Relationship between unusual hepatic acyl coenzyme A profiles and the pathogenesis of Reye syndrome.
This study examines the relationship between impaired fatty acid oxidation and the pathogenesis of Reye syndrome. We present a hypothesis proposing that many clinical signs of this childhood disease are caused by accumulation of unusual acyl CoA esters, precursors to deacylated metabolites found in the patients' blood and urine. A new method was developed to measure acyl CoA compounds in small human liver biopsy samples, offering several advantages over previous techniques. A major finding was an accumulation in Reye syndrome patients of short- and medium-chain acyl CoA intermediates of fatty acid and branched-chain amino acid oxidation. These metabolites included octanoyl, isovaleryl, butyryl, isobutyryl, propionyl, and methylmalonyl CoA esters. The findings were explained in a model of hepatic fatty acid oxidation involving three interrelated pathways: mitochondrial beta-oxidation, peroxisomal beta-oxidation, and omega-oxidation in the endoplasmic reticulum. The results suggest that pathogenesis in Reye syndrome stems from generalized mitochondrial damage resulting in accumulation of acyl CoA esters. High levels of these compounds lead to inhibition of mitochondrial pathways for ureogenesis, gluconeogenesis, and fatty acid oxidation. The inhibited pathways, in turn, could cause the hyperammonemia, hypoglycemia, and hypoketonemia observed in patients. The model also explains underlying biochemical differences between patients with Reye syndrome and medium-chain acyl CoA dehydrogenase deficiency, another disorder of fatty acid metabolism. Acetyl CoA levels, in the latter disease, were dramatically decreased, compared with both human controls and Reye syndrome patients.
Division of Diabetes and Metabolism, Boston University School of Medicine, Massachusetts 02118.
B E
BE
Corkey
D E
DE
Hale
M C
MC
Glennon
R I
RI
Kelley
P M
PM
Coates
L
L
Kilpatrick
C A
CA
Stanley
D000214:Acyl Coenzyme A / Q000032:analysis / Q000378:metabolism*; D000227:Adenine Nucleotides / Q000032:analysis; D000293:Adolescent; D002648:Child; D005260:Female; D006801:Humans; D008099:Liver / Q000201:enzymology*; D008297:Male; D008316:Malonyl Coenzyme A / Q000032:analysis; D011742:Pyrimidine Nucleotides / Q000032:analysis; D012202:Reye Syndrome / Q000201:enzymology / Q000209:etiology*
D000214:Acyl Coenzyme A; D000227:Adenine Nucleotides; D011742:Pyrimidine Nucleotides; C034681:octanoyl-coenzyme A; D008316:Malonyl Coenzyme A