Pediatrics

Metabolic: glycogen disorders

OVERVIEW: What every practitioner needs to know

Are you sure your patient has a glycogen storage disease? What are the typical findings for this disease?

The hepatic glycogen storage diseases (GSDs) comprise several inherited diseases caused by abnormalities of the enzymes that regulate the synthesis or degradation of glycogen (See Figure 1). There are five major types of hepatic GSDs that affect glucose homeostasis and cause hypoglycemia, which is the cardinal clinical manifestation of all the hepatic glycogen storage diseases. Patients with mutations that severely limit glucose production may present with severe hypoglycemia, seizures, failure to thrive, and delay in psychomotor development. Abnormal hepatic glycogen storage causes marked hepatomegaly and a protuberant abdomen.

Figure 1.

Patients with type 0GSD (hepatic glycogen synthase deficiency) present with fasting ketotic hypoglycemia that alternates with postprandial hyperglycemia and hyperlactatemia. The liver is not enlarged. An oral glucose load causes mild hyperglycemia and hyperlactatemia.

Patients with type 1a GSD (glucose-6-phosphatase deficiency) have impaired production of glucose from both glycogenolysis and gluconeogenesis and develop hypoglycemia within 3 to 4 hours after a meal. Serum lactic acid, uric acid and triglyceride levels are increased. Blood lactate concentrations decrease after an oral glucose load. The liver typically is markedly enlarged causing a protuberant abdomen. Infants have a round "doll" face. Untreated or inadequately treated patients exhibit muscle weakness and failure to thrive in infancy, whereas older children show poor growth and delayed puberty.

Patients with type 1b GSD (glucose-6-phosphate transporter deficiency) have the same clinical and biochemical features as those with type 1a, but also have neutropenia and neutrophil dysfunction (impairment of chemotaxis, calcium mobilization, respiratory burst and phagocytic activity) that predisposes to recurrent bacterial infections.

Patients with type IIIa GSD (glycogen debranching enzyme deficiency in liver and muscle) have ketotic hypoglycemia associated with increased cholesterol and triglyceride concentrations, but normal fasting lactate and uric acid concentrations. Serum transaminase and creatine kinase concentrations are increased; AST and ALT levels exceeding 1000 U/L are suggestive of GSD III. The liver typically is markedly enlarged causing a protuberant abdomen. Infants have a round "doll" face. Deficiency of the debranching enzyme in skeletal muscle and heart causes a progressive myopathy that usually is mild in childhood but can be severe in adulthood.

Patients with type IIIb GSD (debranching enzyme deficiency in liver only) have ketotic hypoglycemia associated with increased cholesterol and triglyceride concentrations, but normal fasting blood lactate and uric acid concentrations. Serum transaminase concentrations are increased; creatine kinase levels are normal. The liver typically is markedly enlarged causing a protuberant abdomen. Infants have a round "doll" face.

Patients with type VI (hepatic phosphorylase deficiency) and IX (hepatic phosphorylase kinase deficiency) GSD are clinically indistinguishable and have ketotic hypoglycemia associated with normal to increased cholesterol and triglyceride concentrations, but usually have normal fasting lactate and uric acid concentrations. Hepatomegaly and short stature may be the only clinical manifestations in childhood.

Table I. Differential Diagnosis of Glycogen Storage Disorder

Table I.

Differential Diagnosis of Glycogen Storage Diseases
Disorder Enzyme Deficiency Cardinal Clinical Features Distinctive Features
 Type 0 Glycogen synthase Fasting hypoglycemia and ketosis No hepatomegaly; postprandial hyperglycemia and hyperlactatemia 
 Type IA Glucose-6-phosphatase Severe hypoglycemia; hepatomegaly;  No splenomegaly; nephromegaly; lactic acidemia, hyperuricemia, hypertriglycedemia, bleeding diathesis; neutropenia in type IB 
 Type II Acid alpha glucosidase deficiency Myopathy involving diaphragm; increased creatinine kinase (CK)  No hypoglycemia; histology shows lysosomal glycogen storage 
 Type III  Glycogen debranching enzyme Severe ketotic hypoglycemia; hepatomegaly; markedly increased AST, ALT, CK (type IIIA); hypertriglyceridemia Uric acid and lactic acid not increased; proximal and distal myopathy (usually mild in childhood) that does not affect muscles of respiration 
 Type IV (hepatic presentation) Glycogen branching enzyme deficiency Hepatomegaly; increased AST, ALT   No hypoglycemia until end-stage liver disease; muscle biopsy shows polyglucosan storage 
Type IV (neuromuscular presentation)  Glycogen branching enzyme deficiency Myopathy; increased CK  No hypoglycemia; hypotonia, muscle atrophy; amylopectin-like inclusions; respiratory insufficiency; may have cardiomyopathy or neuronal involvement 
 Type V Muscle glycogen phophorylase Exertional muscle fatigue, myalgia, muscle cramps, muscle swelling; myoglobinuria due to rhabdomyolysis may occur after exercise; severe myoglobinuria may lead to acute renal failure; increased serum CK No hypoglycemia; muscle glycogen storage 
 Type VI Hepatic glycogen phosphorylase Hepatomegaly; growth retardation; moderate ketotic hypoglycemia; increased serum AST, ALT, cholesterol and triglycerides  Muscle not affected; CK, uric acid and lactic acid normal
 Type VII Muscle phosphofructokinase Presents in childhood with fatigue, muscle cramps, exercise intolerance; rhabdomyolysis and myoglobinuria with strenuous physical exertion; increased CK  No hypoglycemia
 Type IX Phosphorylase b kinase Early childhood onset of hepatomegaly and growth retardation; fasting mild to moderate ketotic hypoglycemia; increased AST, ALT, cholesterol and triglycerides Various subtypes; X-linked form usually less severe; other liver forms (gamma 2 variant and autosomal recessive forms) can be more rapidly progressive; clinical variability between and within subtypes. Symptoms and biochemical abnormalities tend to improve with age.
 Type XI  GLUT2 deificiency Hepatomegaly; hypoglycemia; increased AST, ALT Gastrointestinal symptoms; renal tubular acidosis
       

What other disease/condition shares some of these symptoms?

A hepatic glycogen storage disease should be considered in the differential diagnosis of hypoglycemia, especially when hypoglycemia occurs within a few hours of a feed or a meal, as is typical for type 1 GSD, or when hypoglycemia is associated with metabolic acidosis, ketosis, hyperlactatemia, hypertriglyceridemia, hepatomegaly, failure to thrive.

What caused this disease to develop at this time?

All the hepatic glycogen storage diseases are inborn errors of metabolism caused by mutations in genes encoding enzymes that regulate the synthesis or degradation of hepatic glycogen.

Type 0 GSD (hepatic glycogen synthase deficiency) is caused by deficiency of the hepatic isoform of glycogen synthase due to mutations in the GYS2 gene located on chromosome 12p12.2. It is inherited in an autosomal recessive manner. It is a rare disorder that has been identified throughout Europe, and North and South America.

Type Ia GSD (glucose-6-phosphatase-a deficiency) is caused by mutations in the G6PC gene located on chromosome 17q21. It is inherited in an autosomal recessive manner. The overall incidence is estimated to be approximately 1 in 1000,000 births. Type Ia GSD occurs in all ethnic groups, and common mutations occur in the Ashkenazi Jewish, Chinese, Japanese and Mexican populations.

Type Ib GSD (glucose-6-phosphate transporter deficiency) is caused by mutations in SLC37A4, the gene that encodes the synthesis of glucose-6-phosphate transporter (G6PT), an antiporter that transports glucose-6-phosphate (G6P) into the lumen of the endoplasmic reticulum in exchange for inorganic phosphate. The SLC37A4 gene is located on chromosome 11q23. The disorder is inherited in an autosomal recessive manner. The incidence is estimated to be 1 in 1,000,000 births. No high-risk ethnic group or population has been identified.

Type III GSD (glycogen debrancher enzyme deficiency) is caused by mutations in the AGL gene located on chromosome 1p21. It is inherited in an autosomal recessive manner. The gene encodes four major nuclear RNA isoforms formed from differential splicing. Isoform 1 is the predominant form in the liver, and includes exon 1 but exon 2 is spliced out. Transcription starts from exon 2 in isoforms 2, 3 and 4, and these isoforms are expressed in skeletal muscle and heart. Because the isoforms are differentially expressed, the clinical phenotype depends on the location of the mutation. Type IIIA, which affects both liver and muscle, accounts for 85% of patients with type III GSD in the United States; type IIIb GSD affects only the liver. The incidence of type III GSD is estimated to be 1 in 100,000 births. It is unusually frequent in Jews of North African descent living in Israel where the carrier frequency is 1:35.

Type VI GSD (hepatic glycogen phosphorylase deficiency) is caused by mutations in the PYGL gene located on chromosome 14q21-22. It is inherited in an autosomal recessive manner. The disease has been estimated to affect 1 in 1,000 of the Mennonite population.

Type IX GSD (hepatic glycogen phosphorylase kinase deficiency) and type VI GSD both impair hepatic glycogen phosphorylase activity and together account for 25% to 30% of all cases of GSD. Their prevalence is estimated to be approximately 1 in 100,000 births. Phosphorylase kinase of liver and muscle is a complex enzyme consisting of four subunits (alpha, beta, delta, and gamma). Mutations in PHKA2 (gene located at Xp22.2-p22.1), which encodes the liver alpha-subunit, causes the most common form, X-linked liver phosphorylase kinase deficiency. The beta-subunit is expressed in muscle, liver, brain, and kidney and is encoded by the PHKB gene on chromosome 16q12-q13. Mutations lead to an autosomal recessive variant of type IX GSD. The gamma-subunit, encoded by the PHKG gene on chromosome 16p11-p12, contains the catalytic site of the phosphorylase kinase enzyme.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

The simplest means of determining the probable defect in a child suspected of having a hepatic glycogen storage disease is to obtain serial blood glucose, lactate and ketone measurements during a fasting study.

Type 0 GSD:

In a patient with type 0 GSD, frequent measurements of blood glucose, lactate, and ketones (every 30 minutes for 2 hours) following consumption of a glucose load (1.75 grams per kg; 75 grams maximum) demonstrate the unique biochemical pattern of postprandial hyperglycemia and hyperlactatemia. These abnormalities are accentuated by increased concentrations of counter-regulatory hormones; therefore, it is recommended that postprandial biochemical monitoring be performed in the morning after an overnight fast. Despite the decrease in hepatic glycogen content, the glycemic response to glucagon (0.03 mg/kg; 1 mg maximum) is variable and may even be normal because some glycogen can be synthesized even with complete absence of glycogen synthase activity.

Mutation analysis using DNA extracted from blood or saliva is now the gold standard for making the diagnosis of type 0 GSD. A few cases with no identifiable mutations in the GYS2 gene have been diagnosed by liver biopsy and enzyme assay.

Type I GSD:

A brief period of fasting in a patient with type I GSD will cause hypoglycemia and development of lactic acidosis. Because blood glucose concentrations fall rapidly, this test should only be performed with secure intravenous access and with frequent clinical and biochemical monitoring. During the test, blood glucose concentrations should be measured every 20 to 30 minutes after 2 hours. When plasma glucose has decreased to 50 mg/dL and a blood sample for lactate determination has been obtained (free flowing without a tourniquet), glucagon (0.03 mg/kg) is administered intravenously. In type I GSD, glucagon does not elicit a glycemic response and exacerbates lactic acidemia.

When the test has been completed, intravenous glucose should be administered to restore and maintain normal blood glucose concentrations. A liver biopsy is not recommended. Mutation analysis on DNA extracted from leukocytes is now the recommended test for confirming the diagnosis of type I GSD.

Type Ib GSD:

The diagnosis of type Ib GSD is typically made clinically when a patient with the clinical and biochemical features of type I GSD develops neutropenia. Mutation analysis is recommended to confirm the diagnosis. A liver biopsy is not recommended.

Type III GSD:

In type III GSD a fasting study demonstrates ketotic hypoglycemia without the hyperlactatemia characteristic of type I GSD. Glucagon does not elicit a glycemic response after a fast but does elicit a glycemic response when given 2 hours after a carbohydrate-rich meal. Mutation analysis should be performed to confirm the diagnosis of both type IIIa and IIIb GSD.

Type VI or type IX GSD:

Mutation analysis is recommended to confirm the diagnosis in patients suspected of having either type VI or type IX GSD.

If you are able to confirm that the patient has a glycogen storage disease, what treatment should be initiated?

Type 0 GSD:

The goal of treatment is to prevent hypoglycemia and minimize the associated acidosis. Treatment consists of a diet high in protein to provide a substrate for gluconeogenesis and with low glycemic index complex carbohydrates to minimize postprandial hyperglycemia and hyperlactitemia. Uncooked (raw) cornstarch (1-1.5 grams per kg) administered at bedtime prevents morning hypoglycemia and ketosis. Daytime hypoglycemia tends to be mild and snacks every 2 to 4 hours prevent hypoglycemia.

During illness, uncooked cornstarch is given every 6 hours, but intravenous glucose (10% glucose administered at 1.25 times the maintenance rate of fluid administration) may be required with vomiting or a gastrointestinal illness and inability to tolerate enteral intake. Before intense physical activity or participation in sports, smaller doses of cornstarch may improve stamina.

Type I GSD:

Treatment of type I GSD consists of providing a continuous dietary source of glucose to prevent blood glucose from falling below the threshold for glucose counter-regulation (70-80 mg/dL). In infants, the necessary amount of glucose can be delivered by frequent (every 1.5 to 2.5 hours) feedings during the day and continuous feeding at night through a nasogastric or gastrostomy tube using a formula that does not contain sucrose, fructose or galactose.

Uncooked cornstarch can be gradually introduced at 6 to 12 months of age as an alternative method of glucose delivery, although some children may not tolerate it until they are older because of age-related development of amylase activity. The advantage of using cornstarch is that it permits feedings to be more widely spaced, minimizes glucose fluctuations, and because blood glucose levels decline more gradually and blood lactate concentrations increase and serve as an alternative fuel for the brain when hypoglycemia occurs.

For older children and adolescents, use of oral cornstarch as a source of slowly digested and absorbed carbohydrate permits a more normal lifestyle. Cornstarch typically is mixed (just prior to administration) in 3 to 4 ounces of formula, soy milk or water to form a slurry. Cornstarch must not be heated and cannot be administered as a continuous feed because it solidifies and obstructs the feeding tube. Doses of cornstarch and the interval between feedings should be individualized based on the results of periodic metabolic evaluations. The goal is to maintain normal blood glucose concentrations and near-normal lactate concentrations.

In toddlers, cornstarch is typically administered every 3 hours during the day and every 4 hours overnight. Most school-age children receive six doses of cornstarch per day, whereas adults are often able to maintain adequate biochemical control on five doses of cornstarch per day. Most adults are unable to fast for more than 5.5 to 6 hours without deterioration of metabolic control, and continue to require an overnight dose of cornstarch.

Extended release waxy maize cornstarch(Glycosade, Vitaflo, International LTD, Liverpool, England) was approved in England in 2009 for the management of GSD I and was released in the United States as a medical food in 2012. Efficacy studies in children as young as 5-years-old have shown prolongation of fasting tolerance from an average of 4.1 to 7.8 hours using extended release cornstarch as compared to standard uncooked cornstarch.Biochemical markers of metabolic control reportedly remained stable while on the extended release formulation. Gastrointestinal intolerance and exacerbation of inflammatory disease are common side effects of the extended release formulation.

It is important to pay attention to timing and content of the diet. Galactose, fructose, and sucrose should be restricted because these sugars cannot be converted to glucose, are shunted into alternative pathways, and their consumption exacerbates the metabolic derangements.

During an acute illness, it is important to carefully monitor blood glucose and lactate concentrations. Despite normoglycemia, the stress response to illness causes glycogenolysis and may cause lactic acidosis. Intravenous administration of 10% glucose should be initiated at 1.25-1.5 times the usual maintenance rate of fluid administration. After the acute illness has resolved and the patient is able to tolerate enteral feeds, intravenous glucose should be slowly weaned over several hours because the high insulin state induced by intravenous dextrose may cause reactive hypoglycemia.

Type Ib GSD:

In patients with type Ib GSD, cornstarch treatment is individualized as described above for patients with type Ia GSD. Owing to chronic inflammation, patients with type Ib GSD may have higher basal glucose requirements than those with type Ia GSD. Neutropenia is treated with granulocyte-colony stimulating factor (G-CSF) 2-5 mcg/kg per day.

Type III GSD:

Treatment of type III GSD consists of providing a continuous source of glucose to maintain blood glucose above 70 mg/dL. This goal can usually be achieved using uncooked cornstarch at 4 to 6-hour intervals, both during the day and night. The dose of cornstarch and the frequency of its administration should be the minimum necessary to prevent hypoglycemia. One gram per kg may be sufficient to maintain normal blood glucose levels for 4 hours or longer.

In some patients with GSDIII, hypoglycemia may be as severe as in type I GSD, requiring 1.6 grams per kg every 4 hours for infants and young children and 1.75-2.5 grams per kg every 6 hours for an older child. Cornstarch prevents hypoglycemia, but patients with type IIIa GSD continue to have markedly increased serum creatine kinase levels.

A high protein (3-4 grams per kg) diet has been reported to improve symptoms caused by myopathy and retard the rate of its progression. A high protein diet may be beneficial in three ways: 1) because gluconeogenesis is intact, protein derived alanine and other amino acids can be used as an alternate source for glucose during times of fasting; 2) a higher dietary protein intake may improve muscle function by enhancing muscle protein synthesis; 3) by replacing some of the dietary carbohydrates with protein, glycogen storage may be reduced.

The child with myopathy and growth failure should receive a high protein diet. The ideal diet should consist of approximately 55 to 60% carbohydrate, 15 to 20% protein, and 20-25% fat. For patients with cardiomyopathy or severe muscle disease, high-protein nocturnal enteral therapy may be beneficial. The child with GSDIIIb may only need cornstarch therapy; however, it has been suggested that the addition of protein may be beneficial both as an alternaive source of glucose and by decreasing the accumulation of abnormally structured glycogen in the liver. Additional protein may also decrease excessive glycogen storage.

Patients with type III GSD do not need to restrict their consumption of sucrose, galactose or fructose as they are able to convert these sugars into glucose. Low glycemic index carbohydrates are preferred over simple sugars to avoid marked postprandial hyperinsulinemia. Whereas severe hypoglycemia is less common than in type I GSD, hypoglycemia and severe ketosis can develop as a result of intercurrent illness or when enteral intake is decreased for any reason. Intravenous 10% dextrose infused at 1.25 to 1.5 times the basal rate of glucose production is used to normalize glucose concentrations and prevent ketosis during illness.

Type VI and IX GSD:

Treatment of patients with type VI and IX GSD is the same. Hypoglycemia can be prevented with frequent daytime feedings that are high in complex carbohydrates and protein. In early childhood or in the unusual older patient with overnight hypoglycemia, uncooked cornstarch (1.5 grams/kg) at bedtime prevents nocturnal hypoglycemia. The optimal dose is determined by biochemical monitoring. Even when more prolonged fasting can be tolerated without development of hypoglycemia, most children and adults report improved energy and well-being with a bedtime dose of cornstarch, which prevents ketosis.

A diet consisting of a high content of protein and complex carbohydrates is recommended. During acute illness or periods of fasting, intravenous glucose may be required.

What causes this disease and how frequent is it?

Type 0 GSD (hepatic glycogen synthase deficiency) is caused by deficiency of the hepatic isoform of glycogen synthase due to mutations in the GYS2 gene located on chromosome 12p12.2. It is inherited in an autosomal recessive manner. It is a rare disorder that has been identified throughout Europe, and North and South America.

Type Ia GSD(glucose-6-phosphatase-a deficiency) is caused by mutations in the G6PC gene located on chromosome 17q21. It is inherited in an autosomal recessive manner. The overall incidence is estimated to be approximately 1 in 1000,000 births. Type Ia GSD occurs in all ethnic groups, and common mutations occur in the Ashkenazi Jewish, Chinese, Japanese and Mexican populations.

Type Ib GSD(glucose-6-phosphate transporter deficiency) is caused by mutations in SLC37A4, the gene that encodes the synthesis of glucose-6-phosphate transporter (G6PT), an antiporter that transports glucose-6-phosphate (G6P) into the lumen of the endoplasmic reticulum in exchange for inorganic phosphate. The SLC37A4 gene is located on chromosome 11q23. The disorder is inherited in an autosomal recessive manner. The incidence is estimated to be 1 in 1,000,000 births. No high-risk ethnic group or population has been identified.

Type III GSD (glycogen debrancher enzyme deficiency) is caused by mutations in the AGL gene located on chromosome 1p21. It is inherited in an autosomal recessive manner. Type IIIA, which affects both liver and muscle, accounts for 85% of patients with type III GSD in the United States; type IIIb GSD affects only the liver. The incidence of type III GSD is estimated to be 1 in 100,000 births. It is unusually frequent in Jews of North African descent living in Israel where the carrier frequency is 1:35.

Type VI GSD (hepatic glycogen phosphorylase deficiency) is caused by mutations in the PYGL gene located on chromosome 14q21-22. It is inherited in an autosomal recessive manner. The disease has been estimated to affect 1 in 1,000 of the Mennonite population.

Type IX GSD (hepatic glycogen phosphorylase kinase deficiency) and type VI GSD both impair hepatic glycogen phosphorylase activity and together account for 25% to 30% of all cases of GSD. Their prevalence is estimated to be approximately 1 in 100,000 births. Phosphorylase kinase of liver and muscle is a complex enzyme consisting of four subunits (alpha, beta, delta, and gamma). The alpha-subunit is encoded by the PHKA2 gene located at Xp22.2-p22.1; mutations are associated with an X-linked disease. The beta-subunit is expressed in muscle, liver, brain, and kidney and is encoded by the PHKB gene on chromosome 16q12-q13. Mutations lead to an autosomal recessive variant of type IX GSD. The gamma-subunit, encoded by the PHKG gene on chromosome 16p11-p12, contains the catalytic site of the phosphorylase kinase enzyme.

What complications might you expect from the disease or treatment of the disease?

Renal disease is a long-term complication of type I GSD. The earliest sign of renal dysfunction is glomerular hyperfiltration, followed by the appearance of increased microalbuminuria and, subsequently, proteinuria. Patients with type Ia GSD may have distal renal tubular dysfunction characterized by a defect in acidification, hypercalciuria, and hypocitraturia. The combination of hypercalciuria and hypocitraturia predisposes to nephrocalcinosis and nephrolithiasis. Daily potassium citrate supplementation may prevent these complications.

Renal dysfunction may be exacerbated by inadequate biochemical control as evidenced by persistent hyperuricemia, hyperlipidemia and lactic acidemia. Increased urinary albumin excretion (microalbuminuria) is an early indication of renal dysfunction in type I GSD and may first be observed in adolescents. Young adults may have proteinuria, hypertension, and decreased creatinine clearance caused by focal segmental glomerulosclerosis and interstitial fibrosis. Persistent microalbuminuria is treated with a low dose of an angiotensin converting enzyme (ACE) inhibitor such as captopril or lisinopril.

Marked hyperuricemia unresponsive to optimized dietary management is treated with allopurinol.

Severe hypertriglyceridemia unresponsive to optimized dietary management may cause acute pancreatitis; lowering triglyceride concentrations with fenofibrate reduces the risk of pancreatitis.

Severe hypercholesterolemia unresponsive to optimized dietary management is treated with 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors.

Hepatic adenoma is a serious long-term complication of type I GSD that develops in 70-80% of patients more than 25 years of age. Patients may develop multiple hepatic adenomas, some of which may enlarge dramatically and be the cause of a chronic unremitting iron resistant anemia due to aberrant expression of hepcidin. Adenomas may cause local compression, undergo central necrosis, and hemorrhage into the adenoma or, rarely, into the peritoneum can occur. Malignant transformation to hepatocellular carcinoma may occur. Whether optimal metabolic control can prevent their development or retard their rate of growth is unknown; however, some data suggest that this may be the case.

Patients with type Ib GSD are prone to recurrent bacterial infections. Approximately 75% of patients with neutropenia also develop inflammatory bowel disease (enterocolitis) indistinguishable from Crohn disease. Anti-inflammatory agents, including derivatives of 5-aminosalicylic acid (5-ASA) may be helpful adjuncts for treating enterocolitis. An anti-inflammatory monoclonal antibody, adalimumab, which targets tumor necrosis factor-a, is efficacious in patients whose enterocolitis does not respond to GCSF and 5-ASA, and should be considered as another therapeutic option. The prevalence of thyroid autoimmunity and hypothyroidism is increased.

As patients with type III GSD live longer, long-term hepatic manifestations of the disease are being recognized. Several patients have developed cirrhosis and some have progressed to end-stage liver disease.

How can glycogen storage diseases be prevented?

All the glycogen storage diseases are inherited. Genetic counseling is an important component of comprehensive management. Prenatal diagnosis via chorionic villus sampling and mutation analysis is possible.

What is the evidence?

Kishnani, PS, Austin, SL, Abdenur, JE, Arn, P, Bali, DS, Boney, A. "Diagnosis and management of glycogen storage disease type I: a practice guideline of the American College of Medical Genetics and Genomics". Genet Med. 2014. pp. 16-e1.

(This new guideline addresses evaluation and diagnosis across multiple organ systems involved in GSD I. Aspects of diagnostic evaluation and nutritional and medical management, including care coordination, genetic counseling, hepatic and renal transplantation, and prenatal diagnosis, are addressed.)

Kishnani, PS, Austin, SL, Arn, P, Bali, DS, Boney, A, Case, LE. "ACMG. Glycogen storage disease type III diagnosis and management guidelines". Genet Med. vol. 12. 2010. pp. 446-463.

Kishnani, PS, Koeberl, D, Chen, Y-T, Valle, D, Beaudet, AL, Vogelstein, B, Kinzler, KW, Antonarakis, SE, Ballabio, A. "The Online Metabolic & Molecular Bases of Inherited Disease". www.ommbid.com.

Weinstein, DA, Correia, CE, Saunders, AC, Wolfsdorf, JI. "Mol Gen Metab". vol. 87. 2006. pp. 284-288.

Weinstein, DA, Wolfsdorf, JI. "Effect of continuous glucose therapy with uncooked cornstarch on the long-term clinical course of type 1a glycogen storage disease". Eur J Pediatr. vol. 161. 2002. pp. S35-39.

Ross, KM, Brown, LM, Corrado, MM, Chengsupanimit, T, Curry, LM, Ferrecchia, IA, Porras, LY, Mathew, JT, Weinstein, DA. "Safety and efficacy of chronic extended release cornstarch therapy for glycogen storage disease Type I". JIMD Rep. 2015;Aug 25.

(This report describes the results of an open-label overnight trial of extended release cornstarch. Subjects with a successful trial, defined as optimal metabolic control 2 or more hours longer than with traditional cornstarch, were given the option of continuing into the observational phase. Of 106 subjects [93 GSD Ia/13 GSD Ib], efficacy was demonstrated in 82 patients [88%] with GSD Ia and 10 patients [77%] with GSD Ib. Long-term data are available for 44 subjects who entered the longitudinal phase. Mean duration of fasting on traditional cornstarch prior to study for the cohort was 4.1 h as compared to 7.8 h on the extended release cornstarch. Extended release cornstarch appears to improve the quality of life of patients with GSD I without sacrificing metabolic control. Avoiding the overnight dose of cornstarch should enhance safety in patients with GSD I.)

Ongoing controversies regarding etiology, diagnosis, treatment

In 2002, guidelines from the European Study on Glycogen Storage Disease Type I (ESGSDI) recommended liver transplantation in patients with type I GSD and unresectable hepatocellular adenomas that are unresponsive to dietary therapy, particularly if these tumors are associated with serious compression or hemorrhage or show signs of transformation into hepatocellular carcinomas. Although liver transplantation corrects most metabolic derangements of type I GSD, its effect on renal disease and neutropenia or neutrophil dysfunction are uncertain. Combined liver and kidney transplantation should be considered for patients with impending renal failure.

Bone marrow transplantation into a patient with type Ib GSD and severe enterocolitis and recurrent infections improved neutrophil function and reduced the severity of the enterocolitis, although mild neutropenia persisted.

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