VON GIERKE DISEASE - GLYCOGENOSIS Ia
 
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VON GIERKE DISEASE - GLYCOGENOSIS 1a

 

DEFINITION:

A glycogen storage disease characterized by the accumulation of glycogen in the liver and associated with hepatomegaly and hypoglycemia.

EPIDEMIOLOGY:

  • incidence: 1/40,000 live births
  • age of onset:
    • newborn
  • risk factors:
    • familial - autosomal recessive
      • chrom.#: ?
      • gene: glucose-6-phosphatase
    • M = F

PATHOGENESIS:

1. Background

  • glucose-6-phosphatase catalyzes the conversion of glucose-6-phosphate to glucose
  • disease first reported by von Gierke in 1929
  • the enzyme deficiency was first reported by Coris in 1952 and was the first inborn error of metabolism to be enzymatically defined

2. Genetic Defect

  • genetic defect -> deficiency of glucose-6-phosphatase activity
  • inability of cells to metabolize glycogen -> accumulation of glycogen in the liver, kidneys (hepatorenal glycogenosis), and intestinal wall
  • persistent hypoglycemia may cause
    • a reduction in platelet adhesiveness -> bleeding tendency
    • stimulates glucagon secretion -> hepatoproliferative action
    • formation of adenomatous nodules in the liver
  • no involvement of muscle (skeletal or cardiac)
  • Typical Presentation: a short, cherub-faced child with mild hypotonia and protuberant abdomen (due to hepatomegaly) with failure to thrive by 1 year of age

PATHOLOGY:

1. Liver Biopsy

  • cytoplasmic lipid deposition with glycogen deposits in the nucleus
  • adenomas and hepatomas

CLINICAL FEATURES:

1. Hepatic Manifestations

1. Hypoglycemia

  • neonatal/infantile hypoglycemic seizures
  • episodes of hypoglycemia associated with stress or infections in childhood
  • episodes may occur without clinical features

2. Hepatomegaly

  • not associated with splenomegaly
  • may cause a protuberant abdomen

3. Complications

1. Adenomatous Nodules

  • develop during or after the 2nd decade
  • may be associated with massive bleeding
  • may undergo malignant degeneration to a hepatocellular carcinoma (hepatoma)

2. Renal Manifestations

1. Fanconi Syndrome

  • episodes of vomiting, dehydration, weakness, and unexplained fever
  • anorexia, constipation
  • polydipsia and polyuria
  • failure to thrive and growth failure
  • rickets
  • renal failure after 2nd decade

3. Other Manifestations

1. Central Nervous System

  • mild infantile hypotonia
  • gross motor developmental delay
  • normal intelligence

2. Respiratory

  • recurrent lung infections (chronic cough)

3. Hematologic

  • frequent nose bleeds beginning around age 2 and often associated with respiratory tract infections

4. Musculoskeletal

  • gout (in adulthood)
  • lumbar lordosis
  • short stature

5. Integument

  • xanthomas in 10% of cases
    • over elbows, knees, buttocks, and hips

INVESTIGATIONS:

1. Diagnostic

  • deficiency of glucose-6-phosphatase activity in samples from liver (leukocytes and cultured skin fibroblasts do not contain this enzyme and thus prenatal diagnosis by this technique is not feasible)

2. Tolerance Tests

1. Galactose or Fructose

  • contraindicated in this disorder as administration of each may precipitate a severe hypoglycemic episode

2. Glucagon

  • lack of rise in blood glucose after SC epinephrine or IV glucagon but striking increase in lactate
  • used to differentiate between GSD Ia and GSD III

3. Serum

1. Von Gierke Disease

  • hypoglycemia
  • conjugated hyperbilirubinemia
  • hyperlipidemia, hypertriglyceridemia, hypercholesterolemia
  • hyperuric acidemia (gout)
  • glucagonemia
  • abnormal liver function tests (elevated transaminases)
  • anion gap metabolic acidosis with lactic acidosis
  • prolonged bleeding time
  • N: PT, PTT, coagulation factors, CBC

2. Fanconi Syndrome

  • normal anion gap hyperchloremic metabolic acidosis (with low serum bicarbonate)
  • normal or low amino acids
  • normal glucose
  • hypophosphatemia, hypokalemia, hypouricemia
  • elevated BUN and creatinine (CRF, ESRF)

4. Urine

1. Von Gierke Disease

  • excess lactate, 2-oxoglutarate, C-6 to C-10 dicarboxylic acid, uric acid
  • normal ketones, catecholamines

2. Fanconi Syndrome

  • generalized (non-specific) hyperaminoaciduria
  • glucosuria, phosphaturia
  • pH <5.5 with low specific gravity (hyposthenuria)
  • bicarbonaturia, hyperkaliuria, uricosuria, tubular proteinuria, carnitinuria, low urinary ammonia

5. Imaging Studies

1. CT (Abdomen)

  • hepatomegaly +/- adenomas and hepatomas
  • moniter q6-12 months
  • moderately enlarged kidneys

2. Skeletal X-Rays

  • osteoporosis

MANAGEMENT:

1. Supportive

  • no treatment for underlying disease
  • multidisciplinary approach
    • Paediatrics, Nephrology, Gastrology, Orthopedics
    • genetic counselling

2. Medical

  • frequent glucose feeds (at least 6mg glucose/min/kg)
  • allopurinol for elevated uric acid
  • alkalinizing agent (i.e., Polycitra) for acidosis

3. Surgery

  • renal transplantation for ESRF

 

Pediatric Database - VON GIERKE DISEASE - GLYCOGENOSIS Ia

 

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