Early Neonatal Diagnosis of Long-Chain 3-Hydroxyacyl Coenzyme A Dehydrogenase and Mitochondrial Trifunctional Protein Deficiencies (original) (raw)
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Proceedings of the National Academy of Sciences, 1995
Mitochondrial long chain fatty acid beta-oxidation provides the major source of energy in the heart. Deficiencies of human beta-oxidation enzymes produce sudden, unexplained death in childhood, acute hepatic encephalopathy, skeletal myopathy, or cardiomyopathy. Long chain 3-hydroxyacyl-CoA dehydrogenase [LCHAD; long-chain-(S)-3-hydroxyacyl-CoA:NAD+ oxidoreductase, EC 1.1.1.211] catalyzes the third step in beta-oxidation, and this activity is present on the C-terminal portion of the alpha subunit of mitochondrial trifunctional protein. We used single-stranded conformation variance analysis of the exons of the human LCHAD (alpha subunit) gene to determine the molecular basis of LCHAD deficiency in three families with children presenting with sudden unexplained death or hypoglycemia and abnormal liver enzymes (Reye-like syndrome). In all families, the mothers had acute fatty liver and associated sever complications during pregnancies with the affected infants. The analysis in two affec...
Journal of Clinical Investigation, 1996
Mitochondrial trifunctional protein (MTP) is a recently identified enzyme involved in mitochondrial  -oxidation, harboring long-chain enoyl-CoA hydratase, long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) and long-chain 3-ketothiolase activity. A deficiency of this protein is associated with impaired oxidation of long-chain fatty acids which can lead to sudden infant death. Furthermore, it is clear that this inborn error of fatty acid oxidation is very frequent, second to medium chain acyl-CoA dehydrogenase deficiency. In most patients only the LCHAD activity of MTP is deficient with near normal activity of the two other enzyme activities of the complex. We recently described the occurrence of a frequent G1528C mutation in the cDNA coding for the ␣ subunit of MTP. Using S. cerevisiae for expression of wild type and mutant protein we show that the G1528C mutation is directly responsible for the loss of LCHAD activity. Furthermore, we describe a newly developed method allowing identification of the G1528C mutation in genomic DNA. The finding of an 87% allele frequency of the G1528C mutation in 34 LCHAD deficient patients makes this a valuable test for prenatal diagnosis. Finally, we show that the gene encoding the ␣ subunit of MTP is located on chromosome 2p24.1-23.3. ( J. Clin. Invest. 1996. 98:1028-1033.) Key words: fatty acid • 3-hydroxyacyl-CoA dehydrogenase • hereditary disease • chromosome mapping • gene expression
Pediatric and Developmental Pathology, 1999
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 s...
Journal of Inherited Metabolic Disease
General mitochondrial trifunctional protein (TFP) deficiency leads to a wide clinical spectrum of disease ranging from severe neonatal/infantile cardiomyopathy and early death to mild chronic progressive sensorimotor poly-neuropathy with episodic rhabdomyolysis. Isolated long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency resulting from the common Glu510Gln mutation usually gives rise to a moderately severe phenotype with multiorgan involvement with high morbidity and mortality. However, isolated LCHAD deficiency can also be consistent with long-term survival in patients identified and treated from an early age. We present biochemical, clinical and mutation data in 9 patients spanning the full spectrum of disease. Fibroblast acylcarnitine profiling shows good correlation with clinical phenotype using the ratio C18(OH)/(C14(OH)+C12(OH)). This ratio shows a gradation of values, from high in four patients with severe neonatal disease (2.5+/-0.8), to low in two neuromyopathic ...
European Journal of Pediatrics, 1994
Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency is the most common inherited disorder of mitochondrial fatty acid b-oxidation in humans. To better understand the pathogenesis of this disease, we developed a mouse model for MCAD deficiency (MCAD À/À ) by gene targeting in embryonic stem (ES) cells. The MCAD À/À mice developed an organic aciduria and fatty liver, and showed profound cold intolerance at 4 8C with prior fasting. The sporadic cardiac lesions seen in MCAD À/À mice have not been reported in human MCAD patients. There was significant neonatal mortality of MCAD À/À pups demonstrating similarities to patterns of clinical episodes and mortality in MCAD-deficient patients. The MCAD-deficient mouse reproduced important aspects of human MCAD deficiency and is a valuable model for further analysis of the roles of fatty acid oxidation and pathogenesis of human diseases involving fatty acid oxidation. Citation: Tolwani RJ, Hamm DA, Tian L, Sharer JD, Vockley J, et al. (2005) Medium-chain acyl-CoA dehydrogenase deficiency in gene-targeted mice. PLoS Genet 1(2): e23.
Journal of Inherited Metabolic Disease, 2010
Mouse models have been designed for a number of fatty acid oxidation defects. Studies in these mouse models have demonstrated that different pathogenetic mechanisms play a role in the pathophysiology of defects of fatty acid oxidation. Supplementation with L-carnitine does not prevent low tissue carnitine levels and induces acylcarnitine production having potentially toxic effects, as presented in very long-chain acyl-CoA dehydrogenase (VLCAD)-deficient mice. Energy deficiency appears to be an important mechanism in the development of cardiomyopathy and skeletal myopathy in fatty acid oxidation defects and is also the underlying mechanism of cold intolerance. Hypoglycemia as one major clinical sign in all fatty acid oxidation defects occurs due to a reduced hepatic glucose output and an enhanced peripheral glucose uptake rather than to transcriptional changes that are also observed simultaneously as presented in medium-chain acyl-CoA dehydrogenase (MCAD)-deficient mice. There are reports that impaired fatty acid oxidation also plays a role in intrauterine life. The embryonic loss demonstrated for some enzyme defects in the mouse supports this hypothesis, however the exact mechanisms are unknown. This observation correlates to maternal HELLP-syndrome as observed in pregnancies carrying a long-chain 3-hydroxyacyl-Co-A dehydrogenase (LCHAD)-deficient fetus. Synergistic heterozygosity has been shown in isolated patients and in mouse models to be associated with clinical phenotypes common to fatty acid oxidation disorders. Synergistic mutations may also modulate severity of the clinical phenotype and explain in part clinical heterogeneity of fatty acid oxidation defects. In summary, knowledge about the different pathogenetic mechanisms and the resulting pathophysiology allows the development of specific new therapies.
European Journal of Pediatrics, 2022
Medium-chain acyl-coenzyme A dehydrogenase (MCAD) deficiency is the most common disorder of mitochondrial β-oxidation of fatty acids resulting in hypoketotic hypoglycemia, hepatopathy, and often fatal outcome in undiagnosed children. Introduction of tandem mass spectrometry–based newborn screening programs in the late 1990s has significantly reduced morbidity and mortality in MCAD deficiency; however, neonatal death in individuals with early disease manifestation and severe hypoglycemia may still occur. We describe the fatal disease course in eight newborns with MCAD deficiency, aiming to raise awareness for early clinical symptoms and the life-saving treatment, and promote systematic post-mortem protocols for biochemical and genetic testing, necessary for correct diagnosis and counselling of the family if unexpected death occurred in the neonatal period.Conclusion: Early newborn screening and awareness for clinical symptoms is lifesaving in MCAD deficiency, which may present with f...