PROPIONIC ACIDEMIA
 
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PROPIONIC ACIDEMIA

 

DEFINITION:

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

EPIDEMIOLOGY:

  • incidence: rare
  • age of onset:
    • first weeks of life
  • risk factors:
    • familial - autosomal recessive
      • chrom.#: 13q22-q34
      • gene: propionyl-CoA-carboxylase (alpha subunit)
    • M = F

PATHOGENESIS:

1. Background

1. Propionyl-CoA-Carboxylase (PCCA)

  • a mitochondrial enzyme consisting of 12 subunits (dodecamer)
    • 6 biotin-containing alpha-subunits
    • 6 beta-subunits
  • the gene for each subunit is located on different chromosomes: 13 (alpha) and 3q (beta)
  • functions in the catabolic pathway for the odd-chain fatty acids threonine, methionine, isoleucine and valine
  • Propionic Acidemia can arise from mutations in either the alpha or beta subunit

2. Ketotic Hyperglycinemia

  • formally a collection of disorders characterized by the accumulation of glycine in the plasma and urine
  • now known as a heterogeneous group of disorders arising from various enzyme deficiencies, i.e., propionic acidemia,methylmalonic acidemia, isovaleric acidemia, and beta-ketothiolase deficiency

2. Genetic Defect

  • genetic defect -> deficiency of PCCA activity -> accumulation of propionic acid -> direct effect on other systems:
    • inhibition of citric acid cycle enzymes -> ketosis
    • inhibition of acetylglutamate synthetase -> secondary hyperammonemia
    • inhibition of granulocytes, T and B cell development -> recurrent infections
  • multiple mutations have already been identified in the beta-subunit gene (insertion/deletion mutations, in-frame 3 bp deletion, point mutations, 8 bp intron deletion) (Ohura, T. et al., Human Genetics 92: 397 [1993])

CLINICAL FEATURES:

1. Classic Presentation

  • onset within the first few weeks of life with recurrent episodes triggered by intercurrent infections, constipation, and/ or a high-protein diet
  • episodes may be separated by periods of seemingly normal health

1. Metabolic Manifestions

  • apneas
  • hypoglycemia
  • poor feeding
  • vomiting

2. Neurological Manifestations

  • lethargy -> coma -> death
  • infantile hypotonia
  • neonatal seizures (in 30% of cases)
  • mental retardation

3. Hematological Manifestations

  • frequent infections with recurrent candidiasis
  • transient purpura

4. Other Manifestations

  • osteoporosis with pathologic fractures

INVESTIGATIONS:

1. Diagnostic

  • deficiency of propionyl-CoA-carboxylase activity in leukocytes or cultured skin fibroblasts
  • perinatal
    • deficiency of PCCA activity in cultured chorionic villi or amniocytes

2. Serum (during an acute episode)

  • metabolic acidosis with a wide anion gap, dehydration, hypoglycemia
  • secondary hyperammonemia
  • secondary carnitine deficiency
  • serum amino acids (chromatography)
    • elevated glycine
  • serum organic acids
    • eleved propionic and methylcitric acids
  • CBC
    • neutropenia, thrombocytopenia

3. Urine

  • urine amino acids
    • elevated glycine
  • urine organic acids
    • elevated ketoacids - propionic acid, methylcitric acid, 3-hydroxypropionic acid, propionylglycine, tiglic acid, tiglylglycine, 2-methyloacetoacetic acid

MANAGEMENT:

1. Diagnosis

  • 1. Clinical - History, Physical
  • 2. Laboratory - enzyme deficiency on assay

    • 2. Education

    • diagnosis, definition, epidemiology, treatment options, prognosis

    3. Goals of Therapy

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

    4. Management Strategies

    1. Acute Episodes

  • 1. Supportive
    • correct dehydration, electrolytes disturbances, and metabolic acidosis (bicarbonate)
    • correct triggers - constipation, intercurrent infections
    • may need peritoneal dialysis to remove ketoacids and ammonia
  • 2. Diet
    • parenteral hyperalimentation with minimal amounts of protein (0.25 g/kg/day) to provide adequate calories to prevent a catabolic state
  • 3. Medications
  • 1. Oral Neomycin
    • prevents the production of propionic acid by intestinal bacteria by sterilizing the intestinal tract flora
  • 2. L-Carnitine
    • 50-100 mg/kg/day
  • 3. Biotin
    • 10 mg/day in case biotin-responsive

    • 2. Chronic Management

  • 1. Counselling
    • a chronic long-term disorder where the patient may decompensate when stressed and is at risk for mental retardation and sudden death
    • moniter gases, serum/urine ammino acids/organic acids, growth parameters
  • 2. Diet
    • dietary consultation
    • Milupa OS1 - a formula low in propionate precursors (isoleucine, valine, methionine threonine)
    • diet restricted in protein (1-1.5 g/kg/day) consisting of 50-75% natural protein to prevent deficiency of essential amino acids
  • 3. Medications
    • chronic alkaline therapy to correct low-grade chronic acidosis

    • 5. Prognosis

    • death early in life if untreated
    • depends upon the severity of the enzyme deficiency and management of the initial and subsequent acute episodes
    • normal development is possible but most patients have some degree of permanent neurodevelopmental deficit despite adequate therapy

     

     

     

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