Glycogen storage disease type I

Glycogen storage disease (GSD) type I, also known as von Gierke disease, is a group of inherited autosomal recessive metabolic disorders of the glucose-6- phosphatase system which helps maintain glucose homeostasis. Von Gierke described the first patient with GSD type I in 1929 under the name hepatonephromegalia glycogenica.[1] In 1952, Cori and Cori demonstrated that glucose-6-phosphatase (G6Pase) deficiency was a cause of GSD type I.[2] In 1978, Narisawa et al proposed that a transport defect of glucose-6-phosphate (G6P) into the microsomal compartment may be present in some patients with GSD type I.[3] 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. These subtypes are clinically indistinguishable from one another, except for the fact that 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.[4]

Glycogen storage disease type II

GSD type II, also known as alpha glucosidase deficiency (GAA, acid maltase deficiency) or Pompe disease, is a prototypic lysosomal disease. Pompe initially described the disease in 1932. Its clinical presentation clearly differs from other forms of GSD, because it is caused by the deficiency of the lysosomal enzyme, alpha-1,4-glucosidase, leading to the pathologic accumulation of normally structured glycogen within the lysosomes of most tissues, differs Three forms of the disease exist: infantile-onset, late-onset juvenile and adult onset. In the classic infantile for, the main clinical signs are cardiomyopathy and muscular hypotonia (smooth and skeletal muscle). In the juvenile and adult form, the involvement of the skeletal muscle dominates the clinical presentation.[5] The images below illustrate histologic findings of GSD type II.

Glycogen storage disease type III

GSD type III is also known as Forbes-Cori disease or limit dextrinosis. It is an autosomal recessive disorder in which there is an AGL gene mutations which causes deficiency in glycogen debranchinging enzyme and limited storage of dextrin. The disease presents with variable cardiac muscle, skeletal muscle and liver involvement and has different subtypes. GSD IIIa is the most common subtype, affecting about 85% of patients with this disease. GSD IIIb is less severe and less common, affecting 15% of patients with the disease.[6, 7]  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.[8]

Glycogen storage disease type IV

GSD type IV, also known as amylopectinosis, Glycogen Branching enzyme deficiency (GBE) 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.[9]  

Glycogen storage disease type V

GSD type V, also known as McArdle disease, affects the skeletal muscles. It is an autosomal recessive disorder in which there is a deficiency of glycogen phosphorylase.McArdle 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.[10, 11]

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.[12] Hepatic phosphorylase deficiency or deficiency of other enzymes that form a cascade necessary for liver phosphorylase activation cause the disease.[13] 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. Tarui reported the first patients in 1965. The clinical and laboratory features are similar to those of GSD type V.[14]

Medscape Reference Endocrinology articles on GSD

See the list below:

• Type Ia Glycogen Storage Disease

• Type Ib Glycogen Storage Disease

• Glycogen Storage Disease, Type II (Pompe Disease)

• Glycogen Storage Disease, Type III

• Type IV Glycogen Storage Disease

• Type V Glycogen Storage Disease

• Glycogen Storage Disease, Type VI

• Glycogen Storage Disease, Type VII

Glycogen storage disease type I

G6Pase is mainly found in the liver, kidneys and intestines to maintain glycogenolysis and gluconeogenesis. Because of insufficient G6Pase activity, G6P cannot be converted into free glucose, and instead is metabolized to lactic acid or incorporated into glycogen. The excess glycogen that is formed is stored as molecules with normal structure in the cytoplasm of hepatocytes, renal and intestinal mucosa cells. The excess storage of glycogen causes enlarged liver and kidneys, which dominate the clinical presentation of this disease. The chief biochemical alteration is non ketotic hypoglycemia, while secondary biochemical abnormalities are hyperlactatemia, metabolic acidosis, hyperlipidemia, and hyperuricemia which cause metabolic decompensation.[15]

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 acts hydrolyzing the alpha 1,4 and 1,6 glucosidic linkages of the glycogen molecule within the lysosome, hence, causes its degradation. In the GSD II, this enzyme is deficient, leading to the progressive accumulation of glycogen in the lysosomes and cytoplasm of different tissues causing its destruction.

GSD type 2 is an autosomal recessive disorder with significant heterogeneity. Multiple mutations in the gene encoding for the enzyme (17q25.2-q25.3) have been identified. These factors contribute to the different phenotypic presentation of the disease. 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.[16] Depending on the degree of residual enzyme activity, GSD type II manifests in infantile, juvenile, or adult forms. Mutations where the enzyme activity is minimal or absent (activity < 1% of normal control) leads to severe infantile onset form, develops. In cases where the enzyme activity is reduced(activity of 2-40%) then it presents as an early non classic onset or late onset. GSD II is progressive in all ages.[17]

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. This enzyme is located on the AGL gene on chromosome 1p21.It is inherited in an autosomal recessive fashion. Abnormal glycogen with short external branches is stored in the liver, heart, and skeletal muscle cells.[18]  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

GSD IV is an autosomal recessive disorder caused by the mutation of the GBE1 gene (3p14) in which there is deficiency or reduced activity of the glycogen branching enzyme. The glycogen branching enzyme (GBE) is an enzyme that catalyze the formation of α-1,6-glycosidic bonds to the linear α-1,4-glycosidic bonds that forms the skeleton of the glycogen molecule. In case of deficiency, abnormal glycogen is formed, with long linear α-1,4 polymers and less branches. The abnormal glycogen has long branches that resemble amylopectin. The importance of the presence of polymer branches, relies in the fact that it provides multiple free ends that are easily available to the amylase to break down glucose molecules during glycogenolysis. Accumulation of abnormally structured glycogen in the liver, heart, and neuromuscular system characterizes this disease. Different phenotypes have been identified, based on genetical heterogeneity: fatal perinatal neuromuscular subtype, congenital neuromuscular subtype, classic (progressive) hepatic subtype, non-progressive hepatic subtype and the childhood neuromuscular subtype.[19]  

Glycogen storage disease type V

GSD type V is an autosomal recessive disorder in which there is a deficiency of the enzyme glycogen phosphorylase. This enzyme is required in the first step of glycogen catabolism, where glycogen is released in G1P molecules. This leads to varying degrees of exercise intolerance secondary to affected muscle metabolism.[20]  During the early phase of moderate physical exertion, the principal sources of energy are glycogen and anaerobic glycolysis.[21] 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 and isometric 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

GSD type VI is an autosomal recessive disorder, caused by the deficiency of the hepatic glycogen phosphorylase, which is a rate-limiting enzyme that is necessary during glycogenolysis. It catalyzes the α1,4 glucosidic cleavage, releasing glucose 1-phosphate. Hepatic phosphorylase is activated in a series of reactions that requires adenylate cyclase, protein kinase A, and phosphorylase kinase (the cause of the GSD IX). 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).[22]

GSD type I

GSD type Ia

G6Pase deficiency is the cause of GSD type Ia. G6Pase is an enzyme that hydrolyzes glucose-6-phosphatase into free glucose and a phosphate group.Mutations in the transmembrane helices of the protein cause the most severe deficiency of enzyme activity.

Two different G6Pase enzymes are known. Glucose-6-phosphatase-alpha (G6Pase-alpha), located in the liver, kidney, and intestine, is solely responsible for the final stages of gluconeogenesis and glycogenolysis and for releasing glucose to the blood. Glucose-6-phosphatase-beta (Glc-6-Pase-beta) is also able to hydrolyze G6P to glucose and is an integral membrane protein in the endoplasmic reticulum. It contains 9 transmembrane domains, like G6Pase-alpha, but is ubiquitously expressed, similar to G6PT, and does not participate in blood glucose homeostasis between meals.

It seems that endoplasmic reticulum G6Pase-beta and G6PT complex is necessary for endogenous production of glucose during specific stress situations in some tissue cells, such as astrocytes, peripheral neutrophils, and bone marrow myelocytes.

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,most of which of missense/nonsense mutations.[23, 24] 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 Caucasians, 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 al[25]  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 al[26]  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 al 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.[27]

In 2007, Cheung et al suggested that the G6Pase-beta/G6PT complex might be functional in neutrophils and in myeloid cells. Therefore, defects in GSD-Ib might be a result of loss in activity of that complex, leading to an increasing rate of neutrophil apoptosis and impairment of hematopoiesis in the bone marrow, with neutropenia and increasing susceptibility to bacterial infections as a consequence.[28]

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 al 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.[26]

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 al confirmed that GSD type Ic is allelic to GSD type Ib.[29]

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  (GAA) coded on bands 17q21.2-q23 causes GSD type II. The GAA 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, mostly in Asian populations, are homozygous for a pseudodeficiency allele [c.1726 G>A (p. Gly576Ser)].[30]

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. Further research is needed to determine whether certain mutations may be associated with particular variants of the disease.

GSD type V

Myophosphorylase (glycogen phosphorylase) 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. The PYGM gene, located on 11q13 codes for myophosphorylase and most mutations are found between exon 1 to 17. More than 50% of the gene mutations found have been missense.[31]  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 al 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.[32]

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.[12]

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,[33]  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.

United States statistics

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 20,000-43,000 live births.[18]

GSD type 1 is the most common type of GSD which accounts for 24.6% of all patients with GSD. 80% of cases of GSD type 1 are classified as type 1a. 

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 with an overall incidence of approximately 1:600,000-1:800,000.

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

GSD type VI is a rare condition, probably due to underdiagnosis. GSD IV and GSD IX (enzymes that regulate liver phosphorylase) accounts for 25%- 30% of all patients with GSD. Prevalence is estimated of 1:100,000. Most of these are GSD IX. 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 statistics

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.

Race-, sex-, and age-related demographics

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. Median age of disease onset is between the 3rd and 4th month. 

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 of age. There are case reports of the disease in babies shortly after birth, but this presentation is rare. 

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.

GSD type I

The prognosis is better than in the past provided that all the available dietary and medical measures are implemented.

GSD type II

Without treatment, the prognosis in the infantile form is poor.

The prognosis varies in the juvenile form.

The prognosis is relatively good in the adult form

GSD type III

The prognosis of GSD III is better than that of GSD I with many patients surviving into adulthood. GSD IIIb is a milder form of the disease, while the prognosis of GSD IIIa depends largely on the extent of cardiac involvement. 

GSD type IV

The prognosis is poor. Most children with GSD type IV die by age 2-4 years because of hepatic insufficiency.

GSD types V and VII

The prognosis varies.

GSD type VI

The course is benign.

The size of the liver decreases with age and returns to baseline at or around puberty.

All the patients attain normal height.

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, myoglobinuria from repeated prolonged exercise may eventually lead to renal failure and death.[20]

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.

Patients with GSD can present with decreased bone mass and may ultimately suffer from fractures. Thus, in the adult population, bone density evaluation is recommended early enough so that patients can be treated adequately and in a timely manner.[34]

GSD type I

Long-term complications for GSD type 1a and 1b include the following[35] : 

• Renal: Later complications of disease include renal function disturbances including nephrocalcinosis, hematuria, proteinuria and hypertension. Nephromegaly is seen secondary to glycogen deposition in the kidney. Renal insufficiency may progress to end stage renal disease, requiring dialysis and transplantation. ^[36]
• Neurocognitive Deficits: Patients with GSD have normal IQ, but because of frequent hypoglycemic episodes, brain function is altered. 
• Anemia
• Bleeding Diathesis: Some patients may bleed easily, usually in the form of epistaxis, easy bruising, or heavy menses. Caution is to be taken during surgical procedures. This tendency is a result of altered platelet function, due to reduced or dysfunctional von Willebrand factor. 
• Osteoporosis: Bone mineral density can be severely reduced in more than half the patients with GSD type 1 mainly because of lack of vitamin D in the diet. These patients are very susceptible to fractures secondary to osteopenia or osteoporosis
• Pancreatitis: This is a consequence to hypertriglyceridemia
• Hepatic Adenomas: hepatic adenomas are common findings in older adults (in 20s-30s). Complications arising from adenomas are intrahepatic hemorrhage and malignant transformation into hepatocellular carcinoma. 

In addition to the above complications, patients with GSD Ib exhibit further complications secondary to neutrophil dysfunction. This includes recurrent infections, inflammatory bowel disease/enterocolitis, thyroid autoimmunity and hypothyroidism.[15]

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.

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 Lee[37]  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.

GSD type II

Aspiration pneumonia may be a complication.

In the infantile form, progressive cardiorespiratory insufficiency usually causes death by the end of the first year of life.

In the juvenile form, 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.

In the adult form, death due to respiratory insufficiency (eg, sleep apnea) may occur many years after the first signs of the disease have appeared.

Patients treated with enzyme replacement therapy are at risk of fractures, facial muscle weakness, dysphagia, and speech disorders. 

GSD type III

The cirrhosis found in some patients is of a mild degree and does not have a significant impact on the course of the disease. Patients can also develop hepatic adenomas which increases the risk of hepatocellular carcinoma. Muscle weakness and hypotonia is more prominent in adults with GSD IIIa, in contrast to children secondary to progression of muscle disease. Also in patients with GSD IIIa, cardiac involvement is seen in the first decade of life, usually in the form of hypertrophic cardiomyopathy and usually remains stable during the patient's life if patient is being treated appropriately. Progression to severe cardiomyopathy is less often seen but can cause severe heart failure and fatal arrhythmias (sudden death).[7]

Growth retardation may be seen in infancy and childhood, but usually reach normal levels at adolescence. Patients usually achieve normal adult height. An increased incidence of Type 2 diabetes mellitus is also being reported in patients with GSD III secondary to increased insulin resistance from constant carbohydrate enriched nutrients to induce euglycemia (same article as above). [7]

GSD type IV

In 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. Rarely, children with GSD type IV may survive longer.

Fetal hydrops and intrauterine leg contractures may be found in more severe forms.

Liver cirrhosis is not always progressive.

Moderately severe variants exist, and affected children survive longer and with predominantly muscular lesions.

GSD type VI

Serious complications are unknown.

GSD types V and VII

Renal insufficiency caused by myoglobinuria may occur. Patients with GSD type V need to take precaution with general anesthesia as it may cause acute rhabdomyolysis and myoglobinuria resulting in possible acute renal failure.[20]

GSD type I

First, instruct parents, and later adult patients, concerning the measures required to control hypoglycemia and other metabolic abnormalities; such measures include proper care and nutrition.

Explain the important role played by continuous overnight feeding by means of a nasogastric tube. Teach parents to place the tube by themselves and control the entire feeding process.

GSD type I

The earliest signs of disease may develop shortly after birth and are usually symptoms of hypoglycemia. Patient's may present with irritability, pallor, cyanosis, hypotonia, tremors, loss of consciousness, apnea and seizures. The median age of symptom presentation is usually four to six months. 

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 and heart failure. Muscle weakness progresses rather rapidly, manifesting as respiratory and feeding difficulties.  An early onset “nonclassic” phenotype has also been described in these cases, hypotonia without cardiomyopathy develops during the first and second year of life.

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.[38]

GSD type III

The first manifestations of the disease usually appear in infants one year of age, although in milder variants, the onset may be delayed into childhood. The symptoms are much less severe than in GSD type 1, and only about half of the patients present with severe hypoglycemia. Hepatomegaly is the most common presenting symptom on routine examination which then prompts further investigation. Other signs such as growth retardation, hyperlipidemia and fasting ketotic hypoglycemia can also be seen.[7, 18]

Liver disease is less common in adolescents and adults. In childhood, weakness and muscle fatigue secondary to skeletal myopathy is less prominently seen. This is in contrast to adulthood where muscle weakness is more commonly seen because of progression of muscle damage and disease . Cardiovascular abnormalities can further dominate the clinical presentation of the disease depending on severity of cardiac involvement. Patients with GSD IIIa may present with hypertrophic cardiomyopathy in which the disease course can range from asymptomatic to severe.[6]

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. (see physical)

GSD type V

The classic form appears in persons aged 10-20 years, most in first decade of life. Degree of exercise intolerance varies per individual. Symptoms are usually exacerbated with sustained aerobic or isometric exercise.[20]  Patients commonly report fatigue during physical exertion, muscle cramps, and later, muscle weakness and burgundy red–colored urine. Patients with GSD type V may also present with the "second wind phenomenon" in which patients have quick relief of muscular fatigue with rest and are then able to resume physical activity without significant symptoms.[20]

GSD type VI

Symptoms, if present, are minimal. Often, patients seek help for retarded growth and prominent hepatomegaly. Hypoglycemia ranges from mild to severe, with ketotic hypoglycemia after fasting. Hypoglycemia can present during pregnancy. 

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.[22]   

Attacks of rhabdomyolysis may be associated with nausea and vomiting, and more often than not, a meal rich in carbohydrates is consumed beforehand.

GSD type I

A leading sign of GSD type I is enlargement of the liver and kidneys. Enlargement of the abdomen due to hepatomegaly can be the first sign noted by the patient's mother. During the first weeks of life, the liver is normal size.It enlarges gradually thereafter, and in some patients, it even reaches the symphysis.  

Because of fat deposition in the cheeks, patient's characteristically resemble a doll's face. See the image below. 

Mental development proceeds normally.

Growth failures, as described as short stature and thin legs, are commonly seen in children affected by GSD type 1. Affected children 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. See the image below.

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 al[39]  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.

Risk factors and adverse events are as follows:

• Foods rich in fructose, galactose, and triglycerides adversely affect the long-term complications caused by lactic acidosis, hyperuricemia, and hyperlipidemia.

• Hypoglycemia and infections are frequent.

GSD type II

Heavy deposits of glycogen in the heart, liver, and tongue characterize the infantile form; as a result of the deposits, these tissues enlarge.

Conspicuous cardiomegaly with cardiomyopathy and heart failure may be present. Macroglossia, tongue fasciculation and moderate hepatomegaly may be noted.

Generalized severe hypotonia and muscle weakness that involves skeletal and respiratory muscles, as well as. delayed motor milestones, feeding and swallowing difficulties are characteristics.  The affected skeletal muscles are firm on palpation and, occasionally, hypertrophic. In some patients. Signs of respiratory insufficiency are due to the involvement of respiratory musculature. Spontaneous movements are scarce, and painful stimuli cause weak motor reactions. Tendon reflexes are diminished or absent. Mental functions are retained.

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.

Juvenile form

Respiratory insufficiency and hypotonia largely of the proximal musculature are present. Macroglossia, cardiomegaly, cardiomyopathy, and hepatomegaly usually are absent.

Adult form

Proximal muscle weakness (difficulty rising from a chair or climbing stairs). Muscle volume is decreased, and tendon reflexes are diminished.  Waddling gait, Gower sign, Trendelenburg sign are seen, the visceral organs are not affected; however, intracranial aneurysms are possible because of glycogen deposits in the smooth muscle cells of the cerebral arteries. Cardiomyopathy is not a feature of the adult form. 

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 is enlarged. In some children, growth retardation, renal tubular dysfunction, liver adenomas, liver cirrhosis can be observed.

GSD type IIIa is more common (approximately 85%) and prognostically more unfavorable than other forms. Hepatomegaly and/or splenomegaly are present with elevated liver transaminases. Muscular weakness and atrophy, particularly of the girdle and limb musculature, may be observed. Cardiomegaly and cardiomyopathy may occur which can lead to heart failure and possibly sudden death.Cardiac and skeletal muscle abnormalities 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

Presentation varies depending on the mutation, however, 5 frequent subtypes have been identified:[19]

Hepatic predominant forms:

• Classic (progressive) hepatic subtype. Failure to thrive, hepatomegaly, liver dysfunction, progressive liver scarring with portal hypertension, ascites, and esophageal varices, jaundice, hypotonia, and cardiomyopathy. Hypoglycemia may develop later in the course of the disease. Disease is evident during the first 18 months of life. Death typically by age five years from liver failure
• Non-progressive hepatic subtype. Liver dysfunction, myopathy, and hypotonia in childhood.

Neuromuscular predominant forms:

• Fatal perinatal neuromuscular subtype. Presents in utero with fetal akinesia deformation sequence (FADS):  Decreased fetal movements, multiple contractures, polyhydramnios, hydrops fetalis, hypotonia, cardiac dysfunction and perinatal death. 
• Congenital neuromuscular subtype. Presents with severe hypotonia at birth, respiratory distress, dilated cardiomyopathy, weakness, muscle atrophy and early infantile death. 
• Childhood neuromuscular subtype. Presents with skeletal myopathy (weakness, fatigue, exercise intolerance, atrophy), and occasionally with dilated cardiomyopathy, arrhythmias and heart failure.
• Adult Polyglucosan body disease. Rare variant, presents with upper and lower motor neuron symptoms, urinary incontinence, sensory deficits, gait disturbances, autonomic dysfunction and cognitive impairment.

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.

Myoglobinuria from repeated strenuous exercise 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.

No intellectual abnormalities.

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.

GSD type I

Hypoglycemia (serum glucose < 60mg/dL), lactic acidosis (blood lactate >2.5 mmol/L), hyperuricemia (uric acid >5.0 mg/dL), hypertriglyceridemia (triglyceride level >250 mg/dL), and hypercholesterolemia (cholesterol level >200 mg/dL) are present in patients with GSD type 1.  Urea and creatinine levels might be elevated when renal function is impaired.[35]  The following laboratory values should be obtained:

• Serum glucose and electrolyte levels (Higher anion gap [also see the anion gap calculator] may suggest lactic acidosis.)

• Serum lactate level

• Blood pH

• Serum uric acid level

• Serum triglyceride and cholesterol levels (see HDL cholesterol and LDL cholesterol)

• 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. Serum creatinine kinase (CK), lactic dehydrogenase and aspartate aminotransferase can be elevated.

Molecular diagnosis:

Definitive diagnosis requires measurement of the activity of acid alpha-1,4-glucosidase in the whole blood or dried blood spots, This assay should be use as initial test.[41, 42]  Gene sequencing is used to confirm diagnosis, two pathogenic mutations in the GAA gene is considered confirmatory.[42]  In case of indeterminate results, enzyme activity can be measure in skin fibroblast or muscle samples.

Urine glucose tetrasaccharide (Glc(4)) can be use adjunctive diagnostic test, moreover for monitoring of effect of enzyme replacement therapy.

Newborn screening is still under investigation. Studies have tried to demonstrate advantages of screening, even though the incidence of GSD II in screened and unscreened population was similar. Those screened were diagnosed and treated earlier.[43, 44, 45]

GSD type III

Fasting hypoglycemia and ketonuria may be noted.

Hyperlipidemia may be present.

Serum aminotransferase and CK levels may be elevated. Normal 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

Liver function test:  Serum aminotransferase levels are elevated. Synthetic function of the liver is also affected: elevated PTT, PT and hypoalbuminemia can be seen as liver failure progress.  Fasting hypoglycemia is present in some patients.  In neuromuscular variants CK is elevated. 

In skin fibroblast cultures, muscle and liver tissues, glycogen branching enzyme activity (GBE assay) can be measured. 

Molecular testing and GBE Assay after histologic work-up is indicated:  identification of biallelic pathogenic variants in GBE1 gene, makes the diagnosis of GSD Type IV.  If biopsy cannot be performed genetic testing or GBE assay can be performed in the setting of high suspicion of disease. 

In families with prior history of GSD type IV, carried testing should be performed.  Prenatal diagnosis can be done by culture of amniocytes.[40]

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.

Molecular gene testing of PYGM is to confirm diagnosis of GSD type V. If genetic diagnosis is unclear, myophosphorylase enzyme activity assay can confirm the diagnosis as well. [46]

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. CK is normal. Uric acid and lactic acid are normal, however post prandial lactic acidosis has also been described. Glucose does not increase after glucagon administration. Biotinidase activity is elevated. 

Molecular testing is the preferred method for diagnosis,  testing of PYGL, is diagnostic.  Enzyme assay are available but low specificity. 

Molecular testing is recommended in families with known mutations, to provide early treatment. 

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.

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, liver ultrasonography should be performed every 12-24 months in patients less than 16 years of age. In adults, imaging of the liver, in the form of CT or MRI should be performed at least every 12 months. 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.[47]  Abdominal CT scanning or MRI is advised whenever the lesions are large, poorly defined, or are growing rapidly. See the image below.

 

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 type IV abdominal ultrasound reveal enlarged, fibrotic or cirrhotic liver. 

In GSD types V and VII, MRI with phosphate-31 is a noninvasive method for the investigation of muscle metabolism.

In GSD type VI, ultrasound is performed for liver measurement and to rule out hepatic adenoma. Bone scan should be performed once the patient stops growing, 

GSD type I

Glucagon or epinephrine challenge test causes little to no increase in glucose levels, but plasma levels of lactic acid are significantly raised.[35]

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.

In pulmonary function test, the force vital capacity is usually reduced.

Genetic counseling and carrier testing is advised to affected families. 

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 IV

Glucose tolerance test results are in the reference range.

Glucagon and epinephrine test results vary.

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.

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.

If the presence of the mutations is known in the family, 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.

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.

A liver biopsy may reveal chronic histologic changes of varying severity despite mild disease. All GSDs may exhibit these findings on liver biopsy. Hence, definitive classification requires a mutational analysis.[48]

In GSD type I, no specific findings occur in the liver, but higher amounts of normal glycogen, as well as fatty infiltration, are found. There may be distention of hepatocytes due to glycogen and lipid deposition. In GSD type I, liver fibrosis and cirrhosis do not occur.[35]  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. In a  muscle biopsy under a light microscope and hematoxylin and eosin staining, a “lace-work pattern can be identified. On periodic acid-Schiff staining, muscle fibers stain strong in infantile form. Under the electron microscope, muscle biopsies show vacuolar myopathy with glycogen storage in lysosomes and free glycogen in the cytoplasm, however, failure to identify this finding cannot rule out the diagnosis. 

See the images below.

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 IV, biopsy of the liver and muscles shows enlarged, PAS- positive hepatocytes, and diastase -resistance inclusions. In the liver, foamy histiocytes in the reticuloendothelial system can also be seen. Interstitial fibrosis is also present, Fibrillar aggregates of amylopectin-like material are seen under a electron-microscope. 

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.

GSD type I

There is no specific treatment available for patients with GSD type I. Symptomatic therapy is the mainstay of medical care. The primary goals are good control of hypoglycemia and other metabolic disturbances, such as hyperlactatemia, hyperuricemia, and hyperlipidemia.[49, 50]  Maintaining nutritional support for these patients is crucial. It helps to prevent hypoglycemia and support growth and development.[35]

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.[51, 52]

Prevention of gouty attacks is important in the event dietary modifications fail to lower uric acid levels. Allopurinol is used to prevent these events. Renal protection is also very important. Urinary calculi are also commonly seen, and supplementation with citrate can help prevent renal calculi from forming. Angiotensin-converting enzyme (ACE) inhibitors may also be utilized to treat microalbuminuria.[35]

Frequent infections in patients with GSD type Ib require intravenous therapy to correct hypoglycemia and intensive intravenous antibiotic treatment to control infections. Patients may even require granulocyte colony-stimulating factor (G-CSF) if infections are recurrent to help boost the immune system. 

Lipid control is also important with lipid lowering therapy, such as statins. This helps to avoid pancreatitis and atherosclerotic disease.[35]

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.[53, 54, 55, 56]

A study by Zhang et al postulates that modulation of hepatic autophagy may be a viable target for future therapies. This group tested a recombinant adeno-associated virus (rAAV) vector that introduces an amino acid substitution into the existing G6PC gene sequence, which allowed G6PC -/- mice to survive long term. This may translate into viable genetic therapy based on the rAAV vector for human patients in the future.[57]

A CRISPR/Cas-9 based genome editing therapy was tested in mice to target a G6PC-p.R83C variant that is prevalent in humans. The study showed that treated mice had increased G6Pase activity to >3% and tolerated longer periods of fasting, which may lead to the development of genetic therapy for GSD Ia.[58, 54]

Although this disease can be overwhelming, a survey showed that patients can live an independent life and they cope with daily activities very well.[59]

GSD type II

Enzyme replacement therapy (ERT)

At present, effective specific treatment for infantile and adult form can be achieved using recombinant DNA alglucosidase alfa (Myozyme®, Lumizyme®), which degrades lysosomal glycogen. On the basis of clinical trials, treatment with ERT markedly improves survival and ventilator-free survival in patients with infantile-onset Pompe disease, especially if therapy is started before muscle damage. Alglucosidase alfa may be administered by intravenous infusion only.[60, 61]  The recommended dosing 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.

Approximately 20% of patient with infantile form lack cross-reactive immunologic material (CRIM-), no endogenous acid alpha glucosidase enzyme is produced, IgG against the exogenous enzyme can be produced, hence ERT is ineffective. For this, immunomodulation protocols with rituximab and methotrexate with or without intravenous immunoglobulin have been developed, to prevent and eliminate immune response, giving CRIM- patient the opportunity to receive ERT. Knowing CRIM status previous to initiation of therapy is important to improve outcomes.[62, 63]

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.

Experimental therapies

Gene therapy is an encouraging mode of treatment but is not yet available. However, in 2002, Martin-Touaux et al 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.[64] 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. Other models are trying to restore the ability of producing the enzyme by transducing the normal gene in the liver or in stem cells.

Exercise therapy, by inspiratory muscle strengthening is also under study, diaphragm pacing has potential rehabilitative to decrease the need of mechanical ventilation.

Other therapies

Respiratory muscle weakness develops, hence, patients are at high risk of infections and respiratory insufficiency, for this, respiratory therapy and noninvasive ventilation (CPAP, BiPAP) can ameliorate symptoms

Physical therapy is necessary not only to develop motors skills and to prevent contractures, but to strengthen respiratory muscles and to manage airway secretion (percussion, suctioning)

Occupational therapy may assist the patient to remain independent, orthopedic braces or surgical intervention may be necessary to alleviate scoliosis and muscle contractures to alleviate pain and/or disability. Audiology testing and sleep studies are warranted in these patients. 

GSD type III

No specific therapy exists. The treatment is somewhat simpler than that of GSD type I. In infancy, high protein diet and frequent feedings every 3-4 hours are required to maintain euglycemia. After the age of 1, patients may transition to cornstarch (1-3g/kg three times daily) and protein (3g/kg) if tolerated and maintaining euglycemia overnight.[6]  Proof that frequent protein meals and overnight nasogastric infusion of proteins can prevent progressive myopathy is not conclusive.

A study by Lim et al demonstrated improvement of GSD III clinical findings using a recombinant adenoviral vector in mice. These findings suggest that corrective gene therapy for GSDs may be possible in humans.[65]

GSD type IV 

Treatment is based on the symptoms. The ultimate treatment is liver transplantation. The prognosis even after liver transplant is poor, due to other systemic comorbidities. 

No medication is necessary.

GSD type V 

No specific therapy is available. Hospital treatment is necessary during renal insufficiency due to rhabdomyolysis. In GSD type V, moderate intensity aerobic exercises should be performed. To increase exercise tolerance and reduce the risk of rhabdomyolysis, simple carbohydrates (sports drinks) are utilized. To prevent symptoms of GSD type V and to avoid rhabdomyolysis, avoiding isometric and maximal aerobic exercise is required.[20]

GSD type VI 

Patients with hypoglycemia should have frequent small meals. Uncooked cornstarch can be used between meals and at bedtime. Delayed puberty, osteoporosis, and short stature can be prevented with good metabolic control, avoiding episodes of hypoglycemia.

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.

In the setting of hepatic adenomas, interventions such as percutaneous ethanol injections and radiofrequency ablation have been utilized in lieu of surgery.[35]

GSD type III

Liver transplantation is not commonly performed in patients with GSD type III. It is usually for patients with severe liver cirrhosis or hepatocellular carcinoma.[6]

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.

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
• Orthopedics for contractures and scoliosis and other musculoskeletal complications
• Nutritionist, physical therapy, speech therapy

GSD type IV

• Cardiology
• Neurology
• Genetics
• Nutrition
• Child development
• Hepatology

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 Mochel reported a clinical benefit with anaplerotic diet therapy in an adult-onset GSD type II patient with skeletal muscle weakness.[66] 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 al from 2006, triheptanoin may be safely administered intravenously for the treatment of decompensated, energy-depleted patients.[67]

In adult form, high protein, low carbohydrate diet with exercise can slow the progression of the muscle dysfunction. 

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. See section on "medical care" for further details. 

GSD type IV

A specific diet is not available. Hypoglycemia should be corrected. A balanced diet favorably influences liver disease.

GSD type V

To increase exercise tolerance and reduce the risk of rhabdomyolysis, simple carbohydrates (sports drinks) are utilized. 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. Studies have shown that patients who followed a low-carbohydrate ketogenic diet had improvement in exercise tolerance. This diet may bypass glycolysis blockage and provide an immediate fuel source that improves normal muscle function.[68, 69]

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. Avoid contact sports when hepatomegaly is present. 

GSD types V and VII

Patients should be instructed to avoid maximal aerobic exercise. In GSD type V, moderate aerobic exercise is beneficial for cardiorespiratory and muscle oxidative capacity.[20]

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. Laboratory testing, such as liver function tests, PT/INR, renal function tests are to be performed every 6-12 months. 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. As per guidelines from the American College of Medical Genetics and Genomics, liver ultrasound should be performed every 12-24 months until age of 16. Liver CT/MRI is to be performed every 6-12 months if the patient has hepatic adenomas.[35]

Importantly, monitor for infections in patients with GSD type Ib. For patients on G-CSF therapy, complete blood count should be performed every 3 months. Routine splenic imaging should also be performed to monitor size of the spleen for patients on G-CSF.[35]

Pulmonary hypertension screening is to be performed in patients after the age of 10 in the form of echocardiography. It should be done every 3 years.[35]

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.

GSD type VI

Liver ultrasound for tumor surveillance should be performed annually starting at age 5. 

Annual measurement and monitor of growth is recommended. 

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.

Class Summary

These agents correct iron deficiency.

Ferrous sulfate (Feosol, Feratab, Fer-Iron)

Ferrous sulfate is used to control anemia in patients with GSD types Ia or Ib.

Class Summary

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

Allopurinol (Zyloprim)

Allopurinol is used to control elevated serum uric acid levels in patients with GSD types Ia or Ib.

Class Summary

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

Filgrastim (Neupogen)

Filgrastim is a granulocyte colony-stimulating factor used in patients with GSD type Ib with severe infections, in those with pseudocolitis, and in patients as a preventive measure.

Class Summary

These agents elevate blood glucose levels.

Glucagon (GlucaGen)

Glucagon is used to treat GSD types V and VII. Pancreatic alpha cells of the islets of Langerhans produce glucagon, a polypeptide hormone. It exerts opposite effects of insulin on blood glucose. Glucagon elevates blood glucose levels by inhibiting glycogen synthesis and by enhancing the formation of glucose from noncarbohydrate sources such as proteins and fats (gluconeogenesis). It increases the hydrolysis of glycogen to glucose (glycogenolysis) in the liver in addition to accelerating hepatic glycogenolysis and lipolysis in adipose tissue. Glucagon also increases the force of contraction in the heart and has a relaxant effect on the GI tract.

Class Summary

These agents reduce microalbuminuria, have antihypertensive effects, and are renoprotective.

Lisinopril (Prinivil, Zestril)

Lisinopril prevents the conversion of angiotensin I to angiotensin II and lowers aldosterone secretion; in some patients, it may cause cough and angioedema.

Ramipril (Altace)

Ramipril prevents the conversion of angiotensin I to angiotensin II, a potent vasoconstrictor, resulting in lower aldosterone secretion.

Captopril (Capoten)

Captopril prevents the conversion of angiotensin I to angiotensin II, resulting in lower aldosterone secretion.

Enalapril (Vasotec)

Enalapril is a competitive inhibitor of ACE. It reduces angiotensin II levels, decreasing aldosterone secretion.

Class Summary

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

Alglucosidase alfa (Myozyme)

Alglucosidase alfa is a recombinant human enzyme alpha-glucosidase (rhGAA) indicated as an orphan drug for the treatment of Pompe disease. It replaces rhGAA, which is deficient or lacking in persons with Pompe disease. Alpha-glucosidase is essential for normal muscle development and function. Alglucosidase alfa binds to mannose-6-phosphate receptors and then is transported into lysosomes; it undergoes proteolytic cleavage that results in increased enzymatic activity and the ability to cleave glycogen. It improves infant survival without requiring invasive ventilatory support compared with historical controls without treatment.