Condition

Organic Acidemias

Editors: Paldeep S. Atwal MD; Zbigniew Fedorowicz PhD, MSc, DPH, BDS, LDSRCS; Scott A. Barron MD, FAAP

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Background Information

Description

  • heterogeneous group of rare, inherited metabolic disorders characterized by the accumulation of metabolites (organic acids) resulting from deficiency of an enzyme or transport protein required in 1 of the metabolic pathways involved in the catabolism of amino acids, carbohydrates, or lipids
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  • > 65 organic acidemias have been identified
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Also Called

  • organic acidurias
  • organic acid disorders

Types

  • classical forms result from accumulation of toxic metabolites (organic acids) from catabolism of branched-chain amino acids
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    • often present in the neonatal period with life-threatening metabolic decompensation
    • examples include methylmalonic acidemia, propionic acidemia, and isovaleric acidemia
  • cerebral forms result from abnormal metabolism of non-branched-chain amino acids, lipids, proteins, and carbohydrates
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    • present with predominantly neurological symptoms, usually in the absence of severe metabolic decompensation
    • examples include glutaric acidemia type 1 and multiple carboxylase deficiency

Epidemiology

Incidence/Prevalence

  • collective reported incidence for organic acidemias is 1 case per 3,000 live births
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    table iconTable 1. Reported Incidence of Select Organic Acidemias
    Table 1: Reported Incidence of Select Organic Acidemias
    Organic Acidemia Incidence
    Isolated methylmalonic acidemia 1 per 50,000 births
    Propionic acidemia 1 per 100,000-150,000 births
    Isovaleric acidemia
    • 1 per 100,000 births diagnosed by newborn screening
    • 1 per 280,000 diagnosed after symptom onset
    Glutaric acidemia type 1 1 per 110,000 births

    Reference -

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  • high incidence of propionic acidemia reported in Arabic countries and Inuit population of Greenland
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Risk Factors

  • consanguineous parents
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Etiology and Pathogenesis

Causes

  • most are inherited in autosomal recessive pattern; few are X-linked
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Pathogenesis

  • inherited enzymatic deficiency in various catabolic pathways results in accumulation of mono-, di-, and tricarboxylic acids (organic acids)
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  • pathologic metabolites (organic acids) are able to inhibit other enzyme systems, especially those involved in oxidative phosphorylation, the glycine cleavage system, and the urea cycle which leads to neurologic derangements and, in select disorders, multisystem disease affecting cardiac, gastrointestinal or renal systems
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  • neurotoxic effects of accumulated organic acids include
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    • inhibiting specific enzymes of brain energy metabolism
    • impairing metabolic coupling between astrocytes and neurons
    • stimulating excitotoxic pathways
    • interfering with autoregulation of cerebral blood flow
    • stimulating production of reactive oxygen species
  • hypotheses for the brain damage seen in organic acidemias include
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    • mitochondrial accumulation of toxic acetyl CoA esters as they do not cross biological membranes
    • retention and increased concentration of toxic metabolites in the brain compartment due to the impermeability of the blood-brain barrier
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