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 29 2006, VOLUME 7, Number 3

INTRODUCTION

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Background: Glycogen-storage disease type VI (GSD VI) represents a heterogeneous group of hepatic glycogenoses with mild clinical manifestations and benign course. Patients typically exhibit prominent hepatomegaly, growth retardation, and variable but mild episodes of fasting hypoglycemia and hyperketosis during childhood. Hyperlacticacidemia and hyperuricemia characteristically are absent. In addition, patients may demonstrate elevated serum transaminases, hyperlipidemia, hypotonia, and muscle weakness. These clinical features and biochemical abnormalities generally resolve by puberty. Rare variants may have associated proximal renal tubule acidosis, myopathy, or fatal cardiomyopathy.

In general, GSD VI is caused by defects in the hepatic glycogen phosphorylase-activating system. The classic form of GSD VI results from a primary deficiency of liver phosphorylase. Other defects of the phosphorylase cascade system now included in this form of GSD are phosphorylase b kinase deficiency (formerly GSD IX, GSD VIII by McKusick) and adenosine 3',5'-cyclic monophosphate (cAMP)-dependent protein kinase deficiency (formerly GSD X).

Pathophysiology: Phosphorylase, the rate-limiting enzyme of glycogenolysis or glycogen breakdown, is activated by a cascade of enzymes, including adenyl cyclase, phosphorylase b kinase, and cAMP-dependent protein kinase. Enzyme deficiency anywhere along this pathway results in impaired cleavage of glucose units from the straight chains of the glycogen molecule. In most patients, the enzyme deficiency is incomplete and gluconeogenesis remains intact. As a result, the ability of the liver to maintain normoglycemia during fasting may be partially impaired, resulting in an increased risk of mild fasting hypoglycemia and associated hyperketosis. Increased levels of urinary ketones and serum ketone bodies (eg, acetoacetate, beta-hydroxybutyrate) are proportional to the degree of fasting. Other biochemical derangements include mild-to-moderate hyperlipidemia, with elevation of serum cholesterol more than elevation of triglycerides and variably elevated serum transaminases with no other evidence of liver dysfunction.

Frequency:

• Internationally: The overall frequency of GSD is 1 case per 20,000-25,000 persons, with approximately 30% of cases representing GSD VI, thus making GSD VI one of the most common forms of GSD. Approximately 75% of all cases of GSD VI result from the X-linked recessive forms of phosphorylase kinase deficiency.

Mortality/Morbidity: GSD VI has a rather benign course with risk of growth retardation, mild fasting hypoglycemia, hypotonia, and delayed motor milestones in early childhood. These clinical features gradually normalize before or at puberty. Adult patients exhibit normal stature, motor function, and biochemical parameters. Rare variants of GSD may cause muscle dysfunction or severe cardiomyopathy.

Race: GSD VI is most common among members of the Mennonite religious group. A specific splice-site mutation in the liver phosphorylase gene (PYGL) occurs in the chromosomes of 3% of this religious group. GSD VI has an estimated frequency of 0.1% in the Mennonite population.

Sex: The X-linked recessive form of liver phosphorylase kinase deficiency is expressed primarily in affected males, although asymptomatic males and heterozygous (carrier) females with mild symptoms have been reported. All other forms of GSD VI are autosomal-recessive and affect both sexes equally.

Age: GSD VI usually manifests during early childhood.

CLINICAL

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History: The most common presentation is in children aged 1-5 years, with a history of protuberant abdomen, growth retardation, and slight delay in motor milestones. These children also may have histories of mild fasting hypoglycemia and hypotonia. Some patients remain asymptomatic, and routine physical examination reveals hepatomegaly.

Physical:

• Although children may have growth delay and short stature, adolescents and adults often have normal stature.



• The abdomen of a child with GSD VI usually protrudes, and abdominal examination reveals hepatomegaly and increased liver span. In some cases, hepatomegaly may be massive. Splenomegaly, however, always is absent. Adult patients may have mild or no hepatomegaly.



• Delay in motor milestones may be noted in a young child, and mild hypotonia and muscle weakness may be present. In an adolescent or adult, muscle strength and tone usually are normal.

Causes: GSD VI results from a deficiency in the activity of one of several enzymes in the phosphorylase-activating cascade. Most cases result from defects of phosphorylase b kinase, an enzyme that activates phosphorylase by phosphorylation. Phosphorylase b kinase is a multimeric unit consisting of 4 different subunits, each coded by a unique gene located on different chromosomes. Mutations in 3 genes (PHKA2, PHKB, and PHKG2) have been demonstrated in patients with phosphorylase b kinase deficiency.

In addition, several subtypes of phosphorylase kinase deficiency have been identified, based on the tissues affected and the mode of inheritance (autosomal recessive or X-linked recessive). The most common subgroup is the X-linked recessive form.

Classic GSD VI results from a primary deficiency of liver phosphorylase (PYGL). Patients with a defect of the cAMP-dependent protein kinase have been reported infrequently.

DIFFERENTIALS

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Fructose 1,6-Diphosphatase Deficiency
Fructose 1-Phosphate Aldolase Deficiency (Fructose Intolerance)
Glycogen-Storage Disease Type 0
Glycogen-Storage Disease Type I
Glycogen-Storage Disease Type II
Glycogen-Storage Disease Type III

WORKUP

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Lab Studies:

• The extent and severity of biochemical abnormalities vary in affected children.



• Blood glucose: After a short fast (3-5 h), mild hypoglycemia may develop in younger patients.



• Urine ketones, serum ketone bodies: Urine ketones and serum ketone bodies (eg, acetoacetate, beta-hydroxybutyrate) may be elevated during a short fast and are proportional to the degree of fasting.



• Lipid profile: Mild hyperlipidemia may be present, with serum cholesterol elevations more than serum triglycerides.



• Serum transaminases: Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels may be elevated mildly. Other LFTs are usually normal.

Imaging Studies:

• Liver volume quantitation may be performed by means of abdominal MRI or CT.

Other Tests:

• Evaluation of a patient with suspected GSD VI requires monitored assessment of fasting adaptation in an inpatient setting. After 3-5 hours fasting, patients with GSD VI typically exhibit hypoglycemia with a normal serum lactic acid level. This same pattern also occurs in patients with GSD 0 and GSD III, and in patients with hereditary fructose intolerance (HFI). Patients with HFI can be identified by development of hypoglycemia and increased lactic acid after PO fructose loading.



• A fasted glucagon challenge may further narrow the field of diagnostic possibilities. Patients with GSD VI may demonstrate a normal hyperglycemic response without change in lactic acid after glucagon administration, although results may be inconclusive.



• Molecular diagnostic testing for a specific mutation in the PYGL gene may be used to identify carriers and affected children in the Mennonite population.

Procedures:

• Definitive diagnosis of GSD VI requires a liver biopsy and enzyme assay. Histological examination and determination of glycogen content also may be performed.



• Enzyme assay can be performed in more easily obtainable cells, including red blood cells and white blood cells. However, due to the presence of isoenzymes, the presence of normal enzyme activity in these cells does not exclude the possibility of isolated hepatic involvement in an affected patient.

TREATMENT

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Consultations:

• Refer the patient to a dietitian experienced with GSD and the management of disorders associated with an increased risk of hypoglycemic episodes.



• Refer families to a medical geneticist or genetic counselor to review the specific inheritance of GSD VI present in the affected child. Inheritance may be autosomal recessive or X-linked recessive. Parents have a 25% risk of an affected offspring with each pregnancy or a 50% risk with each male offspring, respectively. An X-linked dominant inheritance rarely is reported.

Diet: Dietary management is the only form of treatment necessary for this rather mild form of GSD. A high carbohydrate diet and frequent feedings are recommended only for those patients who exhibit fasting hypoglycemia. While some patients have been given a high-protein diet or supplementation of unsaturated fats, most patients require no dietary intervention.

Activity: Do not restrict the patient's activity unless significant hepatomegaly is present; recommend patients with significant hepatomegaly avoid contact sports and activities.

MEDICATION

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Drug therapy currently is not a component of the standard of care for this disease.

FOLLOW-UP

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Further Outpatient Care:

• Perform follow-up evaluation to assess physical growth and to prevent hypoglycemic episodes by adjusting diet, as needed.

Deterrence/Prevention:

• Instruct patients who exhibit episodes of fasting hypoglycemia to avoid prolonged fasts exceeding 5-7 hours.



• During an acute illness with decreased oral intake, maintain normoglycemia with IV infusion of glucose-containing solution.

Prognosis:

• Patients have an excellent prognosis for normal stature and development, even without dietary management during childhood.



• Most patients exhibit resolution of hepatomegaly, hypotonia, muscle weakness, risk of fasting hypoglycemia, and abnormal biochemical parameters before or at puberty.



• The overall prognosis of rare variants with associated muscle or cardiac involvement depends upon the severity of organ dysfunction.

Patient Education:

• Educate patients and parents about proper diet management and fasting avoidance techniques.



• Parents and primary physicians of an affected child with episodes of fasting hypoglycemia should know how to administer IV glucose solutions during periods of acute illness with decreased oral intake.

MISCELLANEOUS

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Medical/Legal Pitfalls:

• Failure to educate the family about the effects of fasting and decreased oral intake during acute illness in those patients with episodes of fasting hypoglycemia

TEST QUESTIONS

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CME Question 1: Which of the following is not characteristic of glycogen-storage disease type VI (GSD VI)?

A: Hepatomegaly and short stature during childhood
B: Episodes of fasting hypoglycemia
C: Delayed motor milestones and hypotonia during childhood
D: Normal intelligence, height, and muscle strength at puberty
E: Progressive liver dysfunction

The correct answer is E: Progressive liver dysfunction is not a characteristic feature of GSD VI. During childhood, serum transaminases may be elevated, and the liver`s ability to maintain normoglycemia during fasting may be mildly impaired. These features usually normalize by puberty.

CME Question 2: Which of the following statements about glycogen-storage disease type VI (GSD VI) is inaccurate?

A: The condition has an incidence of 1 case per 1000 persons in the Ashkenazi Jewish population.
B: The condition is the mildest form of hepatic glycogenosis.
C: The condition may be inherited in an autosomal-recessive or X-linked recessive manner.
D: The condition is a common form of glycogen-storage disease, representing about 30% of all cases.
E: The condition includes defects in at least 3 different enzymes of the phosphorylase-activating pathway

The correct answer is A: The incidence of GSD VI in the Mennonite population is 1 case per 1000 persons, based on the presence of a splice-site mutation in the chromosomes of 3% of the Mennonite population and because this mutation is inherited in an autosomal-recessive manner.

Pearl Question 1 (T/F): The primary treatment for a patient with glycogen-storage disease type VI (GSD VI) is a high carbohydrate diet with frequent meals and overnight cornstarch feeds.

The correct answer is False: Most patients with GSD VI require no treatment. Patients who develop fasting hypoglycemia require dietary management consisting of frequent feedings within a high carbohydrate diet regimen.

Pearl Question 2 (T/F): A couple with 1 child affected with glycogen-storage disease type VI (GSD VI) due to phosphorylase kinase deficiency arrives for counseling. Their risk of having an affected child in a subsequent pregnancy is 25%.

The correct answer is False: The risk is 50%. Counseling depends upon the particular subgroup of phosphorylase kinase deficiency and its mode of inheritance. X-linked recessive inheritance is demonstrated by patients with a defect in the alpha subunit of phosphorylase kinase and is associated with a 50% risk in any male offspring. Carrier (heterozygous) females may be mildly affected. Autosomal-recessive inheritance is demonstrated by patients with a defect in other subunits of phosphorylase kinase and is associated with a 25% risk of an affected offspring in each pregnancy.

Pearl Question 3 (T/F): The liver is the only organ system affected in patients with glycogen-storage disease type VI (GSD VI) with a primary defect of phosphorylase.

The correct answer is True: The liver is the only organ involved. Patients with GSD VI have a defect in the liver-specific phosphorylase enzyme, which is coded by a gene located on chromosome 14. Defects of the muscle-specific enzyme phosphorylase, which is coded by a gene located on chromosome 11, results in GSD V or McArdle disease, which is characterized by exercise intolerance, muscle cramps, and myoglobinuria. Different subgroups of GSD VI resulting from phosphorylase kinase deficiency may involve muscle and blood cells in addition to the liver.

Pearl Question 4 (T/F): Definitive diagnosis of a patient with glycogen-storage disease type VI (GSD VI) involves enzyme assay of a liver biopsy specimen or peripheral blood cells.

The correct answer is False: Definitive diagnosis of GSD VI requires liver biopsy and enzyme assay. A monitored assessment of fasting adaptation and fasted glucagon challenge may help narrow the diagnostic possibilities. Enzyme assay in peripheral blood cells may be misleading if results are within reference ranges because an isolated defect in the liver isoenzyme may be responsible for the disease. Molecular diagnostic testing may be performed in selected cases in which a specific mutation has been identified in a proband or population (eg, Mennonite population).

BIBLIOGRAPHY

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• Bashan N, Iancu TC, Lerner A: Glycogenosis due to liver and muscle phosphorylase kinase deficiency. Pediatr Res 1981 Apr; 15(4 Pt 1): 299-303[Medline].
• Burwinkel B, Bakker HD, Herschkovitz E: Mutations in the liver glycogen phosphorylase gene (PYGL) underlying glycogenosis type VI. Am J Hum Genet 1998 Apr; 62(4): 785-91[Medline].
• Burwinkel B, Amat L, Gray RG: Variability of biochemical and clinical phenotype in X-linked liver glycogenosis with mutations in the phosphorylase kinase PHKA2 gene. Hum Genet 1998 Apr; 102(4): 423-9[Medline].
• Burwinkel B, Bakker HD, Herschkovitz E, et al: Mutations in the liver glycogen phosphorylase gene (PYGL) underlying glycogenosis type VI. Am J Hum Genet 1998 Apr; 62(4): 785-91[Medline].
• Burwinkel B, Rootwelt T, Kvittingen EA: Severe phenotype of phosphorylase kinase-deficient liver glycogenosis with mutations in the PHKG2 gene. Pediatr Res 2003; 54(6): 834-839[Medline].
• Chang S, Rosenberg MJ, Morton H: Identification of a mutation in liver glycogen phosphorylase in glycogen storage disease type VI. Hum Mol Genet 1998 May; 7(5): 865-70[Medline].
• Chen Y-T, Burchell A: Glycogen Storage Diseases. The Metabolic and Molecular Bases of Inherited Disease 1995; I: 935-65.
• Goldberg T, Slonim AE: Nutrition therapy for hepatic glycogen storage diseases. J Am Diet Assoc 1993 Dec; 93(12): 1423-30[Medline].
• Hendrickx J, Bosshard NU, Willems P: Clinical, biochemical and molecular findings in a patient with X-linked liver glycogenosis followed for 40 years. Eur J Pediatr 1998 Nov; 157(11): 919-23[Medline].
• Hendrickx J, Lee P, Keating JP: Complete genomic structure and mutational spectrum of PHKA2 in patients with x-linked liver glycogenosis type I and II. Am J Hum Genet 1999 Jun; 64(6): 1541-9[Medline].
• Kotb MA, Abdallah HK, Kotb A: Liver glycogenoses: are they a possible cause of polyneuropathy? A cross-sectional study. J Trop Pediatr 2004 Aug; 50(4): 196-202[Medline].
• Newgard CB, Fletterick RJ, Anderson LA: The polymorphic locus for glycogen storage disease VI (liver glycogen phosphorylase) maps to chromosome 14. Am J Hum Genet 1987 Apr; 40(4): 351-64[Medline].
• Tang NL, Hui J, Young E, et al: A novel mutation (G233D) in the glycogen phosphorylase gene in a patient with hepatic glycogen storage disease and residual enzyme activity. Mol Genet Metab 2003 Jun; 79(2): 142-5[Medline].
• Willems PJ, Gerver WJ, Berger R: The natural history of liver glycogenosis due to phosphorylase kinase deficiency: a longitudinal study of 41 patients. Eur J Pediatr 1990 Jan; 149(4): 268-71[Medline].

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