Extremely low values of serum leptin in children with congenital generalized lipoatrophy.
Congenital generalized lipoatrophy (CGL) is a syndrome with multiple clinical manifestations and complete atrophy of adipose tissue. The exact mechanism of this disease remains unknown. One hypothesis presupposes an abnormal development of adipocytes. Leptin, the adipocyte-specific product of the ob gene, acts as a regulatory factor of body weight. In children, as in adults, leptin levels are correlated with body mass index (BMI) and body fat mass. Some authors have demonstrated that adults with congenital or acquired generalized lipoatrophy have decreased leptin concentrations. In order to study serum leptin profile during childhood in this disease, we measured serum leptin concentrations in six children aged 5.5-11 years suffering from CGL, and investigated the relationship between metabolic parameters and the variations in leptin levels. Serum leptin concentrations (1.19+/-0.32 ng/ml (+/- S.D.)) were extremely low compared with those observed in normal children. No significant correlation was found with BMI, which is known to be one of the major determinants of serum leptin. Serum leptin values were significantly correlated with fasting insulin levels (r=0.83, P=0.024). In conclusion, extremely low leptin values measured in children with CGL could be regarded as one among other diagnostic parameters. However, the detectable levels observed in all of these children support the evidence that a small amount of body fat is likely to be present in these patients, despite complete subcutaneous lipoatrophy. Our data suggest that this small amount of adipose tissue could be metabolically active and, at least in part, sensitive to insulin. Further investigations are required to uncover the pathophysiological mechanisms of this syndrome, known to be commonly associated with insulin resistance. (+info)
Outcome of medium chain acyl-CoA dehydrogenase deficiency after diagnosis.
BACKGROUND: Medium chain acyl-CoA dehydrogenase (MCAD) deficiency is the most common inborn error of fatty acid metabolism. Undiagnosed, it has a mortality rate of 20-25%. Neonatal screening for the disorder is now possible but it is not known whether this would alter the prognosis. OBJECTIVE: To investigate the outcome of MCAD deficiency after the diagnosis has been established. METHOD: All patients with a proved diagnosis of MCAD deficiency attending one centre in a four year period were reviewed. RESULTS: Forty one patients were identified. Follow up was for a median of 6.7 years (range, 9 months to 14 years). Nearly half of the patients were admitted to hospital with symptoms characteristic of MCAD deficiency before the correct diagnosis was made. After diagnosis, two patients were admitted to hospital with severe encephalopathy but there were no additional deaths or appreciable morbidity. There was a high incidence (about one fifth) of previous sibling deaths among the cohort. CONCLUSIONS: Undiagnosed, MCAD deficiency results in considerable mortality and morbidity. However, current management improves outcome, supporting the view that the disorder should be included in newborn screening programmes. (+info)
Dietary management of long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD). A case report and survey.
Current dietary management of long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD; long-chain-(S)-3-hydroxyacyl-CoA:NAD+ oxido-reductase, EC 220.127.116.11) deficiency (LCHADD) is based on avoiding fasting, and minimizing energy production from long-chain fatty acids. We report the effects of various dietary manipulations on plasma and urinary laboratory values in a child with LCHADD. In our patient, a diet restricted to 9% of total energy from long-chain fatty acids and administration of 1.5 g medium-chain triglyceride oil per kg body weight normalized plasma acylcarnitine and lactate levels, but dicarboxylic acid excretion remained approximately ten times normal. Plasma docosahexaenoic acid (DHA, 22:6n-3) was consistently low over a 2-year period; DHA deficiency may be related to the development of pigmentary retinopathy seen in this patient population. We also conducted a survey of metabolic physicians who treat children with LCHADD to determine current dietary interventions employed and the effects of these interventions on symptoms of this disease. Survey results indicate that a diet low in long-chain fatty acids, supplemented with medium-chain triclyceride oil, decreased the incidence of hypoketotic hypoglycaemia, and improved hypotonia, hepatomegaly, cardiomyopathy, and lactic acidosis. However, dietary treatment did not appear to effect peripheral neuropathy, pigmentary retinopathy or myoglobinuria. (+info)
A fetal fatty-acid oxidation disorder as a cause of liver disease in pregnant women.
BACKGROUND: Acute fatty liver of pregnancy and the HELLP syndrome (hemolysis, elevated liver-enzyme levels, and a low platelet count) are serious hepatic disorders that may occur during pregnancy in women whose fetuses are later found to have a deficiency of long-chain 3-hydroxyacyl-coenzyme A (CoA) dehydrogenase. This enzyme resides in the mitochondrial trifunctional protein, which also contains the active site of long-chain 2,3-enoyl-CoA hydratase and long-chain 3-ketoacyl-CoA thiolase. We undertook this study to determine the relation between mutations in the trifunctional protein in infants with defects in fatty-acid oxidation and acute liver disease during pregnancy in their mothers. METHODS: In 24 children with 3-hydroxyacyl-CoA dehydrogenase deficiency, we used DNA amplification and nucleotide-sequence analyses to identify mutations in the alpha subunit of the trifunctional protein. We then correlated the results with the presence of liver disease during pregnancy in the mothers. RESULTS: Nineteen children had a deficiency only of long-chain 3-hydroxyacyl-CoA dehydrogenase and presented with hypoketotic hypoglycemia and fatty liver. In eight children, we identified a homozygous mutation in which glutamic acid at residue 474 was changed to glutamine. Eleven other children were compound heterozygotes, with this mutation in one allele of the alpha-subunit gene and a different mutation in the other allele. While carrying fetuses with the Glu474Gln mutation, 79 percent of the heterozygous mothers had fatty liver of pregnancy or the HELLP syndrome. Five other children, who presented with neonatal dilated cardiomyopathy or progressive neuromyopathy, had complete deficiency of the trifunctional protein (loss of activity of all three enzymes). None had the Glu474Gln mutation, and none of their mothers had liver disease during pregnancy. CONCLUSIONS: Women with acute liver disease during pregnancy may have a Glu474Gln mutation in long-chain hydroxyacyl-CoA dehydrogenase. Their infants are at risk for hypoketotic hypoglycemia and fatty liver. (+info)
Mobilisation of triacylglycerol stores.
Triacylglycerol (TAG) is an energy dense substance which is stored by several body tissues, principally adipose tissue and the liver. Utilisation of stored TAG as an energy source requires its mobilisation from these depots and transfer into the blood plasma. The means by which TAG is mobilised differs in adipose tissue and liver although the regulation of lipid metabolism in each of these organs is interdependent and synchronised in an integrated manner. This review deals principally with the mechanism of hepatic TAG mobilisation since this is a rapidly expanding area of research and may have important implications for the regulation of plasma very-low-density lipoprotein metabolism. TAG mobilisation plays an important role in fuel selection in non-hepatic tissues such as cardiac muscle and pancreatic islets and these aspects are also reviewed briefly. Finally, studies of certain rare inherited disorders of neutral lipid storage and mobilisation may provide useful information about the normal enzymology of TAG mobilisation in healthy tissues. (+info)
Improved stable isotope dilution-gas chromatography-mass spectrometry method for serum or plasma free 3-hydroxy-fatty acids and its utility for the study of disorders of mitochondrial fatty acid beta-oxidation.
BACKGROUND: Disorders of fatty acid oxidation (FAO) are difficult to diagnose, primarily because in many of the FAO disorders measurable biochemical intermediates accumulate in body fluids only during acute illness. Increased concentrations of 3-hydroxy-fatty acids (3-OH-FAs) in the blood are indicative of FAO disorders of the long- and short-chain 3-hydroxy-acyl-CoA dehydrogenases, LCHAD and SCHAD. We describe a serum/plasma assay for the measurement of 3-OH-FAs with carbon chain lengths from C(6) to C(16). METHODS: We used stable isotope dilution gas chromatography-mass spectrometry (GC-MS) with electron impact ionization and selected ion monitoring. Natural and isotope-labeled compounds were synthesized for the assay. RESULTS: The assay was linear from 0.2 to 50 micromol/L for all six 3-OH-FAs. CVs were 5-15% at concentrations near the upper limits seen in healthy subjects. In 43 subjects, the medians (and ranges) in micromol/L were as follows: 3-OH-C(6), 0.8 (0.3-2.2); 3-OH-C(8), 0.4 (0.2-1.0); 3-OH-C(10), 0.3 (0.2-0.6); 3-OH-C(12), 0.3 (0.2-0.6); 3-OH-C(14), 0.2 (0.0-0.4); and 3-OH-C(16), 0.2 (0.0-0.5). 3-OH-FAs were increased in infants receiving formula containing medium chain triglycerides. Two patients diagnosed with LCHAD deficiency showed marked increases in 3-OH-C(14) and 3-OH-C(16) concentrations. Two patients diagnosed with SCHAD deficiency showed increased shorter chain 3-OH-FAs but no increases in 3-OH-C(14) to 3-OH-C(16). CONCLUSION: Measuring blood concentrations of the 3-OH-FAs with this assay may be a valuable tool for helping to rapidly identify deficiencies in LCHAD and SCHAD and may also provide useful information about the status of the FAO pathway. (+info)
Twenty novel mutations in the alpha-galactosidase A gene causing Fabry disease.
BACKGROUND: Fabry disease, an X-linked inborn error of glycosphingolipid catabolism, results from the deficient activity of the lysosomal exoglycohydrolase alpha-galactosidase A (EC 18.104.22.168; alpha-Gal A). The nature of the molecular lesions in the alpha-Gal A gene in 30 unrelated families was determined to provide precise heterozygote detection, prenatal diagnosis, and define genotype-phenotype correlations. MATERIALS AND METHODS: Genomic DNA was isolated from affected males and/or carrier females from 30 unrelated families with Fabry disease. The entire alpha-Gal A coding region and flanking intronic sequences were analyzed by PCR amplification and automated sequencing. RESULTS: Twenty new mutations were identified, each in a single family: C142R, G183D, S235C, W236L, D244H, P259L, M267I, I289F, Q321E, C378Y, C52X, W277X, IVS4(+4), IVS6(+2), IVS6(-1), 35del13, 256del1, 892ins1, 1176del4, and 1188del1. In the remaining 10 unrelated Fabry families, 9 previously reported mutations were detected: M42V, R112C, S148R, D165V, N215S (in 2 families), Q99X, C142X, R227X, and 1072del3. Haplotype analysis using markers closely flanking the alpha-Gal A gene indicated that the two patients with the N215S lesion were unrelated. The IVS4(+4) mutation was a rare intronic splice site mutation that causes Fabry disease. CONCLUSIONS: These studies further define the heterogeneity of mutations in the alpha-Gal A gene causing Fabry disease, permit precise heterozygote detection and prenatal diagnosis, and help delineate phenotype-genotype correlations in this disease. +info)
Unique electroencephalographic change of acute encephalopathy in glutaric aciduria type 1.
We report the peculiar serial electroencephalographic (EEG) findings in a 7-year-old boy with glutaric aciduria type 1 during an episode of acute encephalopathy. The patient developed Reye-like syndrome triggered by cellulitis. Cranial magnetic resonance imaging demonstrated diffuse softening of cerebral hemisphere. The EEG on the day following onset of acute encephalopathy showed suppression burst pattern including continuous 14-15 Hz rhythmic waves at first. Then, periodic synchronous discharge appeared and lasted for about 40 minutes. Periodic synchronous discharge finally disappeared and nearly total electrocerebral silence continued. There have been no reports indicating such a change of EEG in a short period. The serial EEG changes probably reflect the process of electrical death of neurons in cerebral hemispheres. (+info)