Disease relevance of ACADVL

• This initial delineation of human mutations in VLCAD suggests that VLCAD deficiency reduces myocardial fatty acid beta-oxidation and energy production and is associated with cardiomyopathy and sudden death in childhood [1].
• Quantitative cDNA expression of normal human VLCAD was performed in the patients' fibroblasts, using vaccinia viral system, which demonstrated that the deficiency of the normal VLCAD protein causes impaired long-chain fatty acid beta-oxidation activity in the patients' fibroblasts [2].
• Until now, no clinical signs and symptoms of central nervous system involvement have been reported in VLCAD deficiency [3].
• Unlike wild-type VLCAD, F418L and F418V contained no bound FAD when expressed at extremely high levels in the baculovirus expression system [4].
• We describe the outcome of a 5-year-old girl with VLCAD deficiency who was first seen at 5 months of age with severe hypertrophic cardiomyopathy, hepatomegaly, encephalopathy, and hypotonia [5].

Psychiatry related information on ACADVL

• In this study, using in situ hybridization of the VLCAD and the LCHAD mRNA, we report on the expression of genes involved in the mitochondrial oxidation of long-chain fatty acids during early human development [6].

High impact information on ACADVL

• CONCLUSIONS: Infantile CM is the most common clinical phenotype of VLCAD deficiency [7].
• To examine whether these different phenotypes are due to differences in the VLCAD genotype, we investigated 58 different mutations in 55 unrelated patients representing all known clinical phenotypes and correlated the mutation type with the clinical phenotype [8].
• In patient fibroblasts, raising VLCAD activity to approximately 20% of normal control fibroblast activity raised palmitic acid beta-oxidation flux to the level found in control fibroblasts, which may offer important information for the rational design of future somatic gene therapy for VLCAD deficiency [2].
• We have isolated the human VLCAD cDNA and gene and determined the complete nucleotide sequences [1].
• Bezafibrate also diminished the production of toxic long-chain acylcarnitines by 90% in cells harboring moderate VLCAD deficiency [9].

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 [10].
• Significant laboratory findings included elevated plasma levels of creatine phosphokinase and acyl-carnitine and a fatty liver at biopsy suggesting a diagnosis of VLCAD deficiency [11].
• A patient with very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency presented in the neonatal period with hypoketotic hypoglycaemia and at the age of 1 year with rhabdomyolysis and normal glucose after fasting [12].

Biological context of ACADVL

• Characterization of the bidirectional promoter region between the human genes encoding VLCAD and PSD-95 [13].
• Overlapping gene structure of human VLCAD and DLG4 [14].
• Interestingly, VLCAD and DLG4 genes do not overlap in the mouse or Drosophila genomes [14].
• The transcription start site of the VLCAD gene was determined by primer extension analysis and the overlapping structure of VLCAD and DLG4 was clarified [14].
• Moreover, human VLCAD and human acyl-CoA oxidase showed extensive sequence homology corroborating the notion that these genes are evolutionarily related [15].

Anatomical context of ACADVL

• VLCAD associates with the inner mitochondrial membrane and catalyzes the initial step in mitochondrial long-chain fatty acid beta-oxidation [13].
• PCR-amplified VLCAD cDNAs were sequenced in cultured fibroblasts from two VLCAD-deficient patients [2].
• Using Northern and Western blot analysis to investigate the tissue specific distribution of VLCAD mRNA and protein in several human tissues we showed that VLCAD is most abundant in heart and skeletal muscle [15].
• Southern blot analysis of genomic DNA from hybrid cell lines was used to localize the VLCAD gene to human chromosome 17p11.2-p11.13105 [15].
• However, while mRNA expression of LCHAD could be clearly detected in the retina and spinal cord, expression of VLCAD mRNA was low to undetectable in these tissues [3].

Associations of ACADVL with chemical compounds

• A shared promoter between the two human genes encoding very long chain acyl-CoA dehydrogenase (VLCAD) and postsynaptic density protein 95 (PSD-95) is an ideal model to investigate bidirectional transcription in mammals [13].
• The results from di-(2-ethylhexyl) phthalate (DEHP)-treated HepG2 cells revealed that the minimal VLCAD promoter is able to up-regulate VLCAD expression in response to DEHP treatment [13].
• Replacing Glu-422 with glutamine (E422Q) caused a loss of enzyme activity by preventing the formation of a charge transfer complex between VLCAD and palmitoyl-CoA [4].
• Loss of FAD may change the folding of VLCAD subunit [4].
• The patients with VLCAD deficiency showed increases of mainly 5-tetradecenoic acid (14:1 omega 9) and to a minor extent 5-dodecenoic acid (12:1 omega 7), 5,8-tetradecadienoic acid (14:2 omega 6), and 7,10-hexadecadienoic acid (16:2 omega 6), in both the free and esterified fatty acid fraction [16].

Physical interactions of ACADVL

• Site-directed mutagenesis experiments showed that a mutated activator protein 2-binding site markedly reduced the transcriptional activity of both promoters and abolished the minimal VLCAD promoter's response to DEHP treatment [13].

Other interactions of ACADVL

• Our results showed that the essential promoter activity of PSD-95 is carried within an approximately 400-bp region, which covers the entire approximately 270-bp minimal promoter of VLCAD [13].
• The realization that the effect of the monogene, such as disease-causing mutations in the VLCAD, MCAD, and SCAD genes, may be modified by variations in other genes presages the need for profile analyses of additional genetic variations [17].
• Exposure to fibrates leads to normalization of fatty acid oxidation (FAO) in fibroblasts from patients with myopathic forms of CPT2 deficiency or VLCAD deficiency [18].
• Mature VLCAD is a homodimer of a 70-kDa protein associated with the mitochondrial membrane [19].
• Liver and heart showed expression of both very long-chain acyl-CoA dehydrogenase (VLCAD) and long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) mRNA [3].

Analytical, diagnostic and therapeutic context of ACADVL

• Western blot analysis of patient fibroblasts showed that the identified mutations result in severely reduced amounts of VLCAD protein [15].
• Cell therapy of VLCAD deficiency was related to drug-induced increases in VLCAD mRNA (+44 to +150%; P<0.001), protein (1.5-2-fold) and residual enzyme activity (up to 7.7-fold) in patient cells [9].
• 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 [10].
• The successful prenatal diagnosis of VLCAD and MCAD deficiencies using in vitro probes of fatty acid oxidation in fibroblasts suggests that this approach can potentially recognize many mitochondrial fatty acid oxidation defects even if no prior diagnosis is determined in the family at risk [20].
• A new diagnostic test for VLCAD deficiency using immunohistochemistry [21].

References