High frequency of creatine deficiency syndromes in patients with unexplained mental retardation.
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Adolescent↗
Biomedical subjects
C Vianey-Saban
Publications and source records attributed to C Vianey-Saban.
Persistent increase of plasma butyryl/isobutyrylcarnitine concentrations as marker of SCAD defect and ethylmalonic encephalopathy.
High concentrations of butyryl/isobutyrylcarnitine (C(4)-carnitine) in plasma with increase of ethylmalonic acid (EMA) in urine point to different genetic entities, and further investigations are required to differentiate the possible underlying defect. Here we report three unrelated cases, two neurologically affected and one asymptomatic, with this abnormal metabolite pattern due either to mutations in the ETHE1 gene or to a short-chain acyl-CoA dehydrogenase (SCAD) defect.
Brain Diseases↗
Differentiation of long-chain fatty acid oxidation disorders using alternative precursors and acylcarnitine profiling in fibroblasts.
The differentiation of carnitine-acylcarnitine translocase deficiency (CACT) from carnitine palmitoyltransferase type II deficiency (CPT-II) and long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency from mitochondrial trifunctional protein deficiency (MTP) continues to be ambiguous using current acylcarnitine profiling techniques either from plasma or blood spots, or in the intact cell system (fibroblasts/amniocytes). Currently, enzyme assays are required to unequivocally differentiate CACT from CPT-II, and LCHAD from MTP. Over the years we have studied the responses of numerous FOD deficient cell lines to both even and odd numbered fatty acids of various chain lengths as well as branched-chain amino acids. In doing so, we discovered diagnostic elevations of unlabeled butyrylcarnitine detected only in CACT deficient cell lines when incubated with a shorter chain fatty acid, [7-2H3]heptanoate plus l-carnitine compared to the routinely used long-chain fatty acid, [16-2H3]palmitate. In monitoring the unlabeled C4/C5 acylcarnitine ratio, further differentiation from ETF/ETF-DH is also achieved. Similarly, incubating LCHAD and MTP deficient cell lines with the long-chain branched fatty acid, pristanic acid, and monitoring the C11/C9 acylcarnitine ratio has allowed differentiation between these disorders. These methods may be considered useful alternatives to specific enzyme assays for differentiation between these long-chain fatty acid oxidation disorders, as well as provide insight into new treatment strategies.
3-Hydroxyacyl CoA Dehydrogenases↗
A new reversed-phase liquid chromatographic/tandem mass spectrometric method for analysis of underivatised amino acids: evaluation for the diagnosis and the management of inherited disorders of amino acid metabolism.
Seventy-six compounds of biological interest for the diagnosis of inherited disorders of amino acids (AA) metabolism have previously been demonstrated to be detectable in positive mode electrospray ionisation tandem mass spectrometry (ESI-MS/MS), after separation by ion-pairing reversed-phase liquid chromatography (RPLC). The separation method used tridecafluoroheptanoic acid as ion-pairing agent, and a gradient of acetonitrile for the elution of the most retained compounds. This method had previously been demonstrated to be suitable for the qualitative diagnosis of many AA disorders, and for the quantitative measurement of 16 AA in biological fluids, using their stable isotope labelled (SIL) AA as internal standard. For quantification of the other AA, an internal standard was chosen among the available SIL-AA, as close as possible to the analyte to be measured, in terms of structural analogy, and of retention time in the chromatographic system. The performances of the quantitative analysis of the other AA to be measured are reported here. They show validated results for several AA, allowing their accurate quantification, with another SIL-AA as internal standard. For some other AA, quantitative results were not accurate, allowing only semi-quantitative or qualitative determination for these parameters.
Amino Acid Metabolism, Inborn Errors↗
First-trimester enzymatic and molecular prenatal diagnosis of mevalonic aciduria.
Prenatal diagnosis was offered to a family at risk of mevalonic aciduria. A chorionic villus sample was obtained and both mevalonate kinase activity and mutation analysis were done. An affected fetus was diagnosed.
Chorionic Villi↗
[Creatine deficiency syndromes].
INTRODUCTION: Creatine deficiency syndromes are a newly described group of inborn errors of metabolism affecting creatine metabolism. Three diseases have been described: deficiency of arginine: glycine amidinotransferase (AGAT), deficiency of guanidinoacetate methyltransferase (GAMT) and creatine transporter defect (CRTR). STATE OF ART: These syndromes are characterized by a depletion of creatine/phosphocreatine in the brain. Clinically, most of the patients develop a variable mental retardation and a severe speech delay associated with epilepsy, extra-pyramidal syndrome and behavior disturbances. These diseases are often diagnosed during infancy but a few adult cases have been reported recently. Diagnosis is established by measurement of guanidinoacetate and creatine in biologic fluids and in vivo proton magnetic resonance spectroscopy by the total lack of intra-cerebral creatine/phosphocreatine demonstrating. GAMT and AGAT deficiencies are treatable by oral creatine supplementation whereas patients with CRTR do not respond to the treatment. CONCLUSION: Better knowledge of these syndromes is necessary to optimize diagnosis and patient management of these rare but potentially treatable disorders.
Amidinotransferases↗
CDG IIx with unusual phenotype.
Congenital disorders of glycosylation (CDG) are a group of genetic diseases characterized by defective protein glycosylation. N-glycosylation defects are divided into two groups (I and II). CDG group II (types IIa to IIe) refers to defects in the Golgi processing of protein-bound glycans. We report a patient with CDG IIx and an unusual phenotype.
Anemia, Hemolytic↗
Adult presentation of MCAD deficiency revealed by coma and severe arrythmias.
We report the case of a 33-year-old man who presented with headaches and vomiting. Soon after admission he became drowsy and agitated, developed ventricular tachycardia and his neurological state worsened (Glasgow coma score 6). Blood analysis showed respiratory alkalosis, hyperlactacidemia (8 mmol/l), hyperammonemia (390 micro mol/l) and hypoglycaemia (2.4 mmol/l). Subsequently, he developed supraventricular tachycardia, ventricular tachycardia and ultimately ventricular fibrillation resulting in cardiac arrest, which was successfully treated. A CT scan of the head revealed cerebral oedema. Whilst in the intensive care unit, he developed renal failure and rhabdomyolysis. The metabolic abnormalities seen at the time of admission normalised within 48 h with IV glucose infusion. Biological investigations, including urinary organic acids and plasma acylcarnitines, showed results compatible with MCAD deficiency. Mutation analysis revealed the patient was homozygous for the classical mutation A985G. This is one of only a few reports of severe cardiac arrhythmia in an adult due to MCAD deficiency. This condition is probably under-diagnosed in adult patients with acute neurological and/or cardiac presentations.
Acyl-CoA Dehydrogenase↗
Recurrent vomiting and ethylmalonic aciduria associated with rare mutations of the short-chain acyl-CoA dehydrogenase gene.
We report identification of short-chain acyl-CoA dehydrogenase (SCAD) deficiency in a 12-year-old boy who suffered from recurrent attacks of vomiting once or twice a year from infancy. Growth and development were normal and there were no muscular symptoms. Metabolic screening was performed during a hospitalization at 8 years of age and revealed an increased excretion of ethylmalonic acid (EMA; 45-80 mmol/mol creatinine, normal 0.2-6.6), suggesting a degradation defect of short-chain fatty acids. An increased n-butyrylcarnitine was found in freshly collected serum (0.9 micromol/L; normal <0.4) but not in dry blood spots. Neither of the frequent SCAD gene variants 625G>A and 511C>T was present, but direct sequencing of the promoter and coding regions of the SCAD gene revealed that the patient had mutations on both alleles: 417G>C (Trpl15Cys) and 1095G>T (Gln341His). Neither mutation has been described before in compound heterozygosity or homozygosity. Enzymatic investigations subsequently confirmed a defect of SCAD in both fibroblasts and muscle extracts. Furthermore, expression studies of both mutations demonstrated impaired enzyme function or structure. To our knowledge, this case is the first description of a patient with proven SCAD deficiency presenting with recurrent emesis but without other symptoms, and emphasizes the wide clinical phenotype of this disorder.
Alleles↗
Respiratory complex II defect in siblings associated with a symptomatic secondary block in fatty acid oxidation.
The mitochondrial oxidative phosphorylation and fatty acid oxidation pathways have traditionally been considered independent major sources of cellular energy production; however, case reports of patients with specific enzymatic defects in either pathway have suggested the potential for a complex interference between the two. This study documents a new site of interference between the two pathways, a site in respiratory complex II capable of producing clinical signs of a block in fatty acid oxidation and reduced in vitro activity of acyl-CoA dehydrogenases. The initial patient, and later her newborn sibling, had mildly dysmorphic features, lactic acidosis and a defect in mitochondrial respiratory complex II associated with many biochemical features of a block in fatty acid oxidation. Results of in vitro probing of intact fibroblasts from both patients with methyl[2H3]palmitate and L-carnitine revealed greatly increased [2H3]butyrylcarnitine; however, the ratio of dehydrogenase activity with butyryl-CoA with anti-MCAD inactivating antibody (used to reveal SCAD-specific activity) to that with octanoyl-CoA was normal, excluding a selective SCAD or MCAD deficiency. Respiratory complex II was defective in both patients, with an absent thenoyltrifluoroacetone-sensitive succinate Q reductase activity that was partially restored by supplementation with duroquinone. Although secondary, the block in fatty acid oxidation was a major management problem since attempts to provide essential fatty acids precipitated acidotic decompensations. This study reinforces the need to pursue broadly the primary genetic defect within these two pathways, making full use of increasingly available functional and molecular diagnostic tools.
Acidosis, Lactic↗
Method for determining if a corpse has been frozen: measuring the activity of short-chain 3-hydroxyacyl-CoA dehydrogenase (SCHAD).
Accidental deaths by exposure to the cold have figured in many publications, whereas the freezing of the corpse is not well known. The study which we have reported was motivated by an observation of homicide in which ignorance of the fact that the body had been frozen was responsible for an underestimation of the time since death. It proved that measuring the activity of short-chain 3-hydroxyacyl-CoA dehydrogenase (SCHAD) could reveal that the body had been frozen.
3-Hydroxyacyl CoA Dehydrogenases↗
Oxidation of unsaturated fatty acids by human fibroblasts with very-long-chain acyl-CoA dehydrogenase deficiency: aspects of substrate specificity and correlation with clinical phenotype.
The degradation of unsaturated fatty acids was examined in fibroblasts from 16 patients with very-long-chain acyl-CoA dehydrogenase (VLCAD) deficiency. Analysis of acylcarnitine intermediates following incubation of intact human cells with these compounds revealed that the milder clinical phenotypes could be distinguished from the severe cardiomyopathic phenotype. These findings may reflect more effective contributions of alternate pathways in the milder forms of the disease. Incubation of VLCAD-deficient cells with cis-9 or trans-9 unsaturated fatty acids indicate that VLCAD is largely responsible for the 2,3-dehydrogenation of cis-5 or trans-5 intermediates in fibroblasts. The first two cycles of beta-oxidation with oleic and linoleic acids occur in the absence of VLCAD activity suggesting the presence of an additional acyl-CoA dehydrogenase or alternate pathway for the oxidation of these unsaturated fatty acids. These observations have clinical relevance for determining diagnosis, prognosis and strategies for dietary treatment of these patients.
Acyl-CoA Dehydrogenase, Long-Chain↗
A severe genotype with favourable outcome in very long chain acyl-CoA dehydrogenase deficiency.
A patient with very long chain acyl-CoA dehydrogenase (VLCAD) deficiency is reported. He had a severe neonatal presentation and cardiomyopathy. He was found to be homozygous for a severe mutation with no residual enzyme activity. Tandem mass spectrometry on dried blood spots revealed increased long chain acylcarnitines. VLCAD enzyme activity was severely decreased to 2% of control levels. Dietary management consisted of skimmed milk supplemented with medium chain triglycerides and L-carnitine. Outcome was good and there was no acute recurrence.
Acyl-CoA Dehydrogenase, Long-Chain↗
Antenatal expression of multiple acyl-CoA dehydrogenase deficiency.
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Acyl-CoA Dehydrogenase↗
Adolescent myopathic presentation in two sisters with very long-chain acyl-CoA dehydrogenase deficiency.
Two sisters were investigated at the ages of 20 and 13 years owing to persistently increased serum creatine kinase and recurrent episodes of rhabdomyolysis after emotional stress in the older and myalgias in the younger. The finding of increased levels of cis-5-tetradecenoic acid (C14:1) in plasma, severe hypocarnitinaemia and the absence of a pathological dicarboxylic aciduria in both sisters suggested a very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency. Reduced [1-(14)C]palmitate oxidation and deficient mitochondrial VLCAD activity in fibroblasts were found. Mutation analysis revealed compound heterozygosity for Asp365His and Arg410His changes. This late-onset, milder clinical presentation differs from the other two more severe infantile phenotypes described, since there is no hypoglycaemia or cardiac disease. Fatty acid oxidation defects should be investigated in all cases with rhabdomyolysis beginning in adolescence or early adulthood.
Acyl-CoA Dehydrogenase, Long-Chain↗
Recognition and management of fatty acid oxidation defects: a series of 107 patients.
In a personal series of 107 patients, we describe clinical presentations, methods of recognition and therapeutic management of inherited fatty acid oxidation (FAO) defects. As a whole, FAO disorders appear very severe: among the 107 patients, only 57 are still living. Including 47 siblings who died early in infancy, in total 97 patients died, of whom 30% died within the first week of life and 69% before 1 year. Twenty-eight patients presented in the neonatal period with sudden death, heart beat disorders, or neurological distress with various metabolic disturbances. Hepatic presentations were observed in 73% of patients (steatosis, hypoketotic hypoglycaemia, hepatomegaly, Reye syndrome). True hepatic failure was rare (10%); cholestasis was observed in one patient with LCHAD deficiency. Cardiac presentations were observed in 51% of patients: 67% patients presented with cardiomyopathy, mostly hypertrophic, and 47% of patients had heart beat disorders with various conduction abnormalities and arrhythmias responsible for collapse, near-miss and sudden unexpected death. All enzymatic blocks affecting FAO except CPT I and MCAD were found associated with cardiac signs. Muscular signs were observed in 51% of patients (of whom 64% had myalgias or paroxysmal myoglobinuria, and 29% had progressive proximal myopathy). Chronic neurologic presentation was rare, except in LCHAD deficiency (retinitis pigmentosa and peripheral neuropathy). Renal presentation (tubulopathy) and transient renal failure were observed in 27% of patients. The diagnosis of FAO disorders is generally based on the plasma acylcarnitine profile determined by FAB-MS/MS from simple blood spots collected on a Guthrie card. Urinary organic acid profile and total and free plasma carnitine can also be very helpful, mostly in acute attacks. If there is no significant disturbance between attacks, the diagnosis is based upon a long-chain fatty acid loading test, fasting test, and in vitro studies of fatty acid oxidation on fresh lymphocytes or cultured fibroblasts. Treatment includes avoiding fasting or catabolism, suppressing lipolysis, and carnitine supplementation. The long-term dietary therapy aims to prevent periods of fasting and restrict long-chain fatty acid intake with supplementation of medium-chain triglycerides. Despite these therapeutic measures, the long-term prognosis remains uncertain.
Disease Management↗
DNA-based prenatal diagnosis for very-long-chain acyl-CoA dehydrogenase deficiency.
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Acyl-CoA Dehydrogenase, Long-Chain↗
Determination of total fatty acids in plasma: cis-5-tetradecenoic acid (C14:1 omega-9) in the diagnosis of long-chain fatty acid oxidation defects.
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3-Hydroxyacyl CoA Dehydrogenases↗