AUTHOR AND EDITOR INFORMATION

Section 1 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

INTRODUCTION

Section 2 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Background

Glycogen storage disease type I

Glycogen storage disease (GSD) type I is also known as von Gierke disease or hepatorenal glycogenosis. von Gierke¹ described the first patient with GSD type I in 1929 under the name hepatonephromegalia glycogenica. In 1952, Cori and Cori² demonstrated that glucose-6-phosphatase (G6Pase) deficiency was a cause of GSD type I. In 1978, Narisawa et al³ proposed that a transport defect of glucose-6-phosphate (G6P) into the microsomal compartment may be present in some patients with GSD type I. Thus, GSD type I is divided into GSD type Ia caused by G6Pase deficiency and GSD type Ib resulting from deficiency of a specific translocase T1. Apart from the substrate translocation defect, patients with GSD type Ib have altered neutrophil functions predisposing them to gram-positive bacterial infections.

Later, other translocases were discovered, adding 2 more subtypes of GSD to the disease spectrum. GSD type Ic is deficiency of translocase T2 that carries inorganic phosphates from microsomes into the cytosol and pyrophosphates from the cytosol into microsomes. GSD type Id is deficiency in a transporter that translocates free glucose molecules from microsomes into the cytosol.

For practical purposes, depending on the enzyme activity and the presence of mutations in the G6Pase and T genes, respectively, GSD type I may be subdivided into 2 major forms. GSD type Ia demonstrates deficient G6Pase activity in the fresh and frozen liver tissue. GSD type Ib demonstrates normal G6Pase activity in the frozen tissue samples and lowered activity in the fresh specimens.

Glycogen storage disease type II

GSD type II, also known as acid maltase deficiency or Pompe disease, is a prototypic lysosomal disease. Its clinical presentation clearly differs from other forms of GSD. Deficiency of a lysosomal enzyme, alpha-1,4-glucosidase, causes GSD type II. Pompe initially described the disease in 1932. An essential pathologic finding is the accumulation of normally structured glycogen in most tissues. Three forms of the disease exist: infantile, juvenile, and adult. In the classic infantile form, the main clinical signs are cardiomyopathy and muscular hypotonia. In the juvenile and adult forms, the involvement of skeletal muscles dominates the clinical presentation.

Glycogen storage disease type III

GSD type III is also known as Forbes-Cori disease or limit dextrinosis. In contrast to GSD type I, liver and skeletal muscles are involved in GSD type III. Glycogen deposited in these organs has an abnormal structure. Differentiating patients with GSD type III from those with GSD type I solely on the basis of physical findings is not easy.

Glycogen storage disease type IV

GSD type IV, also known as amylopectinosis or Andersen disease, is a rare disease that leads to early death. In 1956, Andersen reported the first patient with progressive hepatosplenomegaly and accumulation of abnormal polysaccharides. The main clinical features are liver insufficiency and abnormalities of the heart and nervous system.

Glycogen storage disease type V

GSD type V, also known as McArdle disease, affects the skeletal muscles. McArdle⁴ reported the first patient in 1951. Initial signs of the disease usually develop in adolescents or adults. Muscle phosphorylase deficiency adversely affecting the glycolytic pathway in skeletal musculature causes GSD type V. Like other forms of GSD, McArdle disease is heterogeneous.

Glycogen storage disease type VI

GSD type VI, also known as Hers disease, belongs to the group of hepatic glycogenoses and represents a heterogenous disease. Hepatic phosphorylase deficiency or deficiency of other enzymes that form a cascade necessary for liver phosphorylase activation cause the disease.⁵ In 1959, Hers described the first patients with proven phosphorylase deficiency.

Glycogen storage disease type VII

GSD type VII, also known as Tarui disease, arises as a result of phosphofructokinase (PFK) deficiency. The enzyme is located in skeletal muscles and erythrocytes. Tarui⁶ reported the first patients in 1965. The clinical and laboratory features are similar to those of GSD type V.

Pathophysiology

Glycogen storage disease type I

Because of insufficient G6Pase activity, G6P cannot be converted into free glucose, but G6P is metabolized to lactic acid or incorporated into glycogen. In this way, large quantities of glycogen are formed and stored as molecules with normal structure in the cytoplasm of hepatocytes and renal and intestinal mucosa cells; therefore, enlarged liver and kidneys dominate the clinical presentation of the disease. The chief biochemical alteration is hypoglycemia, while secondary abnormalities are hyperlactatemia, metabolic acidosis, hyperlipidemia, and hyperuricemia.

In hypoglycemia, the deficiency of G6Pase blocks the process of glycogen degradation and gluconeogenesis in the liver, preventing the production of free glucose molecules. As a consequence, patients with GSD type I have fasting hypoglycemia. Despite the metabolic block, the endogenous glucose formation is not fully inhibited. In young patients, production of free glucose reaches half that of healthy individuals, whereas adult patients may produce as much as two thirds of the healthy amount of free glucose. Hypoglycemia inhibits insulin secretion and stimulates glucagon and cortisol release.

In hyperlactatemia and acidosis, undegraded G6P, galactose, fructose, and glycerol are metabolized via the G6P pathway to lactate, which is used in the brain as an alternative source of energy. The elevated blood lactate levels cause metabolic acidosis.

In hyperuricemia, blood uric acid levels are raised because of the increased endogenous production and reduced urinary elimination caused by competition with the elevated concentrations of lactate, which should be excreted.

In hyperlipidemia, elevated endogenous triglyceride synthesis from nicotinamide adenine dinucleotide (NADH), NAD phosphate (NADPH), acetyl-coenzyme A (CoA), glycerol, and diminished lipolysis causes hyperlipidemia. Triglycerides increase the risk of fatty liver infiltration, which contributes to the enormous amount of liver enlargement. Despite significantly elevated serum triglyceride levels in patients, vascular lesions and atherosclerosis are rare complications. The increased serum apolipoprotein E concentrations that promote the clearance of triglycerides may explain the rarity of such complications.

Glycogen storage disease type II

Alpha-1,4-glucosidase is important for the degradation of smaller quantities of normally structured glycogen. Deficiency of the enzyme leads to progressive accumulation of glycogen in the cells of numerous tissues, mostly in lysosomes, which transform into large vacuoles. The most abundant deposits are in the cardiac and skeletal muscles, depending on the degree of residual enzyme activity. Glycogenolysis is not impaired. Acid alpha-glycosidase in its mature form has a molecular weight of 70 kd. Some patients have a deficiency in precursor protein synthesis, while in others, because of inadequate processing, the amount of mature molecule is insufficient or the enzyme has no catalytic activity.

Depending on the degree of residual enzyme activity, GSD type II manifests in infantile, juvenile, or adult forms. Heavy deposits of glycogen in the heart, liver, and tongue characterize the infantile form; as a result of the deposits, these tissues enlarge. The hypotonia and muscle weakness involve skeletal and respiratory muscles as well with progressive respiratory insufficiency. In the CNS, the disease primarily affects the nuclei of the brainstem and the cells of the ventral horn of the spinal cord. Mental functions are preserved.

In the juvenile and adult forms, skeletal muscles are the primary sites of glycogen deposition. The involvement of the cardiac muscle varies in the juvenile form, whereas the muscle is unaffected in the adult form; therefore, cardiomegaly is not a feature of the adult form.

Glycogen storage disease type III

Deficiency of the cytosolic debrancher enzyme, a monomeric high-molecular-weight protein that consists of 2 catalytic units (amylo-1,6-glucosidase and oligo-1,4-1,4-glucanotransferase), causes GSD type III. Abnormal glycogen with short external branches is stored in the liver, heart, and skeletal muscle cells. The accumulated glycogen resembles the limit dextrin, which is a product of glycogen degradation by phosphorylase. Two forms of the disease exist. In GSD type IIIa, the liver, skeletal muscles, and cardiac muscle are involved. In GSD type IIIb, only the liver is involved.

Glycogen storage disease type IV

Accumulation of abnormally structured glycogen in the liver, heart, and neuromuscular system characterizes this disease. The abnormal glycogen has long external branches that resemble amylopectin. This form of glycogen is less soluble; liver cirrhosis probably arises as a reaction to this insoluble material. In a predominantly myopathic form, light microscopy reveals polyglucosan inclusions in myofibrils; the inclusions are characteristic of brancher enzyme deficiency.

Glycogen storage disease type V

During the early phase of moderate physical exertion, the principal sources of energy are glycogen and anaerobic glycolysis. This phase is distinct from the resting phase when energy for the skeletal muscles is obtained through fatty acid oxidation. With further physical activity, glucose and fatty acids become irreplaceable energy sources for the skeletal muscles. However, during intense physical exertion, the skeletal muscles use energy released from endogenous glycogen (glycogenolysis by way of muscle phosphorylase), and signs of muscle fatigue occur after glycogen depletion. This effect is the reason patients with McArdle disease tolerate moderate physical activity relatively well, while intense physical exertion leads to disturbances and symptoms of the disease. The muscle glycogen concentration is increased, but its molecules are normal in structure.

Glycogen storage disease type VI

Hepatic phosphorylase is a rate-limiting enzyme that is necessary during glycogenolysis. Hepatic phosphorylase is activated in a series of reactions that requires adenylate cyclase, protein kinase A, and phosphorylase kinase. Glucagon stimulates the chain of reactions involved in the activation of phosphorylase.

Glycogen storage disease type VII

PFK catalyzes the irreversible conversion of fructose-6-phosphate to fructose-1,6-biphosphate. PFK consists of 3 subunits: muscle (M), liver (L), and platelet (P). Each subunit is coded by a gene located on different chromosomes: The PFKM gene is located on chromosome 1; the PFKL gene, on chromosome 21; and the PFKP gene, on chromosome 10. The PFKL subunit is expressed in the liver and kidneys, whereas muscles contain only the M subunit. Therefore, muscles harbor only homotetramers of M subunits, and erythrocytes contain L and M subunits, which randomly tetramerize to form M4, L4, and 3 additional hybrid forms of the holoenzyme (ie, M3L, M2L2, ML3).

Frequency

United States

Without systematic neonatal screening, no reliable data on the frequency of specific types of GSD exist. Based on the results of combined US and European studies, the cumulative incidence is estimated at 1 in 20,000-25,000 live births.

Patients with GSD type I account for 24.6% of all patients with GSD.

The precise frequency of GSD type II is not known because no systematic neonatal screening programs exist; however, GSD type II may be found in 15.3% of all patients with GSD. In the United States, the incidence of all 3 forms of GSD type II, calculated on the basis of mutated gene frequencies in healthy individuals of different ethnic backgrounds, has been estimated at 1 in 40,000 live births.

Combined data from the United States and other countries suggest that GSD type III accounts for 24.2% of all patients with GSD.

Because of its rarity, the precise incidence is not known, but GSD type IV is believed to represent 3.3% of all GSD cases.

GSD type V is rare. McArdle disease accounts for 2.4% of all patients with GSD.

GSD type VI is the most common of the glycogenoses (30% of all patients). The X-linked form of hepatic phosphorylase kinase deficiency is the most common among patients with GSD type VI.

GSD type VII is rare and is present in only 0.2% of all cases of GSD. GSD type VII most frequently affects Japanese persons and Jewish persons with Russian ancestry.

International

Approximately 2.3 children per 100,000 births have some form of GSD in British Columbia, Canada.

In GSD type II, frequencies similar to those in the United States have been found in the Netherlands (1 in 40,000 births), as well as in Taiwan and southern China (1 in 50,000 births). In a study from Australia, birth prevalence of GSD type II, including early and late-onset phenotypes, was estimated as 1 in 146,000.

Mortality/Morbidity

• In GSD type I, acute hypoglycemia may be fatal. Early death is now uncommon with improving care and treatment. Late complications, such as renal failure, hypertension, or malignant alteration of hepatic adenomas, may be responsible for mortality in adolescent and adult patients. See Complications.
• In GSD type II, morbidity and mortality differ among the subtypes of the disease. The infantile form has a lethal outcome caused by progressive cardiorespiratory insufficiency that usually begins by the end of the first year of life. The juvenile form has a slower course. Some patients may survive the third decade of life. Death is usually due to respiratory insufficiency, although a few cases have been described that were caused by the rupture of an intracranial aneurysm formed from glycogen accumulation in the smooth muscle cells of the arterial wall. The adult form manifests in older patients. Death due to respiratory insufficiency (sleep apnea) may occur many years after the first signs of the disease have appeared.
• In GSD type III, the cirrhosis found in some patients is of a mild degree without a significant impact on the course of the disease.
• In GSD type IV, the classic form, progressive liver cirrhosis rapidly leads to hepatic insufficiency so that a fatal outcome may be expected before the end of the second year of life (see Complications). Rarely, children with GSD type IV may survive longer.
• In GSD type V, rhabdomyolysis may lead to renal failure and death.
• In GSD type VI, serious complications are unknown.
• In GSD type VII, skeletal muscles and erythrocytes are affected. Rhabdomyolysis may cause acute renal failure because of myoglobinuria.

Race

• No racial or ethnic differences exist for GSD types I, II, IV, V, and VI.
• Although GSD type III is distributed universally throughout the world, the highest incidence (1 in 5420 births) has been recorded in non-Ashkenazi Jews in northern Africa.
• The patients most commonly reported with GSD type VII are of Japanese or Ashkenazi Jewish descent.

Sex

• GSD types I-V and VII affect both sexes with equal frequency.
• GSD type VI affects both sexes with equal frequency; however, in the X-linked form, most patients are males.

Age

• As with other genetically determined diseases, GSD type I develops during conception, yet the first signs of the disease may appear at birth or later.
• In GSD type II, the age of onset depends on the clinical form of disease. The infantile form develops during the first months of life. In the juvenile form, initial clinical symptoms appear in persons aged 1-15 years. The adult form of disease appears in person aged 10-30 years and, less commonly, later.
• In GSD type III, the first signs of the disease may appear shortly after birth or within several months afterwards.
• In GSD type IV, patients appear healthy at birth, but they fail to thrive soon after birth, and hepatomegaly and/or splenomegaly may be observed in the next few months.
• In GSD type V, the first signs of the disease usually develop in persons aged 10-20 years.
• In GSD type VI, the disease appears in the first months of life.
• In GSD type VII, depending on the genetic variety, the disease usually develops in persons aged 10-20 years and, less frequently, earlier or later in life.

CLINICAL

Section 3 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

History

• GSD type I
• • The earliest signs of the disease may develop shortly after birth and are caused by hypoglycemia and lactic acidosis.
  • Convulsions are a leading sign of disease.
  • Frequently, symptoms of moderate hypoglycemia, such as irritability, pallor, cyanosis, hypotonia, tremors, loss of consciousness, and apnea, are present.
  • Some children have diarrhea due to pseudocolitis.
• GSD type II
• • Symptoms of the infantile form usually begin in infants at the end of the second month of life, with profound hypotonia. Muscle weakness progresses rather rapidly, manifesting as respiratory and feeding difficulties. Spontaneous movements are scarce, and painful stimuli cause weak motor reactions. Mental functions are retained.
  • In the juvenile form, the initial clinical symptoms appear in persons aged 1-15 years. Retarded motor development, hypotonia, and muscle weakness due to slowly progressive skeletal muscle disease characterize the juvenile form. Intellectual development is normal. Atony of the anal sphincter and enlargement of the urinary bladder can be found in only a minority of children.
  • The adult form develops in persons aged 10-30 years and, less commonly, later. Its course progresses slowly. Dyspnea due to the involvement of respiratory muscles and difficulties in climbing up the stairs caused by proximal myopathy are the leading clinical manifestations. In one third of patients, the initial symptoms are somnolence, morning headaches, orthopnea, and exertional dyspnea. Weakness of the respiratory muscles, particularly the diaphragm, causes these symptoms.
• GSD type III
• • The first manifestations of the disease usually appear in infants aged 1 year, although in milder variants, the onset may be delayed.
  • Clinical symptoms of hypoglycemia are rarely encountered.
  • A common reason for patients to undergo detailed investigations is enlargement of the stomach or hepatomegaly disclosed on a routine examination.
  • Retarded growth may be a reason to examine patients.
  • When skeletal and cardiac muscles are involved, muscular weakness or hypotonia and cardiovascular abnormalities dominate the clinical presentation.
• GSD type IV
  • Children affected with GSD type IV are born without signs of the disease, although some of them may have a dysmorphic face.
  • However, in the weeks after birth, failure to thrive, hypotonia, and atrophy of the muscles are noted.
• GSD type V
  • The classic form appears in persons aged 10-20 years.
  • Patients commonly report fatigue during physical exertion, muscle cramps, and later, muscle weakness and burgundy red–colored urine.
• GSD type VI
  • Symptoms, if present, are minimal.
  • Often, patients seek help for retarded growth.
• GSD type VII
• • Similar to that of GSD type V, intolerance of physical activity, muscle cramps, and burgundy red–colored urine occur during a rhabdomyolysis episode.
  • Attacks of rhabdomyolysis may be associated with nausea and vomiting, and more often than not, a meal rich in carbohydrates is consumed beforehand.

Physical

• GSD type I
• • A leading sign of GSD type I is enlargement of the liver and kidneys. During the first weeks of life, the liver is normal size. It enlarges gradually thereafter, and in some patients, it even reaches the symphysis. Enlargement of the abdomen due to hepatomegaly can be the first sign noted by the patient's mother.
  • The patient's face is characteristically reminiscent of a doll's face (rounded cheeks due to fat deposition).
  • Mental development proceeds normally.
  • Growth is retarded, and children affected with GSD type I never gain the height otherwise expected from the genetically determined potential of their families. The patient's height is usually below the third percentile for their age. The onset of puberty is delayed.
  • Late complications of disease are renal function disturbance (including nephrocalcinosis), renal stones, tubular defects, and hypertension, mainly in patients older than 20 years. Renal function deterioration progresses to terminal insufficiency, requiring dialysis and transplantation.
  • Skin and mucous membrane changes include the following:
  • • Eruptive xanthomas develop on the extensor surfaces of the extremities.
    • Tophi or gouty arthritis may occur. Uric tophi often have the same distribution as xanthomas.
    • Spider angiomas may be present.
    • Perianal and gingival abscesses of the oral mucosa and gums may be observed. Aphthous ulcers are often present in patients with GSD type Ib.
    • Perianal erythema and erosions may occur in patients with prolonged diarrhea due to pseudocolitis.
    • In a 2002 report, Visser et al⁷ presumed that the main cause of disturbed intestinal function is loss of the integrity of the mucosal barrier, which occurs as a result of inflammation, and loss of neutrophil function, which often occurs in patients with GSD lb.
  • Many patients bleed easily, particularly from the nose. This tendency is a result of altered platelet function due to the platelets' lower adhesiveness. Frequent and, occasionally, prolonged epistaxis may cause sideropenic anemia. At times, the bleeding may be so severe that blood transfusions are required.
  • Risk factors and adverse events are as follows:
  • • Hypoglycemia and infections are frequent.
    • Assisted ventilation is often not tolerated well.
    • Foods rich in fructose, galactose, and triglycerides adversely affect the long-term complications caused by lactic acidosis, hyperuricemia, and hyperlipidemia.
• GSD type II
• • Infantile form
  • • Generalized severe hypotonia is present. Despite severe hypotonia and weakness, the affected muscles are firm on palpation and, occasionally, hypertrophic. In some patients, tongue fasciculations have been observed.
    • Conspicuous cardiomegaly with cardiomyopathy and heart failure may be present.
    • Macroglossia and hepatomegaly may be noted.
    • Tendon reflexes are diminished or absent.
    • Signs of respiratory insufficiency are due to the involvement of respiratory musculature.
  • Juvenile form
  • • Respiratory insufficiency and hypotonia largely of the proximal musculature are present.
    • Macroglossia, cardiomegaly, cardiomyopathy, and hepatomegaly are absent.
  • Adult form
  • • Proximal muscle weakness is noted.
    • Muscle volume is decreased, and tendon reflexes are diminished.
    • The visceral organs are not affected; however, intracranial aneurysms are possible because of glycogen deposits in the smooth muscle cells of the cerebral arteries.
• GSD type III: GSD type III is a heterogeneous disease. Two subtypes exist: GSD type IIIa and GSD type IIIb. In most patients, the liver and the spleen are enlarged. In some children, growth retardation, renal tubular dysfunction, and liver cirrhosis can be observed.
• • GSD type IIIa is more common and prognostically more unfavorable than other forms. The main clinical features include the following:
  • • Hepatomegaly and/or splenomegaly may be present.
    • Muscular weakness and atrophy, particularly of the girdle and limb musculature, may be observed.
    • Cardiomegaly and cardiomyopathy may occur.
    • Cardiac and skeletal muscle abnormalities possibly taking on a progressive course and possibly appearing at different ages (from early childhood to late adulthood) may be noted.
  • GSD type IIIb is less common (approximately 15%) although prognostically more favorable than other forms.
  • • The liver is the only organ involved.
    • Hepatosplenomegaly is moderate.
    • Mild fibrosis and micronodular cirrhosis of the liver are rare and often clinically silent.
    • Hepatomegaly is pronounced during childhood but usually normalizes at puberty.
    • Growth is accelerated at puberty; therefore, most patients reach their expected height.
• GSD type IV
• • Hepatosplenomegaly is evident in the first months of life. Soon thereafter, signs of progressive liver cirrhosis appear resulting in hepatic insufficiency, portal hypertension, and death.
  • Besides hepatosplenomegaly, heart dilatation and neurologic deficits with muscle atrophy and diminished or absent tendon reflexes can be observed.
  • Patients with fetal hydrops, muscular degeneration, and arthrogryposis have been reported.
  • Prominent venous distention is sometimes visible on the anterior abdominal wall.
• GSD type V
• • In a milder variety, the first symptoms and signs may appear late, even in elderly patients.
  • Forms clinically expressed in the first years of life occur with muscle hypotonia and generalized muscle weakness and occasionally lead to respiratory insufficiency.
  • Rhabdomyolysis can be a cause of renal failure.
• GSD type VI
• • GSD type VI is a benign disease.
  • At times, hepatomegaly is incidentally noted during an investigation of the child's slow growth.
  • Skeletal and cardiac muscles are unaffected.
  • With age, the size of the liver decreases and normalizes at or around puberty.
• GSD type VII
• • GSD type VII is more severe than GSD type V.
  • Rhabdomyolysis with renal failure is common.
  • In some patients, erythrocyte hemolysis occurs.
  • Jaundice is apparent in severe hemolysis.
  • Two rare varieties of GSD type VII exist. One form occurs in infants with hypotonia and weakness of the extremity muscles; this form progresses in severity, with a lethal outcome in early childhood. The other form occurs in young adults or older persons; this form progresses slowly, and its clinical presentation is dominated by the weakness of the different muscle groups rather than the muscle cramps and myoglobinuria.

Causes

• GSD type I
• • GSD type Ia: Deficiency of G6Pase or hydrolase is a cause of GSD type Ia. G6Pase is an integral membrane protein. Mutations in the transmembrane helices of the protein cause the most severe deficiency of enzyme activity.
  • • The G6Pase gene is located on band 17q21 as a single copy. The complementary DNA (cDNA) has been cloned, and the most frequent mutations are known. For optimal catalytic activity, critical residues are 347-354. The gene contains 5 exons and spans approximately 12.5 kb. An analysis of the G6Pase gene in 70 unrelated patients with enzymatically confirmed diagnosis of GSD type Ia revealed that the most frequent mutations were R83C and Q347X in whites, 130X and R83C in Hispanics, and R83H in Chinese.
    • The Q347X mutation was found only in whites, and 130X was found only in Hispanic patients. A mutational analysis in French patients has been published; this analysis reveals 14 different mutations. The most common among them, in as many as 75% of mutated alleles, were Q347X, R83C, D38V, G188R, and 158Cdel.
    • At present, at least 56 mutations in the G6Pase gene have been reported in patients with GSD type Ia. The mutated allele is inherited as an autosomal recessive trait. No strong evidence indicates a clear genotype-phenotype correlation, but in 2002, Matern et al⁸ reported a relationship between (1) a G188R mutation and GSD type I non–a phenotype and a homozygous G727T mutation and (2) a milder form of clinical presentation but with a higher risk for hepatocellular malignancy. On the other hand, in 2005 Melis et al⁹ did not find a correlation between individual mutations and the presence of neutropenia, bacterial infections, and systemic complications in patients with GSD type Ib.
    • Early prenatal genetic diagnosis of disease is possible using chorionic villi or amniocytic DNA samples instead of invasive fetal liver biopsy.
  • GSD type Ib: Deficiency of G6PT1 translocase causes GSD type Ib. The G6PT1 gene is expressed in liver, kidney, and hematopoietic progenitor cells, spans approximately 5 kb and contains 8 exons, and has been mapped to band 11q23. The mutated allele is inherited as an autosomal recessive trait. There is no correlation between the kind of mutation in the G6PT gene and severity of the disease. Therefore, other unknown factors are believed to be responsible for expression of different symptoms, such as neutropenia, in these patients, which dramatically influences the severity and natural course of the disease. In 2003, Kuijpers et al¹⁰ found circulating neutrophils with signs of apoptosis and increased caspase activity in 5 patients with GSD type Ib. However, granulocyte colony–stimulating factor in in vitro cultures did not influence apoptosis.
  • • The G6PT1 gene is strongly expressed in liver, kidney, and hematopoietic progenitor cells, which might explain major clinical symptoms such as hepatomegaly, nephromegaly, and neutropenia in GSD type Ib.
    • In a 2005 multicentric study and review of the literature, Melis et al⁹ from Italy concluded that there is no correlation between individual mutations and the presence of neutropenia, bacterial infections, and systemic complications and suggested that different genes and proteins could be involved in differentiation, maturation, and apoptosis of neutrophils and the severity and frequency of infections. They also found no detectable mutations in 3 patients, indicating that the second protein may play a role in microsomal phosphate transport.
  • GSD type Ic: Deficiency of T2 translocase causes GSD type Ic. The GSD type Ic gene is mapped to bands 11q23. The mutated allele is inherited as an autosomal recessive trait. In 1999, Janecke et al¹¹ confirmed that GSD type Ic is allelic to GSD type Ib.
  • GSD type Id: Deficiency of T3 transposes causes GSD type Id. The gene is mapped to bands 11q23-q24. The mutated allele is inherited as an autosomal recessive trait.
• GSD type II: Deficiency of the acid alpha-1,4-glucosidase coded on bands 17q21.2-q23 causes GSD type II. The gene is 20 kb in length, contains 20 exons, and codes for a 105-kd protein. The mutated allele is inherited as an autosomal recessive trait. The disease is expressed in homozygotic carriers of the mutation. Heterozygotic carriers of the mutation do not show signs of the disease. Thus far, a large number of different mutations (eg, missense, nonsense, deletion, splice site mutations) have been found, and various forms of enzyme deficiency may result from the following mutations: complete loss of the protein (infantile form), decreased enzymatic activity due to reduced affinity for substrate (juvenile and adult forms), and decreased levels of the protein with normal substrate affinity (juvenile and adult forms, IVS1-13T-->G splice site mutation common in adults). Some patients are compound heterozygote and may have a less severe clinical picture than those with homoallelic forms.
• GSD type III: A deficiency of the debrancher enzyme causes the disease. In GSD type IIIb, the enzyme deficit is confined to the liver, whereas in GSD type IIIa, the deficit also occurs in the skeletal muscles and the myocardium. A correlation exists between the residual enzyme activity and the severity of the clinical presentation. A gene mapped to band 1p21 codes the enzyme. More than 30 different mutations have been identified in patients from many different ethnic groups. The cDNA has been cloned. The gene contains 7072 base pairs (bp), of which 4596 bp is in the coding region. Hepatic and muscular messenger RNA (mRNA) differs in the 5' region. Genetic heterogeneity is found at the mRNA level. The disease is inherited as an autosomal recessive trait. Carrier detection and prenatal diagnosis are possible by DNA mutation analysis.
• GSD type IV: Amylo-1,4-1,6-transglucosidase or brancher enzyme deficiency is the cause of this disease. A gene mapped to band 3p12 codes the brancher enzyme. The full-length cDNA is approximately 3 kb. The coding sequence contains 2106 bp that encodes a protein of 702 amino acids. There is a correlation between the various gene mutations and the severity of the clinical manifestations (eg, 210-bp DNA deletion in a patient with fatal neonatal neuromuscular form, Y329S point mutation in a patient with nonprogressive hepatic form). The disease is inherited as an autosomal recessive trait. Carrier detection and prenatal diagnosis are available by DNA analysis.
• GSD type V: Myophosphorylase deficiency causes the disease. Myophosphorylase exists in different tissue-specific isoforms (eg, muscle, liver, brain), and a separate gene codes enzyme isoforms in each tissue. A gene mapped to bands 11q13-qter codes muscle phosphorylase. Myophosphorylase gene mutations are identified. The most common is C-to-T transition at codon 49 in exon 1. The most prevalent mutations in white and Japanese patients are R49X and deletion F708, respectively. Rare mutations include G-to-A transition at codon 204 in exon 5 and A-to-G transversion at codon 542 in exon 14. All other rare mutations occur in approximately fewer than 30% of patients. In 2002, Dimaur et al¹² reported that the mutations in patients with GSD type V are spread throughout the gene and that no clear genotype-phenotype correlation exists. GSD type V is inherited as an autosomal recessive trait.
• GSD type VI
• • Hepatic phosphorylase deficiency or deficiency of other enzymes (eg, adenylate cyclase, protein kinase A, phosphorylase kinase) that form a chain of reactions necessary for the activation of phosphorylase causes GSD type VI. Heterogeneity exists in the clinical symptoms as a result of the different PYGL gene defects observed in affected individuals; they vary from hepatomegaly and subclinical hypoglycemia to severe hepatomegaly, hypoglycemia, and lactic acidosis.
  • The hepatic phosphorylase gene is located on bands 14q21-q22. Mutations responsible for the disease have been identified. Phosphorylase b kinase exists in an inactive form that is activated by the cyclic adenosine monophosphate (cAMP)–dependent protein kinase. The several subunits of phosphorylase kinase are coded by separate genes located on somatic chromosomes (subunits a and c) and the X chromosome (subunit b). A terminological confusion exists when classifying hepatic phosphorylase b kinase deficiencies. Some authors place all the forms under the name GSD type VI, whereas other authors label phosphorylase b kinase deficiency as GSD type IX and cAMP-dependent protein kinase deficiency as GSD type X.
  • The X-linked form of hepatic phosphorylase kinase deficiency is the most common (75%) among patients with GSD type VI. The gene is located on the short arm of the X chromosome at band p22.
  • Other forms of GSD type VI are inherited as an autosomal recessive trait.
• GSD type VII: PFK deficiency causes GSD type VII. The PFKM locus was assigned to band 1cen-q32 by somatic cell hybridization. The genomic organization of cDNA is known. In 1996, Howard et al,¹³ based on physical and genetic mapping, concluded that the PFKM gene is located on band 12q13.3 instead of chromosome 1, as previously believed. The different allelic variants of mutations are detected up to now. The inheritance is autosomal recessive.

DIFFERENTIALS

Section 4 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Other Problems to be Considered

Glycogen storage disease type I

Fructose-1,6-biphosphatase deficiency
Fructose-1-phosphate aldolase deficiency (hereditary fructose intolerance)
Congenital lactic acidosis
GSD type III
GSD type IV
GSD type VI
Niemann-Pick disease, type A
Hyperlipoproteinemia type 1
Disorders of uric acid metabolism

Glycogen storage disease type II

Danon disease (vacuolar cardiomyopathy, skeletal myopathy) caused by mutations of a structural lysosomal protein while the activity of acid maltase is normal
Werdnig-Hoffmann disease
Congenital myopathies
Neurovisceral sphingolipidosis
Ethanol aminosis
Deficiencies of PFK and phosphorylase b kinase
Duchenne muscular dystrophy, especially in the juvenile and adult forms
Organic acidurias
Mitochondrial disorders

Glycogen storage disease type III

Charcot-Marie-Tooth disease
Other myopathies
GSD type I
GSD type II
GSD type IV
GSD type VI

Glycogen storage disease type IV

GSD type II
Other disorders of the neuromuscular system
Galactosemia (galactose-1-phosphate uridyltransferase deficiency)
Organic acidurias

Glycogen storage disease type V

Inflammatory myopathies
GSD type VII
GSD type III

Glycogen storage disease type VI

Other forms of hepatic glycogenoses

Glycogen storage disease type VII

GSD type V

WORKUP

Section 5 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Lab Studies

• GSD type I: Serum glucose and blood pH levels are frequently decreased, while the serum lactate, uric acid, triglyceride, and cholesterol levels are elevated. Urea and creatinine levels might be elevated when renal function is impaired. The following laboratory values should be obtained:
• • Serum glucose and electrolyte levels (Higher anion gap may suggest lactic acidosis.)
  • Serum lactate level
  • Blood pH
  • Serum uric acid level
  • Serum triglyceride and cholesterol levels
  • Gamma glutamyltransferase level
  • CBC and differential (eg, anemia, leukopenia, neutropenia)
  • Coagulation
  • Urinalysis for aminoaciduria, proteinuria, and microalbuminuria in older patients
  • Urinary excretion levels of uric acid and calcium
  • Serum alkaline phosphatase, calcium, phosphorus, urea, and creatinine levels
• GSD type II
• • Findings on laboratory analyses are usually normal.
  • Rarely, creatine kinase (CK) levels are elevated because of skeletal muscle involvement. Rarely, serum aspartate aminotransferase levels are elevated in infants with liver lesions.
  • Definitive diagnosis requires measurement of the activity of acid alpha-1,4-glucosidase.
  • Skin fibroblast culture or peripheral blood lymphocytes should be used in enzymatic assay.
  • Diagnosis may be missed if lymphocyte culture is mixed with granulocytes that contain a renal isoform of acid maltase.
  • Molecular analysis should be performed for prenatal diagnosis.
• GSD type III
• • Fasting hypoglycemia and ketonuria may be noted.
  • Hyperlipidemia may be present.
  • Serum aminotransferase and CK levels may be elevated. Baseline levels of CK do not exclude GSD type III. In GSD type IIIb, serum aminotransferase levels are elevated during childhood but usually normalize at puberty.
  • Usually, serum lactate and uric acid levels are in the reference range.
• GSD type IV
• • Serum aminotransferase levels are elevated.
  • Fasting hypoglycemia is present in some patients.
• GSD type V
• • The main laboratory sign of disease is elevated levels of serum CK at rest. After intensive exercise, CK levels increase further.
  • At the same time, the blood ammonia, inosine, hypoxanthine, and uric acid concentrations are above the reference range. Activities of muscle phosphorylase may be extremely low.
  • Differentiate patients with McArdle disease from patients with other inflammatory myopathies.
  • In addition, GSD type VII has the same clinical manifestations and can be differentiated on the basis of enzymatic study only. The forearm ischemic test, a useful diagnostic test, can produce abnormal results in patients with GSD type VII and in patients with debranching enzyme deficiency (GSD type III) when it is performed after fasting.
• GSD type VI
• • Serum aminotransferase levels are elevated.
  • Hypoglycemia, ketosis, and hyperlipidemia are rare and usually mild.
  • Serum lactic and uric acids levels are baseline.
• GSD type VII
• • CK levels are elevated.
  • Erythrocyte, hemoglobin, and reticulocyte counts, and serum unconjugated bilirubin concentration are important diagnostic measurements in patients with hemolysis.

Imaging Studies

• In GSD type I, liver and kidney ultrasonography should be performed for follow-up of organomegaly and detection of hepatic adenomas and nephrocalcinosis.
• Because of the risk of long-term complications, current guidelines recommend abdominal ultrasonography with tumor marker levels (eg, alpha-fetoprotein [AFP], carcinoembryonic antigen [CEA]) every 3 months if the patient develops hepatic lesions. Abdominal CT scanning or MRI is advised whenever the lesions are large, poorly defined, or are growing rapidly.
• In GSD type II, echocardiography may be performed. It is noninvasive and useful for detection of cardiac muscle involvement. Occasionally, only the left ventricle may be affected. In advanced disease, evaluating the functional reserve of the heart may be helpful.
• In GSD type III, echosonography may be performed. It is a noninvasive method that can provide useful information about the size of the liver, spleen, and heart.
• In GSD types V and VII, MRI with phosphate-31 is a useful noninvasive method for the investigation of muscle metabolism.
• In GSD type VI, echosonography is performed for liver measurement.

Other Tests

• GSD type I
• • Glucagon and epinephrine tests do not cause a rise in glucose levels, but plasma levels of lactic acid are raised.
  • Orally administered galactose and fructose (1.75 g/kg) do not increase glucose levels, but plasma lactic acid levels do increase.
  • Glucose tolerance test (1.75 g/kg PO) progressively lowers lactic acid levels over several hours after the administration of glucose.
• GSD type II
• • ECG is characteristic with shortening of the PR interval and large QRS complex.
  • Electromyography (EMG) reveals a myopathic pattern in all patients with pseudomyotonic discharge. Many patients have fibrillation potentials.
  • Nerve conduction velocities are in the reference range.
• GSD type III
• • In the glucose tolerance test, serum lactate levels increase from the basal levels during the test, gradually returning to baseline values thereafter.
  • Orally administered galactose and fructose are converted into glucose because gluconeogenesis is unaffected.
  • Ingested amino acids and proteins induce a moderate but prolonged increase in blood glucose levels.
  • The response of blood glucose levels to the administration of glucagon and epinephrine varies. Glucagon administered after a fasting period does not induce a rise in glycemia; however, if glucagon is administered 2 hours after a meal, it produces an increase in blood glucose levels.
  • EMG findings are compatible with skeletal myopathy, and peripheral nerve conduction velocities may be abnormal.
  • ECG changes suggest ventricular hypertrophy, but signs of significant cardiac dysfunction are rarely observed.
• GSD type V
• • The forearm ischemic test is a useful diagnostic test. Lack of an increase in blood lactate concentration and exaggerated increase in ammonia concentration simultaneously are reliable signs of disturbed glycogen metabolism in the skeletal muscle.
  • Occasionally, EMG changes may be similar to those of some nonspecific inflammatory myopathies.
• GSD type VI: Diagnosis rests with histologic analysis of liver tissue or determination of the activity of the enzymes hepatic phosphorylase in the liver and phosphorylase b kinase in the liver, skeletal muscle, and heart.
• GSD type VII
• • The forearm ischemic exercise test is a useful diagnostic test.
  • EMG should be performed.

Procedures

• GSD type I
• • For diagnostic purposes, 13C nuclear magnetic resonance spectroscopy may be used for enzyme function assessment.
  • Definitive diagnosis requires determination of G6Pase activity in fresh and frozen liver tissue specimens and/or DNA-based analysis. When assaying for translocases, an open surgical liver biopsy is needed for sampling an adequate tissue specimen.
• GSD type II
• • Skin biopsy should be performed to determine the activity of the enzyme in fibroblast culture.
  • Amniocentesis is necessary for amniotic fluid or chorion biopsy with the aim of prenatal diagnosis.
• GSD type III: Biopsy of the liver and skeletal muscle should be performed for enzyme activity measurements.
• GSD type IV
• • Liver and skeletal muscle biopsies are needed for enzyme activity and microscopic analysis.
  • Glucose tolerance test results are in the reference range.
  • Glucagon and epinephrine test results vary.
  • Glycogen content in tissues is usually in the reference range, but its structure is abnormal.
• GSD type V
• • Muscle biopsy should be performed.
  • Molecular DNA analysis or analysis of the functional activities of myophosphorylase is necessary for definitive diagnosis of McArdle disease.
  • Prenatal diagnosis is unnecessary.
• GSD type VI: Skeletal muscle and liver biopsy should be performed for microscopic and enzymatic analysis.
• GSD type VII: Muscle biopsy should be performed for microscopic and enzymatic analysis.

Histologic Findings

In GSD type I, no specific findings occur in the liver, but higher amounts of normal glycogen, as well as fatty infiltration, are found. Histologic findings in the kidneys comprise focal glomerular sclerosis, interstitial fibrosis, tubule atrophy or vacuolization, and significant atherosclerosis. A conspicuous glomerular hypertrophy occurs, and less commonly, numerous lipid deposits occur in the glomerular mesangium, tubular epithelial cells, and interstitium. Electron microscopy may reveal diffuse thickening of the glomerular basement membrane and lipid droplets in the mesangium.

In GSD type II, ultrastructural analysis of a large number of different tissue samples reveals large amounts of normal glycogen. Under a light or electron microscope, large vacuoles can be observed in involved organs. The large vacuoles represent secondary lysosomes filled with glycogen.

The histologic picture of the liver in patients with GSD type III is characterized by generalized distension of the hepatic cells by glycogen and fibrous tissue. The fibrotic process may be characterized by minimal periportal disease or micronodular cirrhosis. This is usually nonprogressive.

In GSD type V, histologic findings are nonspecific.

In GSD type VI, hepatocytes distended by the accumulated frayed or burst glycogen (ie, alpha particles, rosette form) may be observed in the liver and are less compact than in classic glycogenoses types I and III.

In GSD type VII, the abnormal polysaccharide accumulates, with fibrillar morphology, in the skeletal muscle.

TREATMENT

Section 6 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical Care

• GSD type I: Most children with GSD type I are admitted to the hospital to make a final diagnosis, to manage hepatomegaly or hypoglycemia, and to perform percutaneous needle biopsy or open surgical biopsy of the liver (admission to the hospital is required for these procedures). At times, surgical abscess incision is necessary in children with GSD type Ib. Frequent infections in patients with GSD type Ib require intravenous therapy to correct hypoglycemia and intensive intravenous antibiotic treatment to control infections.
• • Because no specific treatment is available, symptomatic therapy is very important.
  • In the past, treatment had been focused on correcting hypoglycemia and other metabolic disturbances using raw cornstarch. At present, a novel form of physically modified cornstarch (WMHM20, Glycologic Ltd; Glasgow, Scotland) is in clinical practice. It differs from classic cornstarch in regard to amylopectin content. Evidence suggests better control of hypoglycemia in persons with GSD types I and III  and an extended duration of euglycemia and better metabolic control for patients.¹⁴
  • Additionally, for patients with GSD type I, the future may bring adeno-associated virus vector–mediated gene experimental therapy, which may result in curative therapy, as is possible in patients with GSD type II.¹⁵
• GSD type II
• • At present, effective specific treatment can be achieved using recombinant DNA alglucosidase alfa (Myozyme), which degrades lysosomal glycogen. On the basis of clinical trials, including pediatric patients aged 1 month to 3.5 years at time of first infusion, it can be concluded that alglucosidase alfa is efficient in improving ventilator-free survival in patients with infantile-onset Pompe disease. However, conclusions regarding its efficacy in patients with other forms of Pompe disease require additional investigation.
  • Alglucosidase alfa may be administered by intravenous infusion only. The recommended dosis is 20 mg/kg as a 4-hour infusion every 2 weeks. The initial rate of infusion should be 1 mg/kg/h, which may then be increased by 2 mg/kg/h every 30 minutes to a maximum rate of 7 mg/kg/h using an infusion pump.
  • Contraindications are not known. However, some risk of different hypersensitivity reactions exist for treated patients, and some of these reactions are life-threatening anaphylaxis, including anaphylactic shock.
  • Preliminary results of alglucosidase alfa treatment have shown prolonged survival for patients with cardiomyopathy and those with motor deficit.
  • Gene therapy is an encouraging mode of treatment but is not yet available. However, in 2002, Martin-Touaux et al¹⁶ reported using a GSD type II mouse model, a new mode of gene therapy using muscle as a secretary organ, and an adenovirus vector encoding AdGAA. They injected adenovirus vector encoding AdGAA in the gastrocnemius of neonates and detected a strong expression of GAA in the injected muscle, secretion into plasma, and uptake by the peripheral skeletal muscle and the heart. Furthermore, the glycogen content in these tissues decreased and the destruction foci usually present in untreated mice and visible by electron microscopy disappeared.
• GSD type III: No specific therapy exists. The treatment is somewhat simpler than that of GSD type I. When hypoglycemia is a problem, the patient should consume frequent high-protein meals to preserve gluconeogenesis. Hydrolyzable cornstarch should be slowly administered between meals and overnight as well; this therapy is particularly important to prevent overnight hypoglycemia. Proof that frequent protein meals and overnight nasogastric infusion of proteins can prevent progressive myopathy is not conclusive.
• GSD types IV and VI: No medication is necessary.
• GSD types V and VII: No specific therapy is available.

Surgical Care

• GSD type I: In view of short- and long-term complications, orthotopic liver transplantation is a last resort when other conservative measures have failed or if hepatic adenomas become malignant. A large liver adenoma may be successfully treated with ethanol injection under ultrasonographic or CT control. Kidney transplantation has been performed in cases of end-stage renal insufficiency. If a surgical procedure is to be performed, a bleeding test must be performed and any metabolic disturbances must be corrected. In patients with prolonged bleeding times, treatment with 1-deamino-8-D-arginine vasopressin (DDAVP) together with an intravenous 10% glucose infusion 1-2 days before and again during the procedure can be useful. Avoid administering lactated Ringer solution alone because it contains lactate but does not contain glucose.
• GSD type IV: In case of progressive liver cirrhosis, liver transplantation may be performed. However, because of the systemic nature of the disease, the long-term favorable effects of the procedure are not feasible.
• GSD type VI: Surgical care is not necessary.
• GSD type VII: Surgical care should be performed if necessary for other reasons, such as muscle biopsy and hemodialysis.

Consultations

• The following specialists may be consulted for patients with GSD type II:
• • Intensive care therapists to perform assisted ventilation during respiratory insufficiency
  • Pediatric cardiologist to treat cardiovascular insufficiency
  • Clinical geneticist to counsel families
  • Neurologist for EMG investigations
• A pediatric cardiologist can be consulted for patients with GSD type III.

Diet

• GSD type I: The primary goal of treatment is to correct hypoglycemia and maintain a normoglycemic state. The normoglycemic state can be achieved with overnight nasogastric infusion of glucose, its polymers and elemental enteral formula, parenteral nutrition, or peroral administration of raw cornstarch.
• • In young infants, the best results are obtained with nocturnal nasogastric tube feeding with elemental enteral formula, glucose, or glucose polymers. One third of the total caloric need should be provided by nasogastric drip feeding. An infant should receive 8-10 mg/kg/min of glucose, and an older child should receive 5-7 mg/kg/min of glucose. The infusion should be administered with a special pump. In the daytime, patients should consume frequent meals that contain higher quantities of carbohydrates (eg, carbohydrates 65-70%, proteins 10-15%, fat 20-25%). The first meal should be consumed no longer than 15-30 minutes after stopping the nasogastric infusion.
  • In older infants and children, raw cornstarch is administered instead of continuous overnight feeding by means of a nasogastric tube. Glucose molecules are continuously released by hydrolysis of raw cornstarch in the digestive tract over 4 hours following its intake. The cornstarch is administered between meals in a dose of 1.6 g/kg every 4 hours in children younger than 2 years and in a dose of 1.75-2.5 g/kg every 6 hours in children older than 2 years. The cornstarch is usually dissolved in lukewarm water in a weight-to-volume ratio of 1:2. In children with diminished pancreatic function, the treatment is not effective. In young adult patients, a single dose of uncooked cornstarch given at bedtime can be enough to maintain overnight blood glucose concentration in the reference range.
  • The intake of fructose and galactose should be restricted because it has been shown that they cannot be converted to glucose but that they do increase lactate production.
  • Limited intake of lipids is advisable for the existing hyperlipidemia.
• GSD type II
• • A specific diet is not available. However, because of difficulties in swallowing and risks of aspiration, many children require feeding by means of a nasogastric or gastrostomy tube.
  • In 2006, Roe and Mochel¹⁷ reported a clinical benefit with anaplerotic diet therapy in an adult-onset GSD type II patient with skeletal muscle weakness. Because patients with adult-onset disease have cataplerotic events as a result of acid maltase deficiency (from muscle to liver), triheptanoin may have a beneficial effect. Triheptanoin is a medium-odd-chain triglyceride and serves as an anaplerotic substrate for the citric acid cycle in all tissue. Heptanoate and C5-ketone bodies derived from partial oxidation of triheptanoin (C7 triglyceride) in the liver are precursors of anaplerotic propionyl-coenzyme A in peripheral tissues, including skeletal muscle, where they increase ATP production, resulting in augmentation of mass and strength of striated muscle. Besides the anaplerotic effect, triheptanoin is a gluconeogenic compound in the liver and kidney cortex.
  • According to data from Kinman et al¹⁸ from 2006, triheptanoin may be safely administered intravenously for the treatment of decompensated, energy-depleted patients.
• GSD type III: A specific diet is not available. In addition, no need exists for any dietary restrictions as in patients with GSD type I. Similarly to GSD type I, patients with hypoglycemia may benefit from frequent and nocturnal tube feeding, as well as cornstarch and a high-protein diet.
• GSD type IV: A specific diet is not available. Hypoglycemia should be corrected. A balanced diet favorably influences liver disease.
• GSD type V: Glucose and fructose administered by mouth increases the patient's tolerance of physical exertion. A high-protein diet may also increase the patient's tolerance of physical exertion.
• GSD type VI: A specialized diet is not necessary unless hypoglycemia with ketosis is a problem. Frequent carbohydrate meals are then recommended.
• GSD type VII: Patients should be instructed to avoid carbohydrate-rich foods.

Activity

• GSD type I: Physical activity is not restricted. Patients or their parents should be informed about the risks of aggressive and dangerous sports in view of the bleeding tendency and a possibility of a traumatic injury to the liver.
• GSD type II: In the juvenile and adult forms, physical activity is not restricted. Activity is limited by the capacity of the patient's musculature.
• GSD types III and VI: Physical activity is not restricted.
• GSD types V and VII: Patients should be instructed to avoid physical activity.

MEDICATION

Section 7 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

No specific drug treatment is recommended for GSD type Ia. Appropriately treat concurrent infections with antibiotics. Allopurinol (Zyloprim), a xanthine oxidase inhibitor, therapy can reduce uric acid levels in the blood and prevent occurrence of gout and kidney stones in adult life.

Hyperlipidemia can be reduced by lipid-lowering drugs (eg, 3-hydroxy-3-methylglutaryl coenzyme A [HMG-CoA] reductase inhibitors, fibric acid derivatives). HMG-CoA reductase inhibitors of cholesterol biosynthesis in the liver are known as statins. Because of a high risk of myositis, the drugs may be recommended only after age 12 years. A new inhibitor of cholesterol absorption, ezetimibe, in a dose of 10 mg/d, can reduce low-density lipoprotein (LDL) cholesterol levels and has small triglyceride-lowering effects.

In patients with renal lesions, microalbuminuria can be reduced with angiotensin-converting enzyme (ACE) inhibitor therapy. In addition to their antihypertensive effects, ACE inhibitors are renoprotective and reduce albuminuria. Nephrocalcinosis and renal calculi can be prevented with citrate therapy.

Severe infection and chronic inflammatory bowel disease in patients with GSD type Ib should be treated with antibiotics and granulocyte-macrophage colony-stimulating factors (Neupogen).

Cardioglycosides and diuretics are prescribed for cardiovascular insufficiency in patients with GSD type II. Respiratory bacterial infections (aspiration pneumonia) in patients with GSD type II are treated with antibiotics. Enzyme replacement therapy has been approved as an orphan drug by the FDA.

No effective treatment is available for GSD types III, IV, V, and VII. Some patients with GSD type V may benefit from creatine supplement.

Drug Category: Iron salts

These agents correct iron deficiency.

Drug Category: Uricosuric agents

These agents reduce production of uric acid without disrupting the biosynthesis of vital purines.

Drug Category: Growth factors

These agents activate and stimulate production, maturation, migration, and cytotoxicity of neutrophils.

Drug Category: Glycogenolytic agents

These agents elevate blood glucose levels.

Drug Category: Angiotensin-converting enzyme (ACE) inhibitors

Reduce microalbuminuria, have antihypertensive effects, and are renoprotective.

Drug Category: Enzyme replacements

Recombinant human enzyme glucosidase alfa has recently been designated an orphan drug for GSD type II (Pompe disease).

FOLLOW-UP

Section 8 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Further Inpatient Care

• GSD type I: The primary goals are good control of hypoglycemia and other metabolic disturbances, such as hyperlactatemia, hyperuricemia, and hyperlipidemia.
• GSD type II: Further inpatient care is necessary in instances of respiratory insufficiency.
• GSD types V and VII: Hospital treatment is necessary during renal insufficiency due to rhabdomyolysis.

Further Outpatient Care

• GSD type I
• • After the initial diagnostic hospitalization, conduct further follow-up on an outpatient basis.
  • In infants and young children, follow-up is usually planned bimonthly. Examine the patient regularly for other metabolic disturbances, such as hyperlactatemia, hyperuricemia, and hyperlipidemia, in addition to glycemia. Check arterial blood pressure and renal function regularly.
  • Importantly, monitor for infections in patients with GSD type Ib.
  • In older children, perform liver ultrasonography at least once a year to rule out hepatic adenomas. When hepatic adenomas are found, commonly around the end of the second decade of life, close follow-up is necessary for early detection of possible malignant change.
• GSD type II
• • Counsel patients with juvenile and adult forms concerning possible complications and risks of respiratory disorders.
  • Provide genetic counseling for prenatal diagnosis in further pregnancies.
• GSD type III
• • Follow-up examination of glycemia and transaminase levels is indicated.
  • Follow-up with a cardiologist is required.
• GSD type IV
• • Regular checkup of liver function is indicated.
  • Genetic counseling concerning recurrent risks in future pregnancies is necessary.
• GSD types V and VII: Instruct patients to avoid strenuous physical activities.

Complications

• GSD type I
• • Bacterial infections and cerebral edema are caused by prolonged hypoglycemia and metabolic acidosis. Patients with GSD type Ib are susceptible to bacterial infections, including CNS infections.
  • Long-term complications encompass growth retardation, hepatic adenomas with a high rate of malignant change, xanthomas, gout, and glomerulosclerosis. Long-term complications result from metabolic disturbances, mostly hypoglycemia.
  • • Chronic metabolic lactic acidosis and changes in the proximal renal tubule cells can lead to osteopenia and rickets with severe skeletal deformities or bone fractures, particularly of the distal extremities. Such skeletal problems seriously impair the patient's mobility.
    • Elevated uric acid excretion along with segmental glomerular sclerosis gradually causes a decrease in the glomerular function with proteinuria, hematuria, arterial hypertension, and chronic renal failure. Because of incomplete distal tubular acidosis, a number of patients develop hypercalciuria, nephrocalcinosis, and calculosis. In a 2002 report, Mundy and Lee¹⁹ presented the hypothesis that GSD type I and diabetes mellitus share the common mechanism for renal dysfunction. This mechanism may be due to a convergence of their metabolic sequelae in upregulation of flux through the pentose phosphate pathway that yields triose phosphate molecules, which are precursors of the lipid diacylglycerol. Diacylglycerol plays an important role in the intrarenal renin-angiotensin system via the protein kinase C pathway.
    • Long-standing disease may be accompanied by hepatic adenomas prone to malignant alteration.
  • Other uncommon complications include vaso-obstructive pulmonary disease and chronic pancreatitis caused by hyperlipidemia.
  • Acute hypoglycemia may be fatal, and long-term complications include irreversible damage to the CNS.
  • Early death usually caused by acute metabolic complications (eg, hypoglycemia, acidosis), bleeding in the course of various surgical procedures (in all patients with GSD type I), and infections (in patients with GSD type Ib) is now uncommon with improving care and treatment.
  • Late complications, such as renal failure, hypertension, or malignant alteration of hepatic adenomas, may be responsible for mortality in adolescent and adult patients.
• GSD type II
• • Aspiration pneumonia may be a complication.
  • In the infantile form, progress