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Key Points

  • Disease summary:

    • Organic acidemias are disorders of intermediary metabolism of one or more amino acid constituents of protein, due to a deficiency of an enzyme in the respective catabolic pathway, or an essential enzyme cofactor.

    • The accumulation of the toxic intermediates (organic acids) can result in life-threatening organ damage, primarily of the brain, liver, and kidneys.

    • There is a phenotypic spectrum, ranging from severe neonatal presentation to later onset of milder symptoms in childhood or adulthood. Clinical phenotype depends largely on the amount of residual enzyme activity, determined by the mutations.

  • Hereditary basis:

    • Autosomal recessive

  • Differential diagnosis:

    • Sepsis

    • Drug or chemical intoxication

    • Mitochondrial disease

Diagnostic Criteria and Clinical Characteristics

Urine organic acid analysis demonstrates accumulation of specific metabolites. Plasma acylcarnitine analysis detects characteristic acylcarnitine conjugates of accumulated metabolites, but is not always diagnostic, for example, propionylcarnitine (C3) accumulates in both propionic acidemia (PA) and methylmalonic acidemia (MMA), and hydroxyisovalerylcarnitine (C5OH) accumulates in several disorders (Table 95-1). The diagnosis can usually be confirmed by measurement of the enzyme activity in fibroblasts or white blood cells. Mutation analysis is clinically available for most organic acidemias, though it is not usually a first-line test because of the large number of mutations in each disorder. In some instances, there are mutation hot spots, or an increased frequency of certain mutations due to a founder effect, such as in the Inuits of Greenland and in Japanese with PA and the Old Order Amish with glutaric aciduria type 1 (GA1). In these cases, targeted mutation analysis is feasible.

Table 95-1Examples of Other Organic Acidemias

Severe metabolic acidosis with ketosis is the hallmark of the organic acidemias. Lactic acidosis may occur, either as ...

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