ISOVALERIC ACIDEMIA
 
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    ISOVALERIC ACIDEMIA

     

    DEFINITION:

    A disorder of branch-chain amino acid metabolism characterized by the build-up of isovaleric acid resulting in episodes of vomiting, dehydration, and severe metabolic acidosis.

    EPIDEMIOLOGY:

    • incidence: rare, over 40 cases reported
    • age of onset:
      • first few days after birth
    • risk factors:
      • familial - autosomal recessive
        • chrom.#: 15q14-q15
        • gene: isovaleryl coenzyme A (CoA) dehydrogenase
      • M = F

    PATHOGENESIS:

    1. Background

    • isovaleryl CoA dehydrogenase catalyzes the conversion of isovaleric acid to 3-methylcrotonic acid in the branch-chain amino acid leucine degradation pathway
    • the resultant build up of isovaleric acid and its metabolites are toxic to the body resulting in the metabolic and neurological manifestations of the disease

    2. Genetic Defect

    • genetic defect -> defective expression of isovaleryl CoA dehydrogenase -> build up of isovaleric acid and its metabolites (isovalerylglycine, 3-hydroxyisovaleric acid) in body fluids (blood, urine) -> metabolic and neurological manifestations

    CLINICAL FEATURES:

    1. Classic (Acute) Form

    • onset within the first few days of life
    • infants who survive the neonatal period may have acute attacks of vomiting, acidosis, and ataxia usually triggered by stresses such as infection or surgery
    • these acute episodes may decrease in frequency with age

    1. Metabolic Manifestations

    • vomiting (may be severe)
    • characteristic "sweaty foot" odour of isovaleric acid with each acute episode

    2. Neurological Manifestations

    • lethargy -> coma
    • neonatal seizures
    • mental retardation

    2. Chronic Intermittent Form

    • onset from infancy to childhood
    • represents a milder form of the disease
    • present with acute episodes of vomiting, "sweaty foot" odour, acidosis, lethargy, and coma

    INVESTIGATIONS:

    1. Diagnostic

    • deficiency of isovaleryl CoA dehydrogenase in leukocytes or cultured skin fibroblasts
    • perinatal
      • deficiency of isovaleryl CoA dehydrogenase in cultured chorionic villi or amniocytes

    2. Serum (during an acute episode)

    • metabolic acidosis
    • serum amino acids (chromatography)
      • elevated isovaleric acid, glycine
    • moderate to severe hyperammonemia
    • hypocalcemia
    • pancytopenia - neutropenia, thrombocytopenia, and/or anemia (due to bone marrow suppression)

    3. Urine

    • elevated isovalerylglycine
      • during an acute attack and between episodes
      • more stable than isovaleric acid and therefore a more reliable urinary biochemical test than urinary isovaleric acid
      • excretion may be as high as 3 g/day (normal is less than 2 mg/day)
    • elevated isovaleric acid, glycine, 3-hydroxyisovaleric acid

    MANAGEMENT:

    1. Diagnosis

    1. Clinical - History, Physical

    2. Laboratory - enzyme deficiency on assay

    2. Goals of Therapy

    • avoidance of and symptomatic control of acute episodes
    • not curative

    3. Management of Strategies

    1. Acute Episodes

    • correct dehydration, electrolyte disturbances, and metabolic acidosis
    • may need exchange transfusion, hemodialysis, or peritoneal dialysis
    • diet
      • reverse catabolic state by providing sufficient calories orally or intravenously (i.e., with glucose)
      • reduce protein intake to 1-2 gm/kg/day
    • remove excess isovalerylic acid
      • administer glycine (250 mg/kg/day) to enhance the formation of isovalerylglycine which has a high urinary clearance
      • administer carnitine (100 mg/kg/day) to enhance the formation of isovalerylcarnitine which is also excreted in the urine
    • if severe hyperammonemia (blood ammonia greater than 200 uM) reduce blood ammonia

    2. Chronic Management

    1. Counselling

    • a chronic long-term disorder where the patient may decompensate when stressed and is at risk for mental and neurological deficits and sudden death
    • plan for acute episodes
      • aggressively treat infections
      • guidelines on when to contact the physician

    2. Diet

    • dietary consultation
    • diet restricted in protein (1-1.5 gm/kg/day) to reduce the intake of leucine
    • glycine and carnitine supplements after recovery from an acute attack

    4. Prognosis

    • death soon after birth if untreated in the Classical Form
    • better prognosis in the Chronic Intermittent Form
    • depends upon the severity of the enzyme deficiency and management of the initial and subsequent acute episodes ranging from a relatively normal life to mental and neurological deficits to death
    • some degree of mental retardation is common

     

     

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