding. Early in infancy, children are asymptomatic, but weaning from overnight feeds often proves to be difficult. As children grow, it is not uncommon for fasting hypoglycemia to go unrecognized and even significant hypoglycemia may be asymptomatic. Recurrent hypoglycemia results in up-regulation of cerebral GLUT-1 and GLUT-3 receptors, which allows more efficient delivery of glucose to the brain as blood glucose concentrations fall [6]. In addition, abundant ketones develop with fasting, which may be used as an alternative energy source for the brain. Despite these adaptations, severe hypoglycemia occurs with illness or prolonged fasting and, if recurrent, neurologic sequelae can occur. Developmental delay has been described in 22% of children with GSD0 [5].Most children with GSD0 are identified incidentally during a gastrointestinal illness or period of poor nutrition when hypoglycemia is noted during an evaluation of lethargy. The manifestations of GSD0 are frequently subtle, however, and many patients will come to the attention of an endocrinologist for evaluation of short stature or hyperglycemia. Postprandial hyperglycemia and fasting ketonuria can be confused as early diabetes, and GSD0 should be considered in any child with asymptomatic hyperglycemia or glucosuria [5]. The postprandial hyperlactatemia may cause mild metabolic acidosis, particularly in the morning, and may account for modest growth delay.DiagnosisA typical fasting study, performed without postprandial biochemical monitoring, will often be normal with no obvious hormonal or biochemical abnormalities, leading to misdiagnosis as “ketotic hypoglycemia” or “accelerated starvation”. Frequent measurements of blood glucose, lactate, and ketones after consumption of a glucose load or mixed meal demonstrate the unique biochemical pattern of postprandial hyperglycemia and hyperlactatemia (Table 1). These abnormalities are accentuated in the presence of increased concentrations of counterregulatory hormones. Therefore, postprandial biochemical testing in the morning is recommended.JOURNAL/endst/04.03/00019616-200211000-00010/table1-10/v/2021-02-17T201658Z/r/image-tiff Biochemical Characteristics of the Hepatic Glycogen Storage DiseasesDespite the decrease in hepatic glycogen, response to glucagon is variable and may even be normal [2,5,7]. In the past, confirmation of the diagnosis was dependent upon demonstration of decreased hepatic glycogen content or abnormal enzyme activity on a liver biopsy. The diagnosis can now be made noninvasively through mutation analysis of the hepatic glycogen synthase gene [4]. The protean nature of GSD0 and prior dependence on liver biopsy likely has led to under-diagnosis of this condition.TreatmentThe goal of treatment is to prevent hypoglycemia by avoiding fasting. Daytime hypoglycemia tends to be mild, and frequent protein-rich meals and snacks given every 2–4 hours usually prevents hypoglycemia. Uncooked cornstarch (0.5–1 gram/kg) administered at bedtime and every 6 hours during illness prevents morning hypoglycemia and reduces ketosis. Improved growth velocity occurs on treatment, and most patients report improved energy. As glucose is preferentially shunted to lactate, a diet with increased protein and decreased carbohydrate content is recommended.Glucose-6-Phosphatase Deficiency (Type I Glycogen Storage Disease: von Gierke Disease)Type I glycogen storage disease (GSD I) is caused by deficiency of glucose-6-phosphatase activity. This critical enzyme catalyzes the conversion of glucose-6-phosphate to glucose, and is the final step of both glycogenolysis and gluconeogenesis. As a result, impairment of glucose-6-phosphatase activity results in an inability to form glucose during periods of fasting. When glycogen degradation occurs during fasting or in response to counterregulatory hormone stimulation, glucose-6-phosphate enters alternative metabolic pathways, leading to increased production of lactate, uric acid, and triglycerides (shown schematically in Figure 1) [8].JOURNAL/endst/04.03/00019616-200211000-00010/figure1-10/v/2021-02-17T201658Z/r/image-tiff Schematic representation of biochemical pathways affected in the glycogen storage diseases.Glucose-6-phosphatase is a complex enzyme located on the inner membrane of the endoplasmic reticulum, composed of a catalytic unit, a calcium binding protein, and three transport proteins that facilitate transport of glucose-6-phosphate (T1), phosphate (T2), and glucose (T3). Abnormalities in any of these components can result in abnormal enzyme function and the clinical phenotype of GSD I. More than 80% of patients have mutations that impair the function of the enzyme itself (Type 1A GSD). Defects in the T1 glucose-6-phosphate transporter account for most other cases (Type 1B GSD) [9].GSD I is inherited in an autosomal recessive manner and is caused by mutations in the G6PC gene located on chromosome 17q21. The overall incidence is estimated to be 1 in 200,000 births. More than 70 mutations have been reported from around the world, but the highest incidence is in the Ashkenazi Jewish population with an estimated carrier frequency of approximately 1:65.Clinical FeaturesSymptomatic hypoglycemia may appear soon after birth, but most children present between 3 and 6 months of age when the interval between feeds is lengthened. GSD I is occasionally diagnosed during a routine physical exam after hepatomegaly and a protuberant abdomen are noted. Usually, however, children are diagnosed during an evaluation for tachypnea, seizures, lethargy, developmental delay, or failure to thrive.Most of the clinical features of GSD I are related to the two principal metabolic abnormalities: hypoglycemia and lactic acidosis. As glycogenolysis and gluconeogenesis cannot occur normally, the hypoglycemia associated with untreated GSD I can be severe. Blood glucose concentrations can drop very quickly, and the rapidity with which hypoglycemia develops limits the generation of alternative fuels. This is particularly likely to occur if intravenous glucose administration or a continuous intragastric feed, associated with high blood insulin concentrations, is abruptly discontinued in a patient with GSD I.Chronic adaptation to hypoglycemia can occur, and patients may seek medical attention because of symptoms from chronic lactic acidosis. The metabolic acidosis is associated with tachypnea, exercise intolerance, muscle cramping, and can be associated with vomiting from abnormal gastric motility. Many patients are misdiagnosed as having bronchiolitis and gastroenteritis in the first few months of life leading to delayed diagnosis and prolonged or repeated exposure to hypoglycemia. Even in patients who have been diagnosed, generation of lactic acid during illness and periods of stress can be problematic; counterregulatory hormone activation (i.e., cortisol and epinephrine) or use of high doses of glucocorticoids can cause marked lactic acidosis despite normal blood glucose concentrations [10].Social and cognitive development are not affected if hypoglycemia is prevented; however, developmental delay may occur in GSD I, usually as a result of a delay in the diagnosis and initiation of appropriate treatment. Untreated patients have a cushingoid appearance, failure to thrive, and severely stunted growth. Eruptive xanthomata from extremely high triglyceride concentrations and a bleeding tendency caused by platelet dysfunction may also be noted in the untreated patient. Laboratory evaluation reveals elevations in serum uric acid and triglyceride concentrations, and liver transaminase concentrations are moderately elevated.Although patients may do well overall with intensive treatment, long-term complications of GSD I are common, including hepatic adenomas, focal segmental glomerulosclerosis, renal tubular dysfunction, anemia, and osteoporosis. Poor metabolic control contributes to the pathogenesis of these complications [11].The hepatic complications of GSD I are the most significant cause of morbidity in adults. Hepatic adenomas occur in most patients by the time they finish puberty, although adenomas occasionally develop during childhood. Most adenomas remain stable over time, but they may be associated with hemorrhage or undergo malignant degeneration to hepatocellular carcinoma [12]. High alkaline phosphatase concentrations and elevation in the erythrocyte sedimentation rate (ESR) are often seen in patients with adenomas. Ultrasonography is the preferred method for screening, and magnetic resonance imaging provides greater definition when malignancy is a concern because of changes in the sonographic appearance. Serum α-fetoprotein is normal in patients with adenomas, but may be increased in some cases of hepatocellular carcinoma. Although poor metabolic control is associated with a higher incidence of adenomas, other factors are involved in the pathogenesis of adenoma formation, and continuous glucose therapy from early infancy does not prevent the development of focal hepatic lesions [11]. Adenoma growth appears to be stimulated by the presence of sex hormones; not only do they usually appear during the hormonal surges of puberty, but rapid growth of adenomas on oral contraception therapy has been observed.Nephromegaly was described by von Gierke in the first pathologic description of hepatorenal glycogenosis, and kidney enlargement is readily demonstrated by ultrasonography in GSD I. Proximal tubular dysfunction with glucosuria, phosphaturia, hypokalemia, and a generalized aminoaciduria is associated with suboptimal control, but is reversible when biochemical control of the disease improves [13,14]. Distal renal tubular dysfunction is almost universal over time and is associated with acidification defects, hypercalciuria, and hypocitraturia [15]. This combination of low urinary citrate and high urinary calcium concentrations predisposes patients to nephrocalcinosis and nephrolithiasis, and citrate supplementation may prevent development of these complications [16]. Patients with good metabolic control usually show no significant impairment of renal function except for glomerular hyperfiltration [17]. Increased urinary albumin excretion may be observed in adolescents, and adults may develop more severe renal injury with proteinuria, hypertension, and decreased creatinine clearance because of focal segmental glomerulosclerosis and interstitial fibrosis. Patients with persistently elevated concentrations of blood lactate, serum lipids, and uric acid are at higher risk for development of nephropathy [11]. Improvement of metabolic control and use of an angiotensin converting enzyme inhibitor have been associated with decreased proteinuria and may slow the progression of renal disease [18].Anemia is common in patients with glycogen storage disease and is associated with suboptimal metabolic control [11]. Although most anemia is mild, an unusual unremitting, iron resistant anemia occurs in a subset of patients. This anemia can be profound with hemoglobin concentrations as low as 4 g/dL and is characterized by microcytosis (mean corpuscular volume [MCV] 50–70 fL), widening of the red cell distribution width (RDW), and iron studies consistent with iron deficiency. Treatment with oral and intravenous iron, however, fails to significantly improve the anemia. This iron-resistant anemia has recently been associated with large hepatic adenomas (> 7cm in diameter) and a peptide (hepcidin), which inhibits intestinal absorption of iron and macrophage recycling of iron, has been found to be inappropriately expressed in these liver lesions. Resection of hepatic adenomas has been associated with rapid correction of this anemia [19].Now that patients with GSD I are surviving into adulthood, osteoporosis is likely to be a more common cause of morbidity. Osteoporosis develops without evidence of abnormalities in calcium, phosphate, parathyroid, or vitamin D metabolism. Poor metabolic control has been associated with decrease bone mineral content in GSD, but the etiology is likely multifactorial because of systemic acidosis, elevated cortisol concentrations, delayed pubertal development, and inadequate dietary calcium [20].Patients with type IB GSD have similar symptoms with the addition of neutropenia and inflammatory bowel disease. Neutropenia is a consequence of disturbed myeloid maturation and is also associated with functional defects of circulating neutrophils and monocytes. The neutropenia can be either cyclic or constant. Although the severity of the neutrophil dysfunction is variable, recurrent bacterial infections and oral ulcers are common. Inflammatory bowel disease resembling Crohns disease develops in most patients and may be the major cause of morbidity in patients with type 1B GSD [21].DiagnosisThe simplest means of determining the probable defect in a child suspected of having a glycogenosis is to obtain serial blood measurements of glucose, lactate, and ketones during a fasting study. A brief fasting study (3–4 hours) in GSD I will result in hypoglycemia and progressive lactic acidosis. Glucagon (30 mcg/kg) should be administered when the plasma glucose falls to 50 mg/dL; in GSD I, glucagon fails to elicit a glycemic response (Table 1). As glucagon administration may exacerbate the lactic acidosis, the testing should be performed under close observation, and administration of intravenous glucose is warranted if an adequate glycemic response has not occurred after 30 minutes.An assay of glucose-6-phosphatase activity on a liver biopsy has been the primary method for confirming the diagnosis of GSD I. Differentiation between the types requires an analysis of glucose-6-phosphatase activity in both intact and fully disrupted microsomes as enzyme activity normalizes in type 1B when freezing disrupts the membrane integrity. Mutation analysis of the glucose-6-phosphatase gene is now available using blood allowing for a noninvasive method for confirming the diagnosis [22].TreatmentTreatment consists of providing a continuous dietary source of glucose to prevent blood glucose from falling below the threshold (∼70 mg/dL) for glucose counterregulation. Glucose delivery in infants is usually achieved with frequent feeds every 1.5 to 2.5 hours during the day and continuous feeds at night through a nasogastric or gastrostomy tube. Cornstarch can be gradually introduced at 6 to 12 months of age as an alternative method of glucose delivery. Cornstarch allows feedings to be more widely spaced, glucose fluctuations to be minimized, and is neuroprotective as the slow drop in blood glucose in patients treated with cornstarch allows for accumulation of alternative fuels (i.e., lactate), which the brain can use.Glucose requirements can be estimated by calculating the basal glucose production rate using the following formula: y = 0.0014x3−0.214x2+10.411x−9.084 where y = mg/min of glucose and x = weight in kilograms. Cornstarch doses and the interval between feeds should be individualized based upon results of periodic metabolic evaluations and glucose monitoring. The timing of cornstarch is also individualized to keep plasma glucose concentrations above 70–75 mg/dL and lactate concentrations near normal (<2.2 mmol/L). Cornstarch doses are typically administered every 3 to 5 hours during the day and every 4 to 5 hours overnight. If fasting is ever required (e.g., for a surgical procedure or a radiologic study) or if gastrointestinal illness does not allow adequate intake of carbohydrate, intravenous glucose must be administered using 10% dextrose at 1 to 1.25 times the estimated hepatic production rate to ensure maintenance of euglycemia and to minimize lactic acidosis.Particular attention and care is required whenever a patient with GSD I requires surgery. Anesthesia and the stress of surgery causes increased secretion of counterregulatory hormones, and severe lactic acidosis can develop despite maintenance of normal blood glucose concentrations. Cardiac arrhythmias and sudden death have occurred in patients with GSD I owing to inadequate glucose administration or profound lactic acidosis. Intravenous glucose should be commenced at 1.25 to 1.5 times the estimated hepatic production rate before the procedure to induce insulin secretion and reduce the effect of the stress response. The combination of the high glucose infusion rate and insulin resistance associated with counterregulatory hormone secretion can result in hyperglycemia. Any reduction in glucose infusion rate, however, must be performed with extreme caution and with frequent monitoring of acid-base status. If acidosis develops, a slow infusion of bicarbonate should be used to normalize the blood pH. Careful treatment with a continuous low dose insulin infusion may be indicated if hyperglycemia and acidosis occur.Restriction of galactose, fructose, sucrose, and lactose is important in GSD I as these sugars cannot be converted to glucose and their consumption in large amounts exacerbates the metabolic derangements. Allopurinol is commonly used to treat hyperuricemia, and gemfibrozil has been moderately effective in treating hyperlipidemia in patients at risk for pancreatitis from triglyceride concentrations greater than 1000 mg/dL. Neutropenia in type IB GSD responds well to G-CSF therapy, and the associated inflammatory bowel disease responds to conventional therapy.Debranching Enzyme Deficiency (Type III Glycogen Storage Disease: Cori Disease; Forbes Disease)Type III GSD is caused by deficiency of glycogen debrancher enzyme. The terminal chains of glycogen can be broken down normally; glycogenolysis, however, is arrested when the outermost branch points are reached. Abnormal glycogen (limit dextrin) accumulates in affected tissues. Type IIIA accounts for 85% of patients in the United States and involves both the liver and muscle, whereas type IIIB only affects the liver.The incidence of GSD III is estimated to be 1 in 100,000 live births. It is unusually frequent in people of North African Jewish descent, where the carrier frequency is 1:35. It is inherited in an autosomal recessive manner, and is caused by mutations in the debrancher gene located on chromosome 1p21 [9].Clinical FeaturesClinical and genetic variability is common in GSD III, and symptoms depend on tissue involvement. Patients with hepatic involvement have hepatomegaly and fasting hypoglycemia which may be indistinguishable in infancy from GSD I. Patients with GSD III are able to synthesize glucose via gluconeogenesis and can utilize the outer segments of glycogen. As a result, the hypoglycemia often is not as severe as in GSD I, and it typically improves with age. A variable myopathy can occur, which is usually mild in childhood, but can become prominent in adulthood. Biochemical abnormalities include a marked elevation in liver transaminase concentrations (often worse than GSD I), elevated creatine kinase concentrations, and hyperlipidemia. Unlike GSD I, however, blood levels of lactate and uric acid are normal as the gluconeogenic pathway is intact and glucose can be synthesized from glucose-6-phosphate [23].The clinical presentation of patients with GSD III is more variable than in GSD I. The disorder is occasionally diagnosed in the newborn period as a result of recurrent hypoglycemia or may remain asymptomatic for much of infancy. Most patients present for evaluation during the first year of life after hepatomegaly is incidentally detected on a physical exam. It is often mistaken for a viral hepatitis or other metabolic disorders as aspartate aminotransferase (AST) and alanine aminotransferase (ALT) concentrations may exceed 1000 U/L in the untreated patient.Most patients with GSD III do well with appropriate therapy, but complications occur with age. Hepatic adenomas are found in approximately 25% of adults with GSD III; to date no cases of hepatocellular carcinoma have been reported [12]. Hepatic fibrosis can occur, and some adult patients develop cirrhosis and portal hypertension and, rarely, liver failure. The myopathy typically becomes more prominent in the third to fourth decades of life, manifesting as slowly progressive proximal muscle weakness [22]. Patients with muscle involvement can also develop cardiac complications. Concentric left ventricular hypertrophy usually develops after puberty and is detectable by echocardiography in most patients, who have relatively normal ventricular function. Severe cardiac dysfunction and arrhythmias rarely occur [24].DiagnosisA fasting study demonstrates ketotic hypoglycemia without the hyperlactatemia characteristic of GSD I. Glucagon fails to elicit a response when given after a fast, but a glycemic response will occur if given 2 hours after a carbohydrate rich meal (Table 1). Definitive diagnosis depends on demonstration of abnormal glycogen (limit dextrin) on biopsy of the liver and muscle together with demonstration of abnormal enzyme activity. Definitive subtyping requires biopsies of both liver and muscle as a normal creatine kinase concentration cannot rule out muscle involvement. Assessment of enzyme activity in skin fibroblasts or lymphocytes can be used to screen for GSD III, but these studies may not be definitive and cannot be used for subtyping.TreatmentAs with GSD I, continuous glucose delivery is required to maintain blood glucose above 70 mg/dL. Uncooked cornstarch (1.75 g/kg) at 6-hour intervals around the clock usually maintains normoglycemia, increases growth velocity, and decreases transaminase concentrations [25]. More frequent cornstarch administration is usually not required to maintain normal plasma glucose concentrations, but in our experience, prevention of glycogen degradation by administering cornstarch every 4 hours decreases biochemical evidence of liver and muscle inflammation. Myopathy and growth failure have been shown to improve with long-term high-protein nocturnal enteral therapy and high protein feeds during the day [26]. Patients do not need to restrict their consumption of fructose or galactose.Glycogen Phosphorylase Deficiency (Type VI Glycogen Storage Disease: Hers Disease)—Glycogen Phosphorylase Kinase Deficiency (Type IX Glycogen Storage Disease)Types VI and IX GSD will be considered together because both disorders result in abnormal hepatic phosphorylase activity. Although glycogen phosphorylase is the rate-limiting step in glycogenolysis, these disorders tend to be mild and can easily be confused with ketotic hypoglycemia. They account for approximately 25–30% of all cases of glycogen storage disease, and may be under-diagnosed because of the mild phenotype and lack of a simple diagnostic test.Phosphorylase kinase of the liver and muscle is a complex enzyme consisting of four subunits encoded by several genes. As this article focuses on the clinical manifestations of the glycogenoses, the reader is referred to other sources for discussion of the genetics of these disorders [9].Clinical FeaturesFasting ketotic hypoglycemia, which is generally milder than in GSD I and III, is the cardinal manifestation of this heterogeneous group of disorders. Gluconeogenesis and lipolysis are intact, and counterregulatory hormone stimulation can usually maintain normal blood glucose con-centrations. As a result, blood glucose may transiently decrease to hypoglycemic levels during an overnight fast (e.g., at 2 a.m.) but return to normal by morning. Hepatomegaly and short stature are common. Mild hyperlipidemia and increased serum transaminase concentrations are characteristic, but blood lactate and serum uric acid concentrations are normal. Muscle involvement can occur, and patients may present with hypotonia, myoglobinuria, muscle weakness, and gross motor delay. Most patients, however, have few symptoms other than ketotic hypoglycemia with fasting, and patients may be several years old before they come to medical attention [27].Adults with types VI and IX GSD may be asymptomatic as frequent feeds usually prevent hypoglycemia. Occasionally, muscle symptoms occur and, rarely, these disorders are associated with a proximal renal tubular acidosis, neurologic abnormalities, and cirrhosis. A severe cardiac-specific phosphorylase kinase variant that can lead to cardiac failure has been reported.DiagnosisIt is possible to diagnose glycogen phosphorylase deficiency by assaying the activity of the enzyme in leukocytes and erythrocytes. The blood assay, however, lacks sensitivity, as there are liver, muscle, heart, and brain isoforms of this enzyme. Definitive diagnosis requires demonstration of abnormal enzyme activity in biopsies of affected tissues. Mutation analysis likely will become the standard for diagnosis of GSD VI and the X-linked variant of GSD IX, but will probably not be able to fully exclude all forms of GSD IX because of the multiple genes involved in synthesizing the phosphorylase kinase protein.TreatmentThe prognosis for these disorders is excellent, and most patients do not require specific treatment except for a bedtime snack and avoidance of fasting. In early childhood or the unusual older patient with overnight hypoglycemia, uncooked cornstarch (2 g/kg) given at bedtime prevents nocturnal hypoglycemia [28]. No dietary restriction is necessary. Patients should be encouraged to have wellbalanced diets that include carbohydrates, fat, and protein. Intravenous glucose may be required during illness or periods of fasting; mild intercurrent illnesses are usually well tolerated.References1. Haymond MW, Sunehag A: Controlling the sugar bowl: Regulation of glucose homeostasis in children. Endocrinol Metab Clin North Am 1999; 28: 663–94.[Context Link][CrossRef][Medline Link]2. Aynsley-Green A, Williamson DH, Gitzelmann R: Hepatic glycogen synthetase deficiency. Definition of syndrome from metabolic and enzyme studies on a 9 year old girl. Arch Dis Child 1977; 52: 573–9.[Context Link][CrossRef][Medline Link]3. Gitzelmann R, Spycher MA, Feil G, et al.: Liver glycogen synthetase deficiency: a rarely diagnosed entity. Eur J Pediatr 1996; 155: 561–7.[Context Link][CrossRef][Medline Link]4. Orho M, Bosshard NU, Buist NR, et al.: Mutations in the liver glycogen synthase gene in children with hypoglycemia due to glycogen storage disease type 0. J Clin Invest 1998; 102: 507–15.[Context Link][Full Text][CrossRef][Medline Link]5. 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