Fatal Hepatic Short-Chain l-3-Hydroxyacyl-Coenzyme a Dehydrogenase Deficiency: Clinical, Biochemical, and Pathological Studies on Three Subjects with This Recently Identified Disorder of Mitochondrial β-Oxidation

Abstract

This report describes the clinical, biochemical, and pathological findings in three infants with hepatic short-chain L-3-hydroxyacyl-coenzyme A dehydrogenase (SCHAD) deficiency, a recently recognized disorder of the mitochondrial oxidation of straight-chain fatty acids. Candidate subjects were identified from an ongoing study of infant deaths. SCHAD analysis was performed on previously frozen liver and skeletal muscle on subjects with a characteristic urine organic acid profile. Autopsy findings were correlated with the biochemical abnormalities. Enzyme analysis in liver revealed marked deficiency in SCHAD with residual activities of 3-11%. All subjects had normal activity in skeletal muscle. However, Western blot analysis of SCHAD revealed an identical truncated protein in both liver and muscle from one patient, suggesting that SCHAD is similar in liver and muscle and that the normal activity in muscle may be due to other enzymes with C4 activity. Autopsy findings revealed marked steatosis and a muscle pattern consistent with spinal muscular atrophy in one patient. Lipid storage was less pronounced in one patient and not detected in the third patient who had a well-documented history of recurrent hypoglycemia. This is the initial pathological characterization of this enzyme defect, and our observations suggest that SCHAD deficiency is a very severe disorder contributing to early infant death.

3‐Hydroxyacyl‐CoA dehydrogenase and short chain 3‐hydroxyacyl‐CoA dehydrogenase in human health and disease

“…differ both quantitatively and qualitatively from liver isoforms [56]. The alternative splicing machinery, which is tissue-specific and development-dependent [60,61], is probably responsible for differences between liver and skeletal muscle HADs.…”

“…However, a second isoform of HAD has now been cloned from skeletal muscle (GenBank accession number ). Moreover, it appears that skeletal muscle may contain HAD isoforms that differ both quantitatively and qualitatively from liver isoforms [56]. The alternative splicing machinery, which is tissue‐specific and development‐dependent [60,61], is probably responsible for differences between liver and skeletal muscle HADs.…”

“…Herbivores adsorb significant amounts of this compound from the alimentary canal, which may be the reason why ruminant liver is a rich source of SCHAD [21]. In contrast, the concentration of SCHAD in rat or human liver has been estimated to be no more than one-tenth that of HAD, and the activity of SCHAD may account for the residual 3-hydroxyacyl-CoA dehydrogenase activity towards the short chain substrate (C 4 ) in livers of previously reported cases of SCHAD deficiency [55][56][57]. SCHAD is identical to the only 17b-HSD found in mitochondria [23,24], and its important role in steroid metabolism has been reviewed recently [25].…”

Identification of fatty acid oxidation disorder patients with lowered acyl‐CoA thioesterase activity in human skin fibroblasts

“…Patients 2 and 4 had normal levels of Type‐II protein, as judged by Western‐blot analysis, which was in line with their acyl‐CoA thioesterase activity. The same blot was stripped and re‐probed with an antibody generated to the mitochondrial short chain 3‐hydroxyacyl‐CoA dehydrogenase (SCHAD) [29], showing that this protein was unaffected in the patients. Quantification of the protein levels in patients relative to controls showed that patients 1 and 3 retained approximately 25–30% Type‐II protein; however, patient 5 retained only 10% of Type‐II protein.…”

“…Patients 2 and 4 had normal levels of Type-II protein, as judged by Western-blot analysis, which was in line with their acyl-CoA thioesterase activity. The same blot was stripped and re-probed with an antibody generated to the mitochondrial short chain 3-hydroxyacyl-CoA dehydrogenase (SCHAD) [29], showing that this protein was unaffected in the patients. Quantification of the protein levels Immunoprecipitation of acyl-CoA thioesterase activity was carried out by incubating human skin fibroblast homogenate with either preimmune serum or an affinity-purified antibody to rat cytosolic acyl-CoA thioesterase II (CTE-II).…”