Mitochondrial very long chain acyl-CoA dehydrogenase deficiency--a new disorder of fatty acid oxidation.

Very long chain acyl-CoA dehydrogenase is a newly characterised enzyme in mitochondrial fatty acid oxidation. A girl who presented on the second day of life with a sudden and severe illness due to deficiency of this enzyme is reported. There is evidence that some children (and perhaps all) originally diagnosed with a deficiency of long-chain acyl-CoA dehydrogenase, in fact, have a defect involving very long chain acyl-CoA dehydrogenase.     

Genetic deficiency of medium-chain acyl coenzyme A dehydrogenase: studies in cultured skin fibroblasts and peripheral mononuclear leukocytes

Medium-chain acyl coenzyme A (CoA) dehydrogenase deficiency was demonstrated in fibroblasts and/or mononuclear leukocytes from 14 patients, most of whom initially presented early in childhood with a Reye-like syndrome associated with hypoketotic hypoglycemia, dicarboxylic aciduria, and low levels of plasma carnitine. Parents of these patients had intermediate levels of medium-chain acyl CoA dehydrogenase activity, consistent with their being heterozygous for an autosomal recessive trait. All patients had normal levels of long-chain acyl CoA dehydrogenase activity, but had reduced short-chain acyl CoA dehydrogenase activity. Fatty acid oxidation was examined in cultured fibroblasts from five of the patients, using a series of 14C-labeled fatty acids of different chain length (palmitic, octanoic, and butyric). Oxidation of [1-14C]-octanoic acid was less than 20% of control levels: [1-14C], [6-14C]-, [16(14)C]-, and [14C(U)]-palmitic acid oxidation rates were 88, 51, 13, and 42% of control rates, respectively. [1-14C]-butyric acid was oxidized normally. These data extend our previous findings of medium-chain acyl CoA dehydrogenase deficiency in liver tissue from three of these patients. They demonstrate the value of cultured fibroblasts and leukocytes in the diagnosis and evaluation of inherited disorders of fatty acid oxidation.     

Long-chain fatty acid oxidation during early human development

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. The observed pattern of expression during early human development is well in line with the spectrum of clinical signs and symptoms reported in patients with VLCAD or LCHAD/MTP deficiency.     

Hypoglycemia, hypotonia, and cardiomyopathy: the evolving clinical picture of long-chain acyl-CoA dehydrogenase deficiency

Inherited defects in fatty acid oxidation, which have been described and diagnosed with increasing frequency in the last decade, are most commonly attributed to a deficiency in the activity of medium-chain acyl-CoA dehydrogenase. Few cases of the related enzyme defect of long-chain acyl-CoA dehydrogenase activity have been reported. An infant with documented long-chain acyl-CoA dehydrogenase deficiency is described with a detailed metabolic profile, long-term clinical follow-up, and response to treatment. This patient is compared with the seven previously published cases of this disorder in order to stress the unique features of the initial presentation, more subtle late manifestations of the disease, and clinical and biochemical differentiation from the more common medium-chain acyl-CoA dehydrogenase deficiency. This report stresses the enlarging spectrum of the clinical presentation and natural history of this defect in fatty acid oxidation.     

Lack of correlation between fatty acid oxidation disorders and haemolysis,elevated liver enzymes,low platelets (HELLP) syndrome?

Aim: Fatty acid β-oxidation defects comprise a heterogeneous group of disorders that may precipitate acute life threatening metabolic crises particularly during catabolic episodes. Several studies have demonstrated a possible association between fatty acid β-oxidation defects, including long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency and severe pregnancy complications. However, the precise percentage of women with haemolysis, elevated liver enzymes, low platelets (HELLP) syndrome associated with foetal fatty acid β-oxidation defects is not known. Methods: We carried out a multicentre retrospective study on 88 infants, born to women with HELLP syndrome. Acylcarnitine profiles from blood dried on filter paper cards were analysed by tandem mass spectrometry for the diagnosis of fatty acid β-oxidation defects. In addition, we screened for the common long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency mutation using a standard restriction fragment length polymorphism polymerase chain reaction method. Results: None of the infants studied carried the common long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency mutation. There was no evidence of fatty acid β-oxidation defects, including long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency, as expected by unremarkable acylcarnitine profiles, while three infants with fatty acid β-oxidation defects were diagnosed in the control group.

Conclusions: Neither foetal long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency, including heterozygosity for the common long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency mutation, nor fatty acid β-oxidation defects in general are a major risk factor for HELLP syndrome in Austria.     

Mitochondrial fatty acid beta-oxidation in the retinal pigment epithelium

Pigmentary retinopathy is an important feature of long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency, a disorder of mitochondrial fatty acid beta-oxidation. Pathogenesis of this complication remains unknown. The retinal pigment epithelium (RPE) is affected early in this retinopathy. We wanted to determine whether there is evidence of mitochondrial fatty acid beta-oxidation in the RPE cells. Fatty acid oxidation was measured from cultured porcine RPE cells by incubating them with [U-13C]-hexadecanoic acid. Acylcarnitine esters were analyzed by tandem mass spectrometry. The activity of LCHAD and carnitine uptake capacity were measured from the cultured cells. Antibodies to the human mitochondrial trifunctional protein (MTP) containing LCHAD activity were used to analyze the expression of the MTP in the cultured RPE cell lysate and in human retinal sections by immunoblotting and immunohistochemistry. Fatty acid oxidation analysis showed normal chain shortening of hexadecanoic acid and production of acetylcarnitine in cultured RPE cells. Immunoblotting revealed expression of the MTP and enzyme assay showed the activity of LCHAD in the RPE cells. RPE cells were also capable of carnitine uptake. Positive labeling to the MTP antibodies was detected in the RPE, photoreceptors, and ganglion cells. The results give strong in vitro evidence for the presence of mitochondrial fatty acid beta-oxidation in RPE cells and the expression of the MTP in the RPE and other layers of the retina. Further studies are required to clarify whether this pathway acts also in vivo in the retina.     

Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency

Long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency is one of the recently discovered defects of mitochondrial fatty acid β-oxidation. As a group, the β-oxidation defects are among the most common inherited metabolic disorders, and LCHAD deficiency appears to be the most frequently diagnosed β-oxidation defect in Finland. In the vast majority of patients, LCHAD deficiency is caused by a common autosomal recessive mutation G1528C. Like several β-oxidation defects, it presents during infancy with hypoglycemic coma, hepatic steatosis, and hypocarnitinemia. Other manifestations are cardiomyopathy and rhabdomyolysis, which are frequent in defects of long-chain fatty acid oxidation. In addition, LCHAD deficiency has specific features, namely peripheral neuropathy and chorioretinopathy. Female carriers of LCHAD deficiency are prone to have preeclampsia-related pregnancy complications. Diagnosis is suggested by 3-hydroxylated acylcarnitine species in blood and the definitive diagnosis can be made by measuring intermediates of fatty acid β-oxidation in fibroblasts or by detecting disease causing mutations. Analysis of the frequency of the G1528C mutation in Finland revealed carrier frequency of 1:240. Because of therapeutic and prenatal diagnostic opportunities in LCHAD deficiency, it is important to recognize this severe disorder early in its course.     

Significance of phototherapy-induced riboflavin deficiency in the full-term neonate.

As a result of impaired fatty acid oxidation, a characteristic urinary dicarboxylic aciduria occurs in the riboflavin deficient animal. We compared the occurrence of riboflavin deficiency induced by phototherapy with changes in urinary organic acid profiles in 8 full-term, breast-fed neonates who received phototherapy for hyperbilirubinemia, and in 10 full-term, breastfed controls. Riboflavin status was assessed by measuring flavin adenine dinucleotide saturation of erythrocyte glutathione reductase. All 8 neonates exposed to phototherapy developed riboflavin deficiency (p less than 0.001). Riboflavin deficiency was progressive with the duration of phototherapy. None of the controls was riboflavin deficient. Urine organic acid profiles indicative of mitochondrial acyl-CoA dehydrogenase activity (fatty acid beta-oxidation, quantitated by gas chromatography mass spectrometry) showed no changes between the study and control groups in mono-, di-, or tricarboxylic acids or other organic acids. The riboflavin deficiency induced by phototherapy in full-term neonates was not of sufficient severity to limit riboflavin-dependent fatty acid oxidation.     

Long-chain acyl coenzyme A dehydrogenase deficiency: an inherited cause of nonketotic hypoglycemia

Three children from unrelated families presented in early childhood with hypoglycemia and cardiorespiratory arrests associated with fasting. Significant hepatomegaly, cardiomegaly, and hypotonia were present at the time of initial presentation. Ketones were not present in the urine at the time of hypoglycemia in any patient; however, dicarboxylic aciduria was documented in one patient at the time of the acute episode and in two patients during fasting studies. Total plasma carnitine concentration was low with an increased esterified carnitine fraction. These findings suggested a defect in mitochondrial fatty acid oxidation, and specific assays were performed for the acyl coenzyme A (CoA) dehydrogenases. These analyses showed that the activity of the long-chain acyl CoA dehydrogenase was less than 10% of control values in fibroblasts, leukocytes, and liver tissue. Activities of the medium-chain, short-chain, and isovaleryl CoA dehydrogenases were not different from control values. With cultured fibroblasts, CO2 evolution from long-chain fatty acids was significantly reduced, while CO2 evolution from medium-chain and short-chain fatty acids was comparable to control values--findings consistent with a defect early in the beta-oxidation sequence. Studies of acyl CoA dehydrogenase activities in fibroblasts and leukocytes from parents of the patients showed levels of long-chain acyl CoA dehydrogenase activity intermediate between affected and control values and indicated an autosomal recessive form of inheritance of this enzymatic defect.(ABSTRACT TRUNCATED AT 250 WORDS)     

Influence of valproic acid on the expression of various acyl-CoA dehydrogenases in rats

BACKGROUND: Valproic acid (2-propyl-N-pentanoic acid, VPA) causes severe hepatic dysfunction, similar to Reye's syndrome, in a small number of patients. An enhanced excretion of dicarboxylic acids by patients indicates an interference with mitochondrial beta-oxidation. We investigated the expression of various acyl-coenzyme A (acyl-CoA) dehydrogenases (ACD), which catalyze the first step of beta-oxidation in VPA-treated rats. METHODS: The control group received normal saline and the experimental group received VPA (500 mg/kg per day) by intraperitoneal injections for 7 days. Various clinical chemistry parameters in rat blood and free and total carnitine levels in plasma and tissue were determined. Mitochondria were isolated from rat liver and heart and the relative amount of each ACD protein was determined by immunoblot analysis. Total RNA was prepared from various tissues and the mRNA levels for various ACD were measured by slot-blot hybridization analysis using respective cDNA probes. RESULTS: Administration of VPA to rats caused various metabolic effects including hypoglycemia, hyperammonemia and decreased beta-hydroxybutyrate concentration. Free carnitine levels in plasma and heart were also decreased. Enzyme activities of various acyl-CoA dehydrogenases, which are involved in fatty acid oxidation, decreased moderately in heart (57-79%), and slightly in liver (78-95%). The most prominent effects were observed in mRNA levels involved in fatty acid oxidation (short-, medium- and long-chain acyl-CoA dehydrogenase). Each mRNA increased in the liver, kidney, skeletal muscle and heart to varying degrees when rats were fed ad libitum. The increase of short- and medium- chain acyl-CoA dehydrogenase mRNA in the heart were particularly large. However, 3 day starvation strongly inhibited expression of ACD in VPA-treated rats. There was an apparent decrease in the amount of ACD mRNA and proteins in VPA-treated liver. CONCLUSIONS: Valproic acid causes enhanced expression of fatty ACD mRNA, especially in the heart, by a feedback mechanism related to inhibition of beta-oxidation in rats fed ad libitum. However, it impairs the expression of ACD in the liver when there is a drastic change in nutritional state.     

Medium-chain acyl-CoA dehydrogenase deficiency in children with non-ketotic hypoglycemia and low carnitine levels

Three children in two families presented in early childhood with episodes of illness associated with fasting which resembled Reye's syndrome: coma, hypoglycemia, hyperammonemia, and fatty liver. One child died with cerebral edema during an episode. Clinical studies revealed an absence of ketosis on fasting (plasma beta-hydroxybutyrate less than 0.4 mmole/liter) despite elevated levels of free fatty acids (2.6-4.2 mmole/liter) which suggested that hepatic fatty acid oxidation was impaired. Urinary dicarboxylic acids were elevated during illness or fasting. Total carnitine levels were low in plasma (18-25 mumole/liter), liver (200-500 nmole/g), and muscle (500-800 nmole/g); however, treatment with L-carnitine failed to correct the defect in ketogenesis. Studies on ketone production from fatty acid substrates by liver tissue in vitro showed normal rates from short-chain fatty acids, but very low rates from all medium and long-chain fatty acid substrates. These results suggested that the defect was in the mid-portion of the intramitochondrial beta-oxidation pathway at the medium-chain acyl-CoA dehydrogenase step. A new assay for the electron transfer flavoprotein-linked acyl-CoA dehydrogenases was used to test this hypothesis. This assay follows the decrease in electron transfer flavoprotein fluorescence as it is reduced by acyl-CoA-acyl-CoA dehydrogenase complex. Results with octanoyl-CoA as substrate indicated that patients had less than 2.5% normal activity of medium-chain acyl-CoA dehydrogenase. The activities of short-chain and isovaleryl acyl-CoA dehydrogenases were normal; the activity of long-chain acyl-CoA dehydrogenase was one-third normal. These results define a previously unrecognized inherited metabolic disorder of fatty acid oxidation due to deficiency of medium-chain acyl-CoA dehydrogenase.     

Immunochemical characterization of variant long-chain acyl-CoA dehydrogenase in cultured fibroblasts from nine patients with long-chain acyl-CoA dehydrogenase deficiency

Long-chain acyl-CoA dehydrogenase (LCAD) deficiency is a disorder of mitochondrial fatty acid oxidation that is characterized by hypoglycemia, muscle weakness, and hepato- and cardiomegaly. To characterize variant LCAD, we first carried out preliminary experiments using pure enzyme preparations. Despite the significant sequence similarity of LCAD to medium-chain acyl-CoA dehydrogenase, the antibody raised against rat LCAD was monospecific for human and rat LCAD and did not cross-react with either human or rat medium-chain acyl-CoA dehydrogenase. Immunoblot analysis of variant LCAD in cultured fibroblasts from nine patients with LCAD deficiency revealed a single LCAD band in all nine LCAD-deficient cell lines. Each variant LCAD was comparable in molecular size and quantity to normal LCAD, suggesting that the LCAD mutation in each of these cell lines is likely to be a point mutation that produces a stable variant LCAD. The uniform nature of variant LCAD suggests that only a single, or at most a few, prevalent point mutations may be found in the majority of LCAD-deficient patients. If this is the case, it should be possible to devise a molecular diagnostic method for LCAD deficiency.     

Creatine kinase and uric acid: early warning for metabolic imbalance resulting from disorders of fatty acid oxidation

In eight patients with disorders of fatty acid oxidation, analysis of uric acid and creatine kinase served as indicators of the underlying disorder in episodes of acute metabolic imbalance. Six patients had deficiency of medium-chain acyl-CoA dehydrogenase, one had long-chain hydroxyacyl-CoA dehydrogenase deficiency, and one very long-chain acyl-CoA dehydrogenase deficiency. The most common presentation was with symptomatic hypoglycemia; there was one Reye-like presentation and one of rhabdomyolysis. The mechanism of the elevation of uric acid and creatine kinase appears to be the breakdown of tissue. Conclusion: it is concluded that uric acid and creatine kinase provide a useful alerting signal to the presence of a disorder of fatty acid oxidation. Maximal levels of uric acid in this series were 6.2-21.5 mg/dl and of creatine kinase 879-27,557 U/l.     

Mitochondrial fatty acid beta-oxidation in the human eye and brain: implications for the retinopathy of long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency

The retinal pigment epithelium (RPE) and the choriocapillaris are affected early in the retinopathy associated with long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency. RPE in culture possesses the machinery needed for mitochondrial fatty acid beta-oxidation in vitro. To further elucidate pathogenesis of LCHAD retinopathy, we performed immunohistochemistry of the human eye and brain with antibodies to beta-oxidation enzymes. Human eye and brain sections were stained with antibodies to medium-chain (MCAD) and very long-chain acyl-CoA dehydrogenase (VLCAD), short-chain 3-hydroxyacyl-CoA dehydrogenase (SCHAD), and mitochondrial trifunctional protein (MTP) harboring LCHAD. Antibodies to 2-methyl-3-hydroxybutyryl-CoA dehydrogenase (MHBD) and cytochrome c oxidase subunit I (COX I) were used as a reference. VLCAD, MTP, MCAD, SCHAD, MHBD, and COX I antibodies labeled most retinal layers and tissues of the human eye actively involved in oxidative metabolism (extraocular and intraocular muscle, the RPE, the corneal endothelium, and the ciliary epithelium). MTP and COX I antibodies labeled the inner segments of photoreceptors. The choriocapillaris was labeled only with SCHAD and MCAD antibodies. In the brain, the choroid plexus and nuclei of the brain stem were most intensely labeled with beta-oxidation antibodies, whereas COX I antibodies strongly labeled neurons in several regions of the brain. Mitochondrial fatty acid beta-oxidation likely plays a role in ocular energy production in vivo. The RPE rather than the choriocapillaris could be the critical affected cell layer in LCHAD retinopathy. Reduced energy generation in the choroid plexus may contribute to the cerebral edema observed in patients with beta-oxidation defects.     

Serum dicarboxylic acids in patients with Reye syndrome

Reye syndrome resembles disorders of fatty acid metabolism. Analysis of serum free fatty acids from 18 patients with Reye syndrome revealed that dicarboxylic acids comprise as much as 55% (range 4% to 55%) of the patients' total free fatty acids; both medium- (6 to 12 carbon lengths) and long-chain (14 to 18 carbon lengths) dicarboxylic acids were identified. Long-chain dicarboxylic acids were not found in any control samples, whereas 86% +/- 4% of the serum dicarboxylic acids were long chain in 10 patients with Reye syndrome in state 3 to 4 coma and 31% +/- 8% in eight patients with a milder illness. The serum concentration of dicarboxylic acids correlated with the clinical state (P less than 0.001) and with the elevation in blood ammonia concentration (r2 = 0.8767). No long-chain dicarboxylic acids were found in the urine. The dicarboxylic acidemia in Reye syndrome may be secondary to the general mitochondrial dysfunction or could indicate that an insult to fatty acid metabolism or the stimulation of omega-oxidation is important in the pathogenesis of the illness. Measurement of serum dicarboxylic acids, especially long chain, may be important in assessing Reye syndrome and may prove useful in distinguishing this from other diseases.     

Metabolic defects with hypoketotic hypoglycemia

Metabolic defects resulting in hypoketotic hypoglycemia can lead to hepato-encephalopathy and can be lethal. Recognition of the association of hypoglycemia with hypoketonemia is essential for efficient diagnostic and therapeutic procedures. The pattern of urinary excretion of organic acids is useful in differential diagnosis between the possible metabolic defects, viz. carnitine deficiency, carnitine palmitoyl transferase deficiency, medium-chain, long-chain and multiple acyl-CoA dehydrogenase deficiencies, and HMG-CoA lyase deficiency. These (except for carnitine deficiency) can be confirmed by enzyme activity measurements in cultured fibroblasts and tissue biopsies and prenatally. Treatment is available for all of them except some cases of multiple acyl-CoA dehydrogenase deficiency. Genetic counselling of the families must be based on a precise biochemical diagnosis.     

3-Hydroxydicarboxylic aciduria due to long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency associated with sudden neonatal death: protective effect of medium-chain triglyceride treatment

Two siblings were found to be affected by longchain 3-hydroxyacyl-CoA dehydrogenase deficiency, one of which died suddenly and unexpectedly on the 3rd day of life suffering from extreme hypoketotic hypoglycaemia. The younger sibling started to have feeding problems, lowered consciousness, and liver dysfunction at the age of 5 months. Her urine contained large amounts of C₆–C₁₄ 3-hydroxydicarboxylic acids and conjugated 3-hydroxyoctanoic acid, as verified by gas chromatography/mass spectrometry. Plasma long-chain acylcarnitine was increased. A clue to the diagnosis was given by the results of a phenylpropionic acid loading test. This revealed small, but significant amounts of conjugated 3-hydroxyphenylpropionic acid (phenylhydracrylic acid) in the patient's urine. Subsequently, the activity of long-chain 3-hydroxyacyl-CoA dehydrogenase was found to be deficient in cultured skin fibroblasts. Based on the findings obtained by a medium-chain triglyceride load, a diet enriched in this type of fat was prescribed. On this regimen the patient started to thrive, signs of cardiomyopathy disappeared, and her liver function normalized.     

Highly active antiretroviral therapy does not affect mitochondrial beta-oxidation of fatty acids: an in vitro study in fibroblasts.

Preeclampsia is a multifactorial pregnancy-specific disease. In some cases, severe preeclampsia and related disorders of acute fatty liver of pregnancy and hemolysis, elevated liver enzymes, low platelets syndrome are associated with inherited defects in mitochondrial beta-oxidation of fatty acids, especially a deficiency of long-chain 3-hydroxyacyl coenzyme A dehydrogenase (LCHAD). Recently, an unexplained increase in the incidence of preeclampsia has been documented in human immunodeficiency virus (HIV)-infected pregnant women on treatment with highly active antiretroviral therapy (HAART). We performed this study to determine if antiretroviral drugs affect mitochondrial beta-oxidation fatty acids in vitro. Two normal and 1 heterozygous LCHAD-deficient cell lines were exposed to up to 5 times the therapeutic concentrations of the following antiretroviral drugs: nevirapine, didanosine, lamivudine, and a combination of nelfinavir, zidovudine, and lamivudine. One homozygous LCHAD-deficient cell line served as the positive control. After exposure of the fibroblasts to these drugs for periods ranging from 2 to 10 days, accumulations of even-chain 3-hydroxy fatty acids (3-OH-C6 to 3-OH-C18) in the culture media were measured by stable-isotope dilution gas chromatography/mass spectrometry. Compared to the respective unexposed fibroblasts, there was no significant build-up of 3-hydroxy fatty acids in the culture media of normal or heterozygous LCHAD-deficient fibroblasts exposed to antiretroviral drugs. Our results show that the commonly used antiretroviral drugs do not adversely affect fatty acid oxidation in fibroblasts. Therefore, an altered fatty acid oxidation may not be the mechanism for the reported increased risk of preeclampsia in HIV-infected pregnant women on HAART.     

Milder childhood form of very long-chain acyl-CoA dehydrogenase deficiency in a 6-year-old Japanese boy

We investigated the clinical and biochemical characteristics of a 6-year-old Japanese boy with very-long-chain acyl-CoA dehydrogenase (VLCAD) deficiency. He had hypoketotic hypoglycaemia, exercise- and fasting-induced lethargy, hepatomegaly and cardiomegaly. 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. Conclusion The diagnosis of very long-chain acyl-CoA dehydrogenase deficiency was supported by the results of acyl-CoA dehydrogenase activity for C₈ and C₁₆ fatty acids in skin fibroblasts from the patient. Treatment with medium chain triglycerides and l-carnitine in the diet improved his hepatomegaly and cardiomegaly. Received: 17 April 2000 / Accepted: 5 July 2000     

Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency: A severe fatty acid oxidation disorder

3-Hydroxyacyl-CoA dehydrogenase deficiency is a newly recognised fatty acid oxidation disorder with a usually fatal outcome. We present a further patient who presented with hypoketotic hypoglycaemia, hepatopathy, secondary carnitine deficiency and increased plasma long-chain acylcarnitines. 3-Hydroxydicarboxylic aciduria was present and the diagnosis confirmed in cultured skin fibroblasts. Our patient is compared with those reported in the literature with respect to clinical symptoms, differential diagnosis and possible therapeutic regimens.