PYROGLUTAMIC ACIDEMIA
 
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PYROGLUTAMIC ACIDEMIA

 

DEFINITION:

An inborn error of glutamic acid metabolism characterized by an enzyme deficiency resulting in hematological and neurological manifestations with episodes of metabolic acidosis.

EPIDEMIOLOGY:

  • incidence: rare (about 16 cases reported)
  • age of onset:
    • familial - autosomal recessive
      • chrom.#: ?
      • gene: glutathione synthetase
    • M = F

PATHOGENESIS:

1. Glutathione Synthetase

  • the gamma-glutamyl cycle is responsible for the synthesis (and degradation) of glutathione
  • glutathione synthetase is the final enzyme in this cycle and catalyzes the conversion of gamma-glutamylcysteine to glutathione (GH)
  • glutathione has several functions in the cell:
    • protects other sulfhydryl-containing compounds (enzymes, CoA) from oxidation
    • detoxifies peroxides (hydrogen peroxide)
    • maintains cells in a reduced state (RBC's)
    • participates in amino acid transport across cell membranes

2. Genetic Defect

  • genetic defect -> deficiency of glutathione synthetase activity
  • reduced synthesis of glutathione plus secondary accumulation of pyroglutamic acid (5-oxoproline) -> severe metabolic acidosis with hematological and neurological manifestations
  • glutathione deficiency in RBC's results in an inability to keep the RBC's in a reduced state -> destabilization of the RBC membrane -> hemolytic anemia and neonatal jaundice
  • there is a secondary accumulation of 5-oxoproline due to the increased conversion of gamma-glutamylcysteine to 5-oxoproline by the enzyme gamma-glutamyl cyclotransferase
  • two clinical variants:
  • Type I - Severe Form
  • Type II - Mild Form
  • in the severe form there is a generalized enzyme deficiency with severe acidosis and 5-oxoprolinuria while in the mild form the enzyme deficiency is limited to the RBC's and there is no acidosis or 5-oxoprolinuria

CLINICAL FEATURES:

1. Metabolic Manifestations

1. Metabolic Acidosis

  • onset within the first week of life
  • severe and chronic
  • acute episodes occur following surgical procedures or intercurrent infections

2. Hematological Manifestations

1. Hemolytic Anemia

  • onset within the first week of life plus neonatal jaundice
  • mild to moderate

2. Others

  • increased tendency for thrombosis

3. Neurological Manifestations

1. Movement Disorder

  • ataxia
  • progressive intention tremor
  • spastic quadriplegia

2. Others

  • mental retardation
  • psychomotor developmental delay

INVESTIGATIONS:

1. Diagnostic

  • deficiency of glutathione synthetase activity in erythrocytes (both forms) and cultured skin fibroblasts (Type I)
  • prenatal - ?

2. Serum

  • severe metabolic acidosis with a wide anion gap
  • elevated levels of 5-oxoproline
  • reduced glutathione content of RBC's (0-25% of normal)

3. Urine

  • massive 5-oxoprolinuria (up to 40g/d)
  • reduced excretion of urea

4. Biopsy of Affected Tissue (Type I)

  • reduced levels of glutathione
  • increased amounts of 5-oxoproline
  • low glutathione synthetase activity

MANAGEMENT:

1. Supportive

  • no treatment for underlying disease
  • multidisciplinary approach
    • Paediatrics, Haematology, Neurology
    • genetic counselling

2. Avoidance

  • avoid drugs and oxidants that may cause hemolysis, i.e., ascorbic acid
  • stress - surgery, infections

3. Medications

  • bicarbonate po or IV for metabolic acidosis
  • use of antioxidants is experimental, i.e., cysteine, penicillamine, mercaptopyridoxal, vitamin E

 

 

 

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