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Glycogen Storage Diseases Types I-VII Clinical Presentation

  • Author: Ljubomir Stojanov, MD, PhD; Chief Editor: William D James, MD  more...
 
Updated: Jul 23, 2014
 

History

See the list below:

  • 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.[10]
  • 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[9]
    • 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.
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Physical

See the list below:

  • 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). See the image below.
      An infant with glycogen storage disease type Ia. NAn infant with glycogen storage disease type Ia. Note the typical facial aspect resembling a doll's face.
    • 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. See the image below.
      A child with glycogen storage disease type Ia. A child with glycogen storage disease type Ia.
    • 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 al[11] 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.
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Causes

See the list below:

  • 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.
      • 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. 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 al[12] 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[13] 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[14] 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.
      • In 2007, Cheung et al[15] 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.
      • 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[13] 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 al[16] 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 al[17] 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,[18] 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.
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Contributor Information and Disclosures
Author

Ljubomir Stojanov, MD, PhD Lecturer in Metabolism and Clinical Genetics, University of Belgrade School of Medicine, Serbia

Disclosure: Nothing to disclose.

Coauthor(s)

Djordjije Karadaglic, MD, DSc Professor, School of Medicine, University of Podgorica, Podgorica, Montenegro

Djordjije Karadaglic, MD, DSc is a member of the following medical societies: American Academy of Dermatology, European Academy of Dermatology and Venereology, Serbian Association of DermatoVenereologists

Disclosure: Nothing to disclose.

Specialty Editor Board

David F Butler, MD Section Chief of Dermatology, Central Texas Veterans Healthcare System; Professor of Dermatology, Texas A&M University College of Medicine; Founding Chair, Department of Dermatology, Scott and White Clinic

David F Butler, MD is a member of the following medical societies: American Medical Association, Alpha Omega Alpha, Association of Military Dermatologists, American Academy of Dermatology, American Society for Dermatologic Surgery, American Society for MOHS Surgery, Phi Beta Kappa

Disclosure: Nothing to disclose.

Jeffrey Meffert, MD Associate Clinical Professor of Dermatology, University of Texas School of Medicine at San Antonio

Jeffrey Meffert, MD is a member of the following medical societies: American Academy of Dermatology, American Medical Association, Association of Military Dermatologists, Texas Dermatological Society

Disclosure: Nothing to disclose.

Chief Editor

William D James, MD Paul R Gross Professor of Dermatology, Vice-Chairman, Residency Program Director, Department of Dermatology, University of Pennsylvania School of Medicine

William D James, MD is a member of the following medical societies: American Academy of Dermatology, Society for Investigative Dermatology

Disclosure: Nothing to disclose.

Additional Contributors

Jacek C Szepietowski, MD, PhD Professor, Vice-Head, Department of Dermatology, Venereology and Allergology, Wroclaw Medical University; Director of the Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Poland

Disclosure: Received consulting fee from Orfagen for consulting; Received consulting fee from Maruho for consulting; Received consulting fee from Astellas for consulting; Received consulting fee from Abbott for consulting; Received consulting fee from Leo Pharma for consulting; Received consulting fee from Biogenoma for consulting; Received honoraria from Janssen for speaking and teaching; Received honoraria from Medac for speaking and teaching; Received consulting fee from Dignity Sciences for consulting; .

Acknowledgements

Milos D Pavlovic, MD, PhD Head of Immunodermatology, Professor, Department of Dermatology and Venereology, Military Medical Academy, Belgrade, Serbia

Milos D Pavlovic, MD, PhD is a member of the following medical societies: European Academy of Dermatology and Venereology

Disclosure: Nothing to disclose.

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An infant with glycogen storage disease type Ia. Note the typical facial aspect resembling a doll's face.
Glycogen storage disease type I. Abdominal sonogram showing large nodules in the liver.
A child with glycogen storage disease type Ia.
Glycogen storage disease type II. Photomicrograph of the liver. Note the intensively stained vacuoles in the hepatocytes (periodic acid-Schiff, original magnification X 27).
Glycogen storage disease type II. Photomicrograph of the liver. Note the regular reticular net and hepatocytes vacuolization (Gordon-Sweet stain, original magnification X 25).
 
 
 
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