Concentrations of
l-carnitine and acylcarnitines have been determined in urine from patients with disorders of organic
acid metabolism associated with an intramitochondrial accumulation of
acyl-CoA intermediates. These included
propionic acidemia,
methylmalonic aciduria,
isovaleric acidemia, multicarboxylase deficiency,
3-hydroxy-3-methylglutaric aciduria, methylacetoacetyl-
CoA thiolase deficiency, and various dicarboxylic acidurias including glutaric aciduria,
medium-chain acyl-CoA dehydrogenase deficiency, and
multiple acyl-CoA dehydrogenase deficiency. In all cases, concentrations of acylcarnitines were greatly increased above normal with free
carnitine concentrations ranging from undetectable to supranormal values. The ratios of
acylcarnitine/
carnitine were elevated above the normal value of 2.0 +/- 1.1.
l-Carnitine was given to three of these patients; in each case, concentrations of plasma and urine carnitines increased accompanied by a marked increase in concentrations of short-chain acylcarnitines. These acylcarnitines have been examined using fast atom bombardment mass spectrometry in some of these diseases and have been shown to be
propionylcarnitine in
methylmalonic aciduria and
propionic acidemia,
isovalerylcarnitine in
isovaleric acidemia, and
hexanoylcarnitine and
octanoylcarnitine in
medium-chain acyl-CoA dehydrogenase deficiency. The excretion of these acylcarnitines is compatible with the known accumulation of the corresponding
acyl-CoA esters in these diseases. In this group of disorders, the increased
acylcarnitine/
carnitine ratio in urine and plasma indicates an imbalance of mitochondrial mass action homeostasis and, hence, of
acyl-CoA/
CoA ratios. Despite naturally occurring attempts to increase endogeneous
l-carnitine biosynthesis, there is insufficient
carnitine available to restore the mass action ratio as demonstrated by the further increase in
acylcarnitine excretion when patients were given oral
l-carnitine.(ABSTRACT TRUNCATED AT 250 WORDS)