AUTHOR INFORMATION

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Authored by Lynne Ierardi-Curto, MD, PhD, Former Clinical Assistant Professor of Pediatrics, University of Medicine and Dentistry of New Jersey; Former Chief, Division of Clinical Genetics, Robert Wood Johnson University Hospital

Lynne Ierardi-Curto, MD, PhD, is a member of the following medical societies: American Society of Human Genetics

Edited by Edward Kaye, MD, Vice President of Clinical Research, Genzyme Corporation; Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc; Hagop Youssoufian, MSc, MD, Medical Director, Adjunct Associate Professor, Clinical Discovery Department, Bristol-Myers Squibb; Paul D Petry, DO, FACOP, FAAP, Clinical Assistant Professor of Pediatrics, University of North Dakota, School of Medicine and Health Sciences; Consulting Staff, Altru Health System; and Bruce A Buehler, MD, Professor, Department of Pathology and Microbiology, Chairman, Department of Pediatrics, Director, Hattie B Munroe Center for Human Genetics, University of Nebraska Medical Center

Author's Email:	Lynne Ierardi-Curto, MD, PhD
Editor's Email:	Edward Kaye, MD

eMedicine Journal, March 27 2006, VOLUME 7, Number 3

INTRODUCTION

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Background: Glycogen-storage disease type IV (GSD IV), also known as Andersen disease, has a classic presentation of hepatosplenomegaly and failure to thrive during the first year of life, followed by progressive liver cirrhosis with portal hypertension and death, usually by the age of 5 years. The disorder is characterized by the appearance of abnormal, relatively insoluble glycogen with long, unbranched outer chains resulting from defective glycogen-branching enzyme activity. GSD IV is actually a clinically heterogeneous disorder with variable age of onset, specific organ involvement, severity of symptoms, and degree of accumulation of abnormal glycogen in different tissues. Hypoglycemia is not a common feature of GSD IV.

Progressive liver cirrhosis characterizes the classic form of GSD IV. Patients with nonprogressive liver disease and later onset represent a milder variant. In addition to these hepatic forms, four neuromuscular forms of GSD IV recently have been identified. A congenital neuromuscular form and childhood neuromuscular form involve isolated or predominant muscle involvement with the development of myopathy or cardiomyopathy at birth or during childhood, respectively. A perinatal form is distinguished by severe neuromuscular involvement and death. Finally, a subset of patients with clinically diagnosed Adult Polyglucosan Body Disease (APBD) have deficient glycogen-branching enzyme activity and diffuse CNS and peripheral nervous system dysfunction.

Pathophysiology: Deficient glycogen-branching enzyme activity results in the formation of abnormal glycogen with long, unbranched outer chains and decreased solubility. Although glycogen concentration in tissue usually is not increased, the presence of insoluble glycogen could induce foreign-body reactions and lead to cellular injury and organ dysfunction. Patients with progressive liver disease ultimately develop cirrhosis and end-stage liver failure. Most of these patients develop portal hypertension and associated complications of portosystemic blood shunting as follows:

• Esophageal varices

• Encephalopathy

• Splenomegaly

• Ascites

• Renal dysfunction

Progressive decline in hepatic functional capacity also occurs, including the following conditions:

• Decreased albumin synthesis

• Decreased vitamin K–dependent coagulation factors

• Decreased fibrinogen

• Decreased urea level

• Decreased clearance of drugs, bilirubin, bile acids, and waste nitrogen

• Abnormal steroid metabolism

• Impaired blood glucose maintenance

Abnormal glycogen in skeletal muscles may cause weakness, exercise intolerance, and muscle atrophy. Patients with cardiac involvement develop dilated cardiomyopathy and symptoms of progressive heart failure. In the nervous system, abnormal glycogen may lead to impaired cognition and both neuromuscular and neurovisceral dysfunction.

Frequency:

• Internationally: GSD IV represents an uncommon form of glycogen-storage disease. The frequency of all forms of glycogen-storage disease is 1 case in 20,000-25,000 persons; type IV represents approximately 3% of all cases.

Mortality/Morbidity:

• Classic GSD IV causes progressive liver cirrhosis and death in children by the age of 5 years unless a liver transplant is performed. The perinatal form of the disease invariably is fatal. Patients with cardiomyopathy often develop progressive heart failure, which may lead to death despite medical and surgical intervention.

• Patients with nonprogressive liver disease usually retain some hepatic function and do not require liver transplantation. An increased risk of hepatocellular adenoma and one case of hepatocellular carcinoma has been reported.

• Neuromuscular dysfunction, though not life-threatening, may be progressive and debilitating.

Race: A subgroup of patients, primarily people of Ashkenazi Jewish origin, have clinically diagnosed polyglucosan body disease and decreased glycogen-branching enzyme activity.

Sex: Both sexes are affected equally because the deficiency of glycogen-branching enzyme activity is inherited as an autosomal-recessive trait.

Age:

• GSD IV in its classic form presents during the first year of life with hepatosplenomegaly and failure to thrive. Patients with nonprogressive liver disease may present later in childhood.

• The perinatal form of GSD IV presents in utero or immediately after birth.

• GSD IV variants with predominantly nerve, muscle, or cardiac involvement may have onset ages ranging from early infancy through adulthood.

CLINICAL

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History:

• The classic presentation of GSD IV is development of hepatosplenomegaly and failure to thrive during the first year of life.



• Patients with progressive liver cirrhosis and associated portal hypertension also may present with the following:


• • Pruritus

  • Fatigue

  • Anorexia
  
  
  
  • Weakness

  • Jaundice
  
  
  
  • Peripheral edema
  
  
  
  • Epistaxis
  
  
  
  • Easy bruising and bleeding
  
  
  
• Hepatic encephalopathy may cause lethargy, disorientation, or coma. Patients may present with hematemesis from bleeding esophageal varices.



• Mildly affected patients with nonprogressive liver disease or early liver cirrhosis may be asymptomatic.



• The perinatal form of GSD IV may include a history of fetal hydrops, cervical cystic hygroma, decreased in utero fetal movements, and severe hypotonia at birth or death in the neonatal period.



• Patients with muscle involvement may present with muscle weakness, fatigue, and muscle atrophy.



• Patients with GSD IV whose conditions involve associated dilated cardiomyopathy may present with the following:


• • Failure to thrive
  
  
  
  • Fatigue
  
  
  
  • Irritability

  • Anorexia and feeding problems

  • Diaphoresis

  • Dyspnea

  • Orthopnea

  • Edema
  
  
  
• Patients with central and peripheral nerve involvement (eg, APBD) may present with the following:


• • Muscle weakness
  
  
  
  • Fatigue
  
  
  
  • Gait disturbances

  • Voiding difficulties (eg, neurogenic bladder)
  
  
  
  • Peripheral neuropathy

  • Mild cognitive impairment and dementia
  
  
  

Physical:

• Physical examination of patients with the classic form of GSD IV shows evidence of liver failure and portal hypertension.

• Patients with other forms of GSD IV present with symptoms of affected organ or tissue dysfunction, including the heart, peripheral muscle, or CNS and peripheral nervous systems.

• Failure to thrive and growth delay may be evident.



• Pallor and pale conjunctiva may be noted in patients with anemia.



• Jaundice may result from hyperbilirubinemia secondary to decreased hepatic excretory function.



• Petechiae and ecchymoses may be observed in patients with thrombocytopenia secondary to splenic sequestration and decreased coagulation factors from hepatic failure.



• Peripheral edema may result from decreased hepatic synthesis of albumin or heart failure.



• The abdomen may protrude. Hepatomegaly often is present with increased liver span and a firm, nontender liver edge. In addition, ascites, splenomegaly, and a prominent abdominal venous pattern occur in patients with associated portal hypertension.



• Hepatomegaly may be mild or absent in patients with nonprogressive liver disease.



• Evidence of early cardiomyopathy includes the following:


• • Decreased peripheral perfusion

  • Decreased pulse pressure
  
  
  
  • Tachycardia

  • Hepatomegaly

  • Peripheral edema
  
  
  
  • Systolic murmur due to valvular incompetence

  • Gallop rhythm
  
  
  
  • Abnormal lung auscultatory findings

  • Costal and subcostal retractions
  
  
  
  • Increased jugular venous pressure
  
  
  
  • Periorbital edema in infants
  
  
  
• Patients with GSD IV involving the muscles may have muscle atrophy, weakness, and decreased strength.



• Patients with peripheral nerve involvement may exhibit decreased or absent deep tendon reflexes and a peripheral neuropathy with sensory loss, primarily in the lower extremities. At times the disorder may mimic signs of amyotrophic lateral sclerosis.



• Patients with CNS involvement and leukoencephalopathy may exhibit mild cognitive impairment or dementia.



• An affected fetus or stillborn baby may exhibit arthrogryposis and fetal hydrops.



• Examination of an affected neonate may reveal severe hypotonia, shallow respirations, muscle atrophy, and signs of heart failure such as tachypnea, poor peripheral perfusion, low blood pressure, and periorbital edema.

Causes:

• All forms of GSD IV result from defects in the gene coding for the glycogen-branching enzyme (GBE1) located on chromosome band 3p12. The function of this enzyme is to increase the number of branch points during glycogen synthesis. The branched nature of the glycogen molecule is important for its compact nature and solubility within the cell. Absence of this branching activity results in abnormal glycogen with long, unbranched outer chains resembling amylopectin. (Amylopectin, a glucose polymer, is a major storage polysaccharide in legumes).



• Deficient branching enzyme activity and mutations in the gene coding for the glycogen-branching enzyme may be generalized or isolated to a specific cell line or tissue.



• Specific mutations have been identified in patients with classic, perinatal, and nonprogressive hepatic forms of GSD IV. Further studies to determine genotype-phenotype correlations are in progress.

DIFFERENTIALS

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Cardiomyopathy, Dilated
Galactose-1-Phosphate Uridyltransferase Deficiency (Galactosemia)
Hemochromatosis, Neonatal
Hydrops Fetalis
Tyrosinemia

Other Problems to be Considered:

Alpha-1 antitrypsin deficiency
Neonatal hepatitis
Respiratory chain defects

WORKUP

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Lab Studies:

• Perform laboratory evaluations with the classic form of GSD IV to assess the degree of liver dysfunction. Patients may exhibit no, any, or all biochemical abnormalities, depending on the degree of liver dysfunction and counter-regulatory processes. In general, prolonged prothrombin time (PT) and decreased plasma albumin levels correlate with the degree of hepatic cirrhosis. Increased plasma levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and gamma-glutamyl transpeptidase (GGT) correlate with the degree of hepatocellular insufficiency. Patients with primary muscle, nervous system, or cardiac involvement and minimal or no liver dysfunction may demonstrate laboratory values within reference ranges.



• Complete blood count: Either normochromic or normocytic anemia usually results from chronic blood loss due to coagulopathy, folate deficiency, and hemolysis. Morphologically abnormal erythrocytes on a peripheral blood smear result from decreased splenic function. Thrombocytopenia and leukopenia result from splenic sequestration.



• Prothrombin time, activated partial thromboplastin time, and fibrinogen: Liver disease causes decreased synthesis of vitamin K–dependent coagulation factors and fibrinogen, inadequate absorption of vitamin K, and thrombocytopenia; therefore, progressive liver failure leads to prolonged PT and activated partial thromboplastin time (aPTT), decreased fibrinogen levels with progressive coagulopathy, and risk of disseminated intravascular coagulation.



• ALT and AST: Measurement of liver enzymes usually shows progressive elevation consistent with hepatocellular damage and release of enzymes into the blood.



• Bilirubin, total and indirect (conjugated): In the early stages of liver dysfunction, conjugated bilirubin rises because the liver can conjugate this fluid but cannot adequately excrete it. With progressive liver failure, both conjugated and unconjugated bilirubin levels rise.



• Serum alkaline phosphatase, GGT, 5' nucleotidase: Levels of these hepatocellular enzymes may be normal or slightly elevated and vary with the degree of hepatic bile secretory function.



• Serum albumin: Hypoalbuminemia is a result of decreased hepatic synthetic function but also depends on dietary protein intake and on fluid and electrolyte dynamics.



• Electrolytes: Associated renal dysfunction causes electrolyte imbalance with hyponatremia, hypokalemia, and decreased serum calcium and magnesium levels.



• BUN: BUN levels are abnormally low despite associated renal dysfunction, secondary to impaired hepatic synthetic function.



• Creatinine: Levels usually are within reference ranges.



• Blood glucose: Hypoglycemia may result from severe hepatocellular damage and from glycogenolysis and gluconeogenesis inadequate to maintain serum glucose.

Imaging Studies:

• An abdominal ultrasound with Doppler may reveal the presence of portal hypertension, esophageal varices, and liver echogenicity. Ultrasound also may determine portal vein diameter and blood flow directionality.



• Abdominal MRI or CT scans may reveal evidence of cirrhotic changes in liver parenchyma and the vascular system. Liver and spleen volume quantitation may be performed.



• Characteristic features on liver-spleen scintigraphy using technetium Tc 99m sulfur colloid include decreased uptake in the liver with an irregular pattern and increased uptake in the spleen and bone marrow.



• An MRI of the head may demonstrate leukoencephaly and cortical atrophy in patients with APBD and CNS involvement.



• Echocardiography may reveal evidence of dilated cardiomyopathy and impaired myocardial function.

Other Tests:

• Definitive diagnosis of GSD IV relies on demonstration of deficient glycogen-branching enzyme activity in liver or muscle tissue. Because GSD IV is a multisystem disorder, evidence of abnormal glycogen content can be demonstrated in many tissues and cells, including liver, leukocytes, erythrocytes, and cultured skin fibroblasts. The sole exception is APBD in Ashkenazi Jewish patients whose deficient glycogen-branching enzyme activity may be demonstrated only in leukocytes and nerve cells. Affected patients demonstrate approximately 1-10% of the glycogen-branching enzyme activity found in persons without GSD. Heterozygotes may be identified by an intermediate reduction in glycogen-branching enzyme activity.



• Prenatal testing is based on the levels of glycogen-branching enzyme activity in cultured amniocytes and chorionic villi. Molecular diagnosis may be performed in selected cases.

Procedures:

• Definitive diagnosis of GSD IV may involve biopsy of the liver or other affected organs (eg, muscle, nerve, heart) for microscopic examination and enzyme assay.



• Esophagogastroduodenoscopy is the definitive procedure to document the presence and position of esophageal varices.

TREATMENT

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Medical Care:

• A patient with liver involvement requires a pediatric gastroenterologist for initial evaluation and long-term management of liver dysfunction and cirrhosis. The severity of liver dysfunction and complications of portal hypertension determine medical management.



• A patient presenting with clinical symptoms of neuromuscular involvement requires a pediatric neurologist for initial evaluation and management.



• A pediatric cardiologist is recommended for initial evaluation and medical management of the few patients who present with symptoms of cardiac compromise.



• Refer a patient with suspected GSD IV to a metabolic or biochemical genetics specialist for diagnostic evaluation.

Surgical Care:

• For patients with classic GSD IV, surgical intervention by liver transplantation is the most effective treatment.


• • Immediate complications of liver transplantation include postoperative complications and organ rejection. Because GSD IV is a multisystem disorder, the long-term success of liver transplantation and its effect on the disease progression in other organs is unclear.

  • Although several patients reportedly have experienced decreased progression and systemic regression after hepatic allografting, presumably due to systemic microchimerism, some transplanted patients develop progressive accumulation of abnormal glycogen in other organs, ultimately leading to death.
  
  
  

Consultations:

• Refer a patient with liver dysfunction to a dietitian experienced with the nutritional support of progressive hepatic failure.



• Refer the family of an affected child to a medical geneticist or genetic counselor to review the inheritance of GSD IV and to discuss prenatal diagnostic testing. Because inheritance is autosomal-recessive, parents have a 25% risk of an affected offspring with each pregnancy.

Diet:

• If the patient has liver disease, dietary management is necessary to provide adequate nutrient intake to maintain normoglycemia and to improve liver function.



• In the patient with classic symptoms who develops progressive liver cirrhosis necessitating liver transplantation, proper dietary intervention has improved muscle strength and allowed additional time for growth before surgery.

Activity: Do not restrict activity unless the patient experiences acute symptoms of liver failure and complications of cirrhosis.

FOLLOW-UP

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Further Outpatient Care:

• Perform follow-up to evaluate the progression of liver disease, determine the need for additional medical and dietary management, and assess the urgency for surgical intervention. Periodic ultrasound examination of the liver to monitor the development of hepatocellular adenoma is suggested.



• Perform periodic follow-ups to evaluate progressive organ involvement and failure for patients with predominant nerve, muscle, and cardiac involvement.

Prognosis:

• Prognosis is poor for the perinatal-onset and classic forms without liver transplantation. Long-term prognosis for others, including the patient with classic GSD IV after transplantation, depends on the extent, severity, and progression of this multisystem disorder.

Patient Education:

• Educate patients and parents about proper diet management to support liver dysfunction.



• Educate patients and parents about proper evaluation and long-term medical management of such complications as cirrhosis and portal hypertension, heart failure, and neuromuscular dysfunction.

MISCELLANEOUS

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Medical/Legal Pitfalls:

• Failure to adequately monitor and manage the case of a patient with progressive organ dysfunction and failure



• Failure to adequately discuss the potential benefits and complications of liver transplantation for patients with classic GSD IV



• Failure to discuss the availability of prenatal diagnosis to a couple with a previously affected child



• Failure to consider the diagnosis of GSD IV in a fetus with cervical cystic hygroma and normal chromosome analysis.

TEST QUESTIONS

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CME Question 1: A newly diagnosed 2-year-old boy presents to a physician's office with classic glycogen-storage disease type IV (GSD IV). Which of the following laboratory values would not be abnormal?

A: Prolonged prothrombin time
B: Thrombocytopenia
C: Elevated BUN
D: Decreased serum albumin
E: Hyponatremia

The correct answer is C: BUN typically is decreased in patients with GSD IV, despite associated renal failure. Liver cirrhosis decreases hepatic synthesis of urea from waste nitrogen.

CME Question 2: Which of the following is not included in the diagnostic testing for glycogen-storage disease type IV (GSD IV)?

A: Inpatient fasting study
B: Nerve biopsy for electron microscopic analysis
C: Enzyme assay on myocardial biopsy
D: Histological analysis of liver section after periodic acid-Schiff (PAS) and diastase treatment
E: Muscle biopsy with iodine staining

The correct answer is A: Unlike other forms of glycogen-storage disease, GSD IV is a multisystem disorder; an accumulation of abnormal glycogen in many tissues causes cellular dysfunction. The maintenance of plasma glucose and availability of glucose for energy supply is not compromised until the development of severe hepatocellular failure; therefore, these patients do not present with hypoglycemia and do not require a controlled fasting assessment for diagnostic evaluation.

Pearl Question 1 (T/F): The first child of a young couple died during the first month of life. Presenting symptoms included severe hypotonia, muscle atrophy, and dilated cardiomyopathy. Pathology reports describe abnormal periodic acid-Schiff (PAS)-positive, diastase-resistant inclusions in nerve and muscle and a tentative diagnosis of glycogen-storage disease type IV (GSD IV). Because the couple plans another pregnancy, physician recommendations should include genetic counseling and the option of prenatal diagnosis due to the couple's 25% risk of an affected baby with each pregnancy.

The correct answer is True: Recommendations include referral to a geneticist or genetics counselor to discuss inheritance and the 25% risk of another affected baby with each pregnancy. Include the option of prenatal diagnosis with enzyme assay for glycogen-branching enzyme activity in cultured chorionic villi or amniocytes. Molecular diagnosis may be used in selected cases.

Pearl Question 2 (T/F): The best treatment for a patient with classic glycogen-storage disease type IV (GSD IV) is a high-carbohydrate, low-protein diet with frequent feeds.

The correct answer is False: The most effective treatment is liver transplantation. Because GSD IV is a multisystem disorder, however, the long-term success of liver transplantation and its effect on the disease progression in other organs is unclear. While several patients reportedly have experienced decreased progression and systemic regression after hepatic allografting, presumably due to systemic microchimerism, some transplanted patients develop progressive accumulation of abnormal glycogen in other organs, ultimately leading to death.

Pearl Question 3 (T/F): The effects of glycogen-storage disease type IV (GSD IV) on the heart involves the excessive accumulation of glycogen and causes hypertrophic cardiomyopathy and characteristic ECG changes with shortened PR interval and wide-amplitude QRS.

The correct answer is False: GSD IV, a glycogen-branching enzyme deficiency, involves the accumulation of abnormal unbranched glycogen and periodic acid-Schiff (PAS)-positive and diastase resistant inclusions that may result in development of dilated cardiomyopathy, progressive heart failure, and possible death. Pompe disease (ie, GSD type II or acid maltase deficiency) involves the lysosomal accumulation of excessive amounts of normal glycogen, resulting in hypertrophic cardiomyopathy and characteristic ECG changes with shortened PR interval, wide-amplitude QRS, left ventricular hypertrophy, progressive heart failure, and death.

Pearl Question 4 (T/F): The liver is the only organ affected by glycogen-storage disease type IV (GSD IV).

The correct answer is False: The liver, heart, muscles (skeletal and smooth), and nerves (brain, spinal cord, peripheral) are the organs or organ systems involved in GSD IV. In addition, accumulation of abnormal glycogen may be identified in histiocytes, lymphocytes, and fibroblasts.

PICTURES

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Caption: Picture 1. Glycogen-storage disease type IV (GSD IV). Liver section from a patient with GSD IV. Stained with hematoxylin and eosin. Characteristic findings include distorted hepatic architecture with diffuse interstitial fibrosis and wide fibrous septa surrounding micronodular areas of parenchyma. Hepatocytes are typically enlarged 2- to 3-fold, with faintly-stained basophilic cytoplasmic inclusions.
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Caption: Picture 2. Glycogen-storage disease type IV (GSD IV). Liver section from a patient with GSD IV. Periodic acid-Schiff (PAS) stain after diastase treatment. Coarsely clumped material cytoplasmic material representing the accumulated abnormal glycogen is resistant to diastase treatment and is readily stained with PAS.
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BIBLIOGRAPHY

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• Bao Y, Kishnani P, Wu JY, Chen YT: Hepatic and neuromuscular forms of glycogen storage disease type IV caused by mutations in the same glycogen-branching enzyme gene. J Clin Invest 1996 Feb 15; 97(4): 941-8[Medline].
• Brown BI, Brown DH: Branching enzyme activity of cultured amniocytes and chorionic villi: prenatal testing for type IV glycogen storage disease. Am J Hum Genet 1989 Mar; 44(3): 378-81[Medline].
• Bruno C, van Diggelen OP, Cassandrini D, et al: Clinical and genetic heterogeneity of branching enzyme deficiency (glycogenosis type IV). Neurology 2004 Sep 28; 63(6): 1053-8[Medline].
• Giuffrè B, Parinii R, Rizzuti T, et al: Severe neonatal onset of glycogenosis type IV: clinical and laboratory findings leading to diagnosis in two siblings. J Inherit Metab Dis 2004; 27(5): 609-19[Medline].
• L'herminé-Coulomb A, Beuzen F, Bouvier R, et al: Fetal type IV glycogen storage disease: clinical, enzymatic, and genetic data of a pure muscular form with variable and early antenatal manifestations in the same family. Am J Med Genet A 2005 Dec 1; 139(2): 118-22[Medline].
• Lossos A, Meiner Z, Barash V, et al: Adult polyglucosan body disease in Ashkenazi Jewish patients carrying the Tyr329Ser mutation in the glycogen-branching enzyme gene. Ann Neurol 1998 Dec; 44(6): 867-72[Medline].
• McConkie-Rosell A, Wilson C, Piccoli DA, et al: Clinical and laboratory findings in four patients with the non-progressive hepatic form of type IV glycogen storage disease. J Inherit Metab Dis 1996; 19(1): 51-8[Medline].
• Nambu M, Kawabe K, Fukuda T, et al: A neonatal form of glycogen storage disease type IV. Neurology 2003 Aug 12; 61(3): 392-4[Medline].
• Nase S, Kunze KP, Sigmund M, et al: A new variant of type IV glycogenosis with primary cardiac manifestation and complete branching enzyme deficiency. In vivo detection by heart muscle biopsy. Eur Heart J 1995 Nov; 16(11): 1698-704[Medline].
• Selby R, Starzl TE, Yunis E, et al: Liver transplantation for type I and type IV glycogen storage disease. Eur J Pediatr 1993; 152 Suppl 1: S71-6[Medline].
• Servidei S, Riepe RE, Langston C, et al: Severe cardiopathy in branching enzyme deficiency. J Pediatr 1987 Jul; 111(1): 51-6[Medline].
• Shen J, Liu HM, McConkie-Rosell A, Chen YT: Prenatal diagnosis of glycogen storage disease type IV using PCR-based DNA mutation analysis. Prenat Diagn 1999 Sep; 19(9): 837-9[Medline].
• Sokal EM, Van Hoof F, Alberti D, et al: Progressive cardiac failure following orthotopic liver transplantation for type IV glycogenosis. Eur J Pediatr 1992 Mar; 151(3): 200-3[Medline].
• Starzl TE, Demetris AJ, Trucco M, et al: Chimerism after liver transplantation for type IV glycogen storage disease and type 1 Gaucher's disease. N Engl J Med 1993 Mar 18; 328(11): 745-9[Medline].

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