Disease relevance of Acadvl

• Mitochondrial very-long-chain acyl-CoA dehydrogenase (VLCAD) deficiency is associated with severe hypoglycemia, cardiac dysfunction, and sudden death in neonates and children [1].
• DESIGN: VLCAD knockout mice exhibit stress-induced hypoglycaemia and skeletal myopathy; symptoms resembling human VLCADD [2].
• Clinically, all patients with VLCAD deficiency exhibited cardiac disease [3].

High impact information on Acadvl

• Skin fibroblasts from 26 patients suspected of having a disorder of mitochondrial beta-oxidation were analyzed for VLCAD protein using immunoblotting, and 7 of them contained undetectable or trace levels of the enzyme [3].
• The seven deficient fibroblast lines were characterized by measuring acyl-coenzyme A dehydrogenation activities, overall palmitic acid oxidation, and VLCAD protein synthesis using pulse-chase, further confirming the diagnosis of VLCAD deficiency [3].
• Although many patients have been found to have very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency, none have been documented with long-chain acyl-CoA dehydrogenase (LCAD) deficiency [4].
• In order to understand the metabolic pathogenesis of long-chain fatty acid oxidation disorders, we generated mice with VLCAD deficiency (VLCAD(-/-)) and compared their pathologic and biochemical phenotypes of mice with LCAD deficiency (LCAD(-/-)) and wild-type mice [4].
• Progeny with the combined LCAD(+/+)//VLCAD(+/-) genotype were over-represented in offspring from sires and dams heterozygous for both LCAD and VLCAD mutations [4].

Chemical compound and disease context of Acadvl

• Very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency is a disorder of fatty acid beta-oxidation that can present at any age with cardiomyopathy, rhabdomyolysis, hepatic dysfunction, and/or nonketotic hypoglycemia [5].

Biological context of Acadvl

• Assignment of the gene for very-long-chain acyl-CoA dehydrogenase (Acadvl) to mouse chromosome band 11B2-B5 by in situ hybridization [6].
• Biochemical assessment of the VLCAD(/- mice BAT showed increased oxygen consumption, attributed to uncoupled respiration in the absence of stress [1].
• We conclude that disturbed mitochondrial bioenergetics in BAT is a critical contributing factor for the cold sensitivity in VLCAD deficiency [1].
• Antibody specificity was demonstrated in Western blots of human VLCAD deficient fibroblasts and in pCMV-hVLCAD transiently transfected VLCAD deficient fibroblasts [5].
• This study gives biochemical evidence of impaired gluconeogenesis as one of the causes for hypoglycaemia observed in VLCAD deficiency [7].

Anatomical context of Acadvl

• We measured carnitine and acylcarnitine profiles in liver, skeletal muscle (SkM), bile, and blood from VLCAD knock-out mice and controls under nonstressed and various stress conditions [8].

Associations of Acadvl with chemical compounds

• Our results demonstrate different tissue-specific long-chain acylcarnitine profiles in response to various stressors, which may be of importance with respect to the heterogeneous clinical manifestations of VLCAD deficiency in humans [8].
• In this paper we have used the VLCAD knockout mouse as a model to study changes in blood carnitine and acylcarnitine profiles under stress [2].
• Palmitoyl-CoA dehydrogenase activity in skin fibroblasts from seven patients with unidentified defects of fatty acid oxidation was measured in the presence and absence of antibodies against medium-chain, long-chain, and very-long-chain acyl-CoA dehydrogenases (VLCAD) [9].
• To study hepatic glucose production in FAO defects, we used the knockout mouse model of very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency presenting with stress-induced hypoglycaemia [7].

Other interactions of Acadvl

• In LCAD-/- and VLCAD-/- mice challenged with fasting and cold exposure, expression of fatty acid oxidation genes was elevated in liver, consistent with increased PPARalpha activity [10].
• Mitochondrial beta-oxidation activity of fatty acids and expression of its related enzymes, including VLCAD, LCAD, and HCD, were down-regulated; on the other hand, peroxisomal beta-oxidation and its related enzymes, including AOX and BFE, were up-regulated [11].
• It is a member of the acyl-CoA dehydrogenase (Acad or ACAD) gene family of enzymes, which also includes very-long-chain (VLCAD), medium-chain (MCAD), and short-chain (SCAD) acyl-CoA dehydrogenases [12].
• We found that VLCAD-deficient hearts have microvesicular lipid accumulation, marked mitochondrial proliferation, and demonstrated facilitated induction of polymorphic ventricular tachycardia, without antecedent stress [13].

Analytical, diagnostic and therapeutic context of Acadvl

• Altogether, these steps are important in the development of a durable gene therapy for VLCAD deficiency [5].
• Transfected fibroblasts showed correction of the metabolic block as demonstrated by normalization of C14- and C16-acylcarnitine species in cell culture media and restoration of VLCAD activity in cells [5].

References