Carnitine deficiency with cardiomyopathy presenting as neonatal hydrops: Successful response to carnitine therapy

Steenhout, Philippe; Elmer, Catherine; Clercx, Anne; Blum, Denise; Gnat, Danielle; Erum, Sajida; Vertongen, Françoise; Vámos, Eszter

doi:10.1007/bf01799334

Cited by 26 publications

(10 citation statements)

References 18 publications

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“…In addition, fetal hydrops due to intrauterine cardiomyopathy was reported recently in a child with MTP deficiency (5,26). Hydrops fetalis due to cardiomyopathy was also reported in relation to carnitine deficiency (27). These observations suggest that longchain FAO is taking place in the myocardium during intrauterine life.…”

Section: Discussionmentioning

confidence: 75%

Long-Chain Fatty Acid Oxidation during Early Human Development

et al. 2005

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Patients with very long-chain acyl-CoA dehydrogenase (VLCAD) and long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD)/mitochondrial trifunctional protein (MTP) deficiency, disorders of the mitochondrial long-chain fatty acid oxidation, can present with hypoketotic hypoglycemia, rhabdomyolysis, and cardiomyopathy. In addition, patients with LCHAD/MTP deficiency may suffer from retinopathy and peripheral neuropathy. Until recently, there was no indication of intrauterine morbidity in these disorders. This observation was in line with the widely accepted view that fatty acid oxidation (FAO) does not play a significant role during fetal life. However, the high incidence of the gestational complications acute fatty liver of pregnancy and hemolysis, elevated liver enzymes, and low platelets syndrome observed in mothers carrying a LCHAD/MTP-deficient child and the recent reports of fetal hydrops due to cardiomyopathy in MTP deficiency, as well as the high incidence of intrauterine growth retardation in children with LCHAD/MTP deficiency, suggest that FAO may play an important role during fetal development. 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. Furthermore, we measured the enzymatic activity of the VLCAD, LCHAD, and carnitine palmitoyl-CoA transferase 2 (CPT2) enzymes in different human fetal tissues. Human embryos (at d 35 and 49 of development) and separate tissues (5-20 wk of development) were used. The results show a strong expression of VLCAD and LCHAD mRNA and a high enzymatic activity of VLCAD, LCHAD, and CPT2 in a number of tissues, such as liver and heart. In addition, high expression of LCHAD mRNA was observed in the neural retina and CNS. Mitochondrial oxidation of fatty acids plays a critical role in energy metabolism after birth. The heart preferentially uses fatty acids as a substrate for energy production. In addition, during moderately severe exercise, skeletal muscle predominantly utilizes fatty acids as an energy source. In the liver, FAO is used during fasting to produce ketone bodies that are exported from the liver and can be used for energy production by peripheral tissues such as the brain. Mitochondrial FAO of long-chain fatty acids involves the concerted action of a multitude of enzymes. This process starts with the carnitinemediated transfer of the long-chain fatty acids, activated to their CoA esters, over the mitochondrial inner-membrane. This involves the activity of three enzymes: CPT1, carnitine acylcarnitine translocase (CACT), and CPT2. Once inside the

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Section: Discussionmentioning

confidence: 75%

Long-Chain Fatty Acid Oxidation during Early Human Development

et al. 2005

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“…Furthermore, defects in genes encoding the peroxisome proliferator-activated receptor (PPAR) β/δ and γ, which are transcriptional factors affecting gene expression of key lipid-metabolizing enzymes such as CPT1, and defects in the gene encoding the co-activator of PPAR γ (PGC-1), result in embryonic lethality and disrupted development of the syncytiotrophoblast (Barak et al 1999(Barak et al , 2002Lim et al 1999). The importance of FAO in the human embryo and fetus is further accentuated by several studies in long-chain FAO defects in which a higher frequency of prematurity, intrauterine growth retardation (IUGR), fetal morbidity and intrauterine death has been noted (Berger and Wood 2004;Chakrapani et al 2000;den Boer et al 2002den Boer et al , 2003Ibdah et al 2001;Schwab et al 2003;Steenhout et al 1990;Tyni et al 1998;Yang et al 2002).…”

Section: Discussionmentioning

confidence: 91%

Fatty acid oxidation in the human fetus: Implications for fetal and adult disease

Oey

Ruiter

Attié‐Bitach

et al. 2006

J of Inher Metab Disea

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Studies in the last few years have shown a remarkably high activity of fatty acid oxidation (FAO) enzymes in human placenta. We have recently shown mRNA expression as well as enzymatic activity of long-chain FAO enzymes in the human embryo and fetus. In this study we show activity of the FAO enzymes carnitine palmitoyltranferase 1, medium-chain acyl-CoA dehydrogenase and short-chain hydroxyacyl-CoA dehydrogenase in embryonic and fetal tissues. In addition, we show the presence of different acylcarnitines in fetal liver and kidney, which substantiates the notion that the mitochondrial FAO enzymes are not only present in human fetal tissues but also metabolically active. In a glucose-rich environment FAO might be necessary for additional ATP production from fatty acids, but also for the breakdown of fatty acids that are products of the turnover of membranes in the growing fetus. The importance of FAO in the human embryo and fetus is further stressed by the fact that a higher frequency of prematurity, intrauterine growth retardation, fetal morbidity and intrauterine death is noted in long-chain FAO defects. Furthermore, in animal studies, gestational loss during early embryonic development has been observed as a consequence of disturbed FAO. Finally, there are indications that regulation of activity of FAO during fetal development might not only be important for fetal life but may also have implications for health and disease in adulthood.

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“…A case of carnitine deficiency with cardiomyopathy resulting in hydrops has been reported with dramatic improvement of the infant's condition after starting carnitine substitution [20].…”

Section: Discussionmentioning

confidence: 98%