Glycogen Storage Disorder in Children: Clinical Case and Viva Q&A

Clinical Case: Glycogen Storage Disorder in a Child

Case Presentation

A 6-month-old male infant is brought to the pediatric clinic by his parents with concerns of poor weight gain and enlarged abdomen. The parents report the following:

• Difficulty feeding and frequent vomiting
• Excessive sweating, especially during feedings
• Lethargy and irritability between meals
• No developmental delays noted

Physical Examination

• Weight: 3rd percentile for age
• Length: 25th percentile for age
• Head circumference: 50th percentile for age
• Marked hepatomegaly: liver edge palpable 4 cm below right costal margin
• Distended abdomen with prominent veins
• Hypotonia

Laboratory Findings

• Fasting blood glucose: 45 mg/dL (hypoglycemia)
• Elevated liver enzymes: AST 150 U/L, ALT 130 U/L
• Elevated lactate: 4.5 mmol/L
• Elevated triglycerides: 300 mg/dL
• Elevated uric acid: 7.5 mg/dL

Diagnosis and Management

Based on the clinical presentation and laboratory findings, a diagnosis of Glycogen Storage Disease Type I (von Gierke's disease) is suspected. Further genetic testing confirms a mutation in the G6PC gene.

Management includes:

1. Frequent feedings with complex carbohydrates
2. Nocturnal gastric drip feeding
3. Dietary restriction of fructose, galactose, and sucrose
4. Supplementation with uncooked cornstarch
5. Regular monitoring of blood glucose levels
6. Long-term follow-up for potential complications

Clinical Presentations of Glycogen Storage Disorders in Children

1. Glycogen Storage Disease Type I (von Gierke's disease)

• Severe fasting hypoglycemia
• Hepatomegaly
• Growth retardation
• Lactic acidosis
• Hyperuricemia
• "Doll-like" facies

2. Glycogen Storage Disease Type II (Pompe's disease)

• Infantile form: severe hypotonia, cardiomegaly, respiratory distress
• Juvenile/adult form: progressive muscle weakness, respiratory insufficiency

3. Glycogen Storage Disease Type III (Cori's disease)

• Hepatomegaly
• Hypoglycemia (less severe than Type I)
• Growth retardation
• Progressive muscle weakness

4. Glycogen Storage Disease Type IV (Andersen's disease)

• Progressive liver cirrhosis
• Failure to thrive
• Hypotonia
• Cardiomyopathy in some cases

5. Glycogen Storage Disease Type V (McArdle's disease)

• Exercise intolerance
• Muscle cramps
• Myoglobinuria after intense exercise

6. Glycogen Storage Disease Type VI (Hers' disease)

• Mild hepatomegaly
• Growth retardation
• Mild fasting hypoglycemia

7. Glycogen Storage Disease Type IX

• Hepatomegaly
• Growth delay
• Mild fasting ketotic hypoglycemia
• Elevated liver enzymes

Viva Questions and Answers on Glycogen Storage Disorders in Children

1. Q: What is the basic pathophysiology of glycogen storage disorders?

   A: Glycogen storage disorders (GSDs) are caused by deficiencies in enzymes involved in glycogen synthesis, breakdown, or regulation. This leads to accumulation of glycogen in various tissues, primarily the liver and muscles, resulting in organ dysfunction and metabolic derangements.

2. Q: Which enzyme is deficient in Glycogen Storage Disease Type I (von Gierke's disease)?

   A: In GSD Type I, there is a deficiency of glucose-6-phosphatase enzyme. Specifically, Type Ia is due to a defect in the catalytic subunit G6PC, while Type Ib is caused by a defect in the glucose-6-phosphate translocase (SLC37A4).

3. Q: What are the main clinical features of GSD Type I?

   A: The main clinical features include severe fasting hypoglycemia, hepatomegaly, growth retardation, lactic acidosis, hyperuricemia, hyperlipidemia, and characteristic "doll-like" facies with fat cheeks.

4. Q: How is the diagnosis of GSD Type I confirmed?

   A: Diagnosis is confirmed through genetic testing for mutations in the G6PC gene (Type Ia) or SLC37A4 gene (Type Ib). Liver biopsy with enzyme assay was historically used but is now less common due to the availability of genetic testing.

5. Q: What is the primary treatment approach for GSD Type I?

   A: The primary treatment involves maintaining normoglycemia through frequent feedings with complex carbohydrates, nocturnal gastric drip feeding, and supplementation with uncooked cornstarch. Dietary restrictions of fructose, galactose, and sucrose are also important.

6. Q: What is the enzyme deficiency in Pompe's disease (GSD Type II)?

   A: Pompe's disease is caused by a deficiency of acid α-glucosidase (GAA) enzyme, also known as acid maltase.

7. Q: How does the clinical presentation differ between infantile and late-onset Pompe's disease?

   A: Infantile-onset Pompe's disease presents with severe hypotonia, cardiomegaly, and respiratory distress, often leading to death within the first year if untreated. Late-onset (juvenile/adult) form presents with progressive proximal muscle weakness and respiratory insufficiency, without significant cardiac involvement.

8. Q: What is the current gold standard treatment for Pompe's disease?

   A: The gold standard treatment is enzyme replacement therapy (ERT) with recombinant human acid α-glucosidase (alglucosidase alfa). This is typically given as an intravenous infusion every two weeks.

9. Q: What is the enzyme deficiency in GSD Type III (Cori's disease)?

   A: GSD Type III is caused by a deficiency of the glycogen debranching enzyme (AGL).

10. Q: How does the clinical presentation of GSD Type III differ from GSD Type I?

    A: While both present with hepatomegaly and hypoglycemia, GSD Type III typically has less severe hypoglycemia. GSD Type III also features progressive muscle weakness and potential cardiac involvement, which are not typical in GSD Type I.

11. Q: What is the characteristic liver pathology seen in GSD Type IV (Andersen's disease)?

    A: GSD Type IV is characterized by the accumulation of an abnormal glycogen called polyglucosan, which leads to progressive liver cirrhosis. This is unique among the GSDs.

12. Q: What is the typical age of onset for symptoms in McArdle's disease (GSD Type V)?

    A: Symptoms of McArdle's disease typically appear in late childhood or adolescence, with exercise intolerance being the primary complaint.

13. Q: What is the "second wind" phenomenon observed in McArdle's disease?

    A: The "second wind" phenomenon refers to an improvement in exercise tolerance after a brief rest following the onset of muscle pain and fatigue. This occurs due to the increased availability of alternative fuel sources, such as fatty acids and glucose from the liver.

14. Q: How does dietary management differ between GSD Type I and GSD Type III?

    A: While both require frequent feedings to maintain normoglycemia, GSD Type I requires strict limitation of fructose, galactose, and sucrose. In contrast, GSD Type III management often includes a high-protein diet to support gluconeogenesis and muscle mass maintenance.

15. Q: What are the potential long-term complications of untreated GSD Type I?

    A: Long-term complications can include growth retardation, osteoporosis, renal dysfunction (including renal stones and renal tubular acidosis), hepatic adenomas with potential for malignant transformation, and polycystic ovaries in females.

16. Q: How is uncooked cornstarch used in the management of some GSDs, and why is it effective?

    A: Uncooked cornstarch is used as a slow-release form of glucose, particularly in GSD Types I and III. It is effective because it is digested slowly, providing a steady release of glucose over 3-4 hours, helping to maintain normoglycemia between meals and during the night.

17. Q: What is the genetic inheritance pattern of most glycogen storage disorders?

    A: Most glycogen storage disorders are inherited in an autosomal recessive pattern. However, GSD Type IX can have X-linked inheritance in some subtypes.

18. Q: Why is fasting particularly dangerous in GSD Type I?

    A: Fasting is dangerous in GSD Type I because these patients cannot mobilize glucose from glycogen or produce glucose through gluconeogenesis due to the lack of glucose-6-phosphatase. This leads to severe hypoglycemia, lactic acidosis, and ketosis during fasting periods.

19. Q: What is the role of liver transplantation in the management of glycogen storage disorders?

    A: Liver transplantation can be curative for the hepatic manifestations of some GSDs, particularly in severe cases of GSD Type I and IV. It corrects the enzymatic deficiency in the liver, improving glucose homeostasis and reversing many metabolic derangements.

20. Q: How does GSD Type VI (Hers' disease) differ clinically from other hepatic GSDs?

    A: GSD Type VI typically presents with a milder clinical course compared to Types I and III. It features mild hepatomegaly, growth retardation, and mild fasting hypoglycemia. Importantly, it often improves with age and may not require intensive dietary management in adulthood.

21. Q: What is the significance of elevated creatine kinase (CK) levels in glycogen storage disorders?

    A: Elevated CK levels are particularly significant in GSDs affecting muscle tissue, such as Types II, III, and V. In these disorders, CK elevation indicates ongoing muscle damage and can be used to monitor disease activity and response to treatment.

22. Q: How does ketotic hypoglycemia in GSD Type IX differ from the hypoglycemia seen in GSD Type I?

    A: In GSD Type IX, hypoglycemia is typically ketotic, meaning there is an increase in ketone production during fasting. This is in contrast to GSD Type I, where hypoglycemia is associated with suppressed ketone production due to the inhibition of fatty acid oxidation by excessive malonyl-CoA.

23. Q: What is the role of echocardiography in the evaluation and follow-up of patients with glycogen storage disorders?

    A: Echocardiography is crucial in evaluating and monitoring cardiac involvement in GSDs, particularly in Types II, III, and IV. It can detect cardiomyopathy, which is a significant feature of infantile-onset Pompe's disease (Type II) and can also occur in some cases of Types III and IV.

24. Q: How does newborn screening contribute to the early diagnosis and management of certain glycogen storage disorders?

    A: Newborn screening, particularly for Pompe's disease (GSD Type II), allows for early diagnosis and prompt initiation of enzyme replacement therapy. This can significantly improve outcomes, especially in infantile-onset cases. Screening typically involves measuring acid α-glucosidase activity in dried blood spots.

25. Q: What are the main differences in the pathophysiology and clinical presentation between hepatic and muscle forms of glycogen storage disorders?

    A: Hepatic forms (e.g., Types I, III, VI, IX) primarily affect glucose homeostasis and liver function, presenting with hepatomegaly, hypoglycemia, and growth issues. Muscle forms (e.g., Types II, V) mainly impact muscle function, presenting with weakness, exercise intolerance, and in some cases, cardiac involvement. Some types, like III, can affect both liver and muscle.

26. Q: How does continuous glucose monitoring (CGM) technology impact the management of glycogen storage disorders, particularly Type I?

    A: Continuous glucose monitoring provides real-time glucose data, allowing for more precise management of blood glucose levels in GSD Type I. It helps in adjusting feeding schedules and cornstarch doses, reduces the frequency of fingerstick tests, and can alert patients to impending hypoglycemia, especially during sleep.