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Organic acids occur as physiological intermediates in a variety of intracellular metabolic pathways, such as catabolism of amino acids, mitochondrial β-oxidation of fatty acids, tricarboxylic acid cycle, and cholesterol and fatty acid biosynthesis (Figure 14-1).

FIGURE 14-1.

Organic acids in small molecule intermediary metabolism. (Modified with permission from Hoffmann GF, Feyh P. Organic acid analysis. Blau N, Duran M, Blaskovics ME, Gibson KM, eds. Physician’s Guide to the Laboratory Diagnosis of Inherited Metabolic Disease. 2nd ed. Heidelberg: Springer; 2003:27.)

Organic acidurias (OAs, also known as organic acidemias, organic acid disorders or organoacidopathies) are a group of disorders characterized by increased excretion of non-amino organic acids in urine. They are caused by deficiencies of single enzymes which are almost all inherited in an autosomal recessive manner. Most are caused by deficiencies of enzymes in the mitochondrial metabolism of coenzyme A (CoA)-activated carboxylic acids, often derived from amino acid breakdown. These disorders result in an accumulation of precursors, which are themselves toxic or are degraded to produce toxic metabolites in the affected pathway. The accumulating acyl-CoA esters are in equilibrium with corresponding acylcarnitines which can be analyzed by tandem mass spectrometry (MS/MS). Analysis of organic acids by gas chromatography-mass spectrometry (GC-MS) has disclosed accumulation of organic acids due to metabolic defects of many pathways beyond amino acid degradation, especially cholesterol, fatty acid oxidation, carbohydrate or energy metabolism (Figure 14-1).1 This chapter summarizes the knowledge on classic OAs caused by defects of amino acid degradation and on the clinically overlapping subgroup termed “cerebral” OAs.2 The cumulative frequency of the most important subgroups detectable by MS/MS newborn screening amounts to 1:6000 newborns, that is, the most common, acutely life-threatening inborn errors of metabolism.3,4

Amino acid degradation generally starts with removal or transamination of the α amino group, and in the associated OAs caused by more distal defects, characteristic organic acids accumulate upstream of the enzymatic block but without elevations of the primary amino acid. The definitive breakdown of many amino acids occurs intramitochondrially by oxidative decarboxylation to CoA derivates or other steps including dehydrogenation through (β-oxidative) degradation of CoA-activated carbonic acids, the so-called acyl-CoA compounds. In contrast to aminoacidopathies like phenylketonuria, OAs therefore frequently disturb the mitochondrial energy metabolism and predispose to acute metabolic decompensations and (keto-/lactic-) acidosis. The accumulating acyl-CoA compounds are esterified with free carnitine to prevent sequestration of CoA, resulting in a diagnostically and pathophysiologically important increase of acylcarnitines. These can be reliably detected by MS/MS even in dried blood spots—the basis for the now quickly spreading expanded newborn population screening for these disorders.3,4

The clinical manifestations of these disorders are due to toxic effects of these molecules on brain, liver, kidney, pancreas, retina, and other organs. In addition to different effects specific to individual organic acids, ...

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