FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2016322898> ?p ?o ?g. }

• W2016322898 endingPage "452" @default.
• W2016322898 startingPage "448" @default.
• W2016322898 abstract "Very-Long-Chain acyl-Coenzyme A dehydrogenase (VLCAD, EC 1.3.99.13) and long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD, EC 1.1.1.35) deficiencies are two of several autosomal recessively inherited disorders of long-chain fatty acid β-oxidation (1). They can produce acute symptoms of multiple organ failure and are recognized causes of sudden infant death and Reye syndrome (2). In VLCAD two phenotypes are observed in infancy: children have either an acute early disease with hypertrophic cardiomyopathy and a high incidence of death, or a milder disease with symptoms resembling those of medium-chain acyl-CoA dehydrogenase (MCAD, EC 1.3.99.3) deficiency with hypoketotic hypoglycemia and a benign course (3,4). An adult-onset form with isolated skeletal muscle involvement, rhabdomyolysis, and exercise-and fasting-induced myoglobinuria is also known (5). Successful treatment with frequent feeds, medium-chain triglycerides, and carnitine supplementation has been reported (6). Patients with LCHAD deficiency, first described in 1989 (7), show a wide range of symptoms expressed to varying degrees. Presentation may be an acute attack of hypoketotic hypoglycemia at a few months of age, often with hypotonia or liver dysfunction, as well as cardiac failure from severe cardiomegaly, without evidence of hypoglycemia; or slowly developing hypotonia, recurrent vomiting, and diarrhea. Pigmentary retinopathy or peripheral neuropathy may develop in long-term survivors (8). Attacks of muscle stiffness associated with myoglobinuria have also been described (9). Treatment involves frequent feeds, medium-chain triglycerides, and supplementation of essential fatty acids. We report one patient with fatal VLCAD deficiency and one with a good outcome of LCHAD deficiency. We stress the need for early diagnosis—that is, through early investigation of urinary organic acid analysis in the metabolic crisis or acylcarnitine profile in dried blood spots. We raise the question as to whether carnitine treatment is adequate during metabolic crisis in these deficiencies. CASE REPORTS Patient 1 Patient 1 was the third child of healthy nonconsanguineous white parents with an older healthy son. Her sister died suddenly at age 3 months. Autopsy showed interstitial pneumonia and diffuse marked fatty infiltration of the liver. Both findings were interpreted as secondary final phenomena, and a diagnosis of sudden infant death syndrome was assumed (Institut für Pathologie, Landeskrankenhaus Feldkirch). The patient was born at term after an uneventful pregnancy. Birth weight was 3470 g, length 50 cm (both 50th percentile), and head circumference 36 cm (75th percentile). Apgar scores were 9/10/10. On the third day of life, she showed asymptomatic hypoglycemia with an undetectable blood glucose level. This finding and the review of the sibling's autopsy prompted investigation of a fatty acid β-oxidation defect. Free carnitine in plasma was reduced to 14.1 μmol/l (normal range 32.6–40.6) and acylcarnitine was increased to 13.3 μmol/l (1–7), showing an acylcarnitine/total carnitine ratio of 0.9 (<0.2). Frequent feeds and supplementation with carnitine 100 mg/kg/d were introduced. Initial urinary organic acid analysis showed a slight elevation of concentrations of dicarboxylic acids, considered to be nonspecific at that age, but further investigation of fatty acid β-oxidation was recommended (Dr. W. Lehnert, Freiburg). MCAD deficiency was excluded by a loading test with phenylpropionic acid (Dr. W. Erwa, Graz). Recommended loading with sunflower oil was not performed, but at age 5 weeks fibroblasts were sent for investigation of fatty acid β-oxidation enzymes. However, the results of enzyme activities in fibroblasts were obtained only after the child's death and using a second skin biopsy obtained at autopsy. At age 2 months the child was seen at a regular visit by her pediatrician and was well. About 12 hours later she vomited twice; 3 hours later she was admitted to the hospital because of reduced general condition. Glucose infusion was started at 4 mg/kg/min. Seven hours after the vomiting episode, she had a generalized seizure. Blood glucose was 2.3 mmol/l (41 mg/dl); blood gas analysis showed a compensated metabolic acidosis. The patient was transferred to a tertiary-care hospital. On arrival she was in poor condition, in shock and comatous. Body weight was 4050 g, length 56 cm, and head circumference 38 cm (10th, 50th, and 25th percentile, respectively). The body temperature was 36.7°C. The liver reached 6 cm under the costal margin in the right midclavicular line. Pathologic laboratory findings were hemoglobin 78 g/l (100–130), uric acid 84 mg/l (18–51), aspartate aminotransferase 55 U/l (9–26), creatine kinase 279 U/l (8–99), choline esterase 2.88 kU/l (3.5–8.5), lactate dehydrogenase 626 U/l (200–495), ammonium 89 umol/l (10–55), lactate 6.3 mmol/l (0.2–2.8), and a compensated metabolic acidosis in the blood gas analysis. Plasma amino acids and cerebrospinal fluid cell count, glucose, and protein values were normal. Cerebrospinal fluid lactate was 6.8 mmol/l (1.0–2.2). Urinary organic acid analysis showed a strongly increased concentration of 4-hydroxy-phenyllactate and several saturated and unsaturated dicarboxylic and 3-hydroxy-dicarboxylic acids, pointing to a long-chain fatty acid β-oxidation defect (Dr. J.O. Sass, Innsbruck). Ultrasound showed nonspecific hepatomegaly; cranial findings were normal. Coma activity was apparent in the electroencephalogram. On admission to the tertiary-care hospital, the glucose infusion rate was increased to 8 mg/kg/min. Four hours after admission she was intubated and mechanically ventilated because of persisting coma. The chest x-ray showed an enlarged cardiac diameter. To reverse a presumed catabolic state, a high-calorie infusion was started through a central venous line. An energy intake of 95 kcal/kg/d in a reasonable fluid amount (100 ml/kg/d) was achieved through Intralipid 20% (intravenous solution consisting of soybean oil, lecithin, and glycerol with a 55% essential fatty acid portion; Pharmacia & Upjohn, Stockholm, Sweden) 1 g/kg/d and a glucose infusion rate of 15 mg/kg/min. Carnitine was added to the infusion (200 mg/kg/d). Twenty-four hours after admission, cardiomyopathy started to develop with low output syndrome, and the child died 17 hours later of a cardiac arrest. The plasma obtained at admission showed a free plasma carnitine concentration of 19.8 μmol/l and a highly abnormal acylcarnitine profile with elevated concentrations of C14:1 (in particular), C14:0 and C14:2, C16:0, C16:1, C18:1, and C18:2 carnitine, considered characteristic of VLCAD deficiency (Dr. P. Vreken, Amsterdam) (Fig. 1). Palmitoyl-CoA oxidation in fibroblasts from a skin biopsy obtained immediately after death was abnormal (8.6 and 3.6 nmol/min/mg protein; controls 14.53 ± 5.83) (Prof. R. Wanders, Amsterdam), indicating VLCAD deficiency. Mutation analysis in fibroblasts (Dr. B. Andresen, Aarhus) revealed a compound heterozygosity (3), later also confirmed in her deceased sister.FIG. 1.: Plasma acylcarnitine profile of a normal control and patients 1 and 2. Acylcarnitines were analyzed according to Vreken et al. (22). Note the elevated concentrations of long-chain acylcarnitines in patient 1, characteristic of Very-long-chain acyl-coenzyme A dehydrogenase deficiency, and the elevated concentrations of long-chain-OH-carnitines in patient 2, characteristic of long-chain 3-hydroxyacyl-CoA dehydrogenase/multiple trifunctional protein deficiency.Patient 2 Patient 2 was the third child of healthy consanguineous (great-grandparents were siblings) white parents with an older healthy son. Their second child, a girl, was delivered through cesarean section in the 33rd gestational week because the pregnancy was complicated by severe HELLP (hemolysis, elevated liver enzymes, low platelets) syndrome. Birth weight was 1630 g (50th percentile), Apgar scores were 1/3/6, and the arterial umbilical pH was 6.97. She showed sequelae of perinatal asphyxia (severe cerebral palsy) and died at 8 months of a pulmonary infection. No metabolic investigations were performed. Patient 2 was delivered in the 37th gestational week through cesarean section because this pregnancy was also complicated by HELLP syndrome. Birth weight was 2420 g, length 47 cm, and head circumference 31.7 cm (all values 3rd percentile). Apgar scores were 8/9/10; the arterial umbilical pH was 7.32. Development was uneventful until age 4.5 months, when the child became sick with an upper respiratory tract infection that persisted for 3 weeks despite treatment. At this time, while still being treated with josamycin, dihydrocodeine, and ambroxol hydrochloride, he became increasingly apathetic and was referred to the hospital. The initial examination showed a pale 5-month-old boy (weight 6000 g, length 67 cm, head circumference 41 cm [10th, 75th, and 10th percentile, respectively]) with a reduced level of consciousness and tachypnea. Pronounced muscular hypotonia and liver enlargement to 4 cm from the costal margin in the right midclavicular line were noted. Body temperature was not elevated, and blood pressure was normal. Blood glucose was 0.6 mmol/l (11 mg/dl); blood gas analysis showed a pH of 7.3, standard bicarbonate of 21.2 mmol/l, and a base excess of −4.8 mmol/l. A test for urine ketones was negative. Administration of glucose returned its level to normal, but this did not change the patient's attentiveness. A neurocranial scan performed to exclude an intracerebral process was normal. The urinary organic acid analysis showed a markedly increased concentration of 4-hydroxy-phenyllactate and a number of saturated and unsaturated dicarboxylic and 3-hydroxy dicarboxylic acids suggestive of LCHAD, multiple trifunctional protein, or VLCAD deficiency (Dr. J.O. Sass, Innsbruck). Other laboratory findings were hemoglobin 85 g/l (100–130), aspartate aminotransferase 76 U/l (9–26), alanine aminotransferase 88 U/l (2–28), creatine kinase 63 U/l (8–99), alkaline phosphatase 566 U/l (155–670), lactate dehydrogenase 285 U/l (200–495), ammonium 10 umol/l (10–55), and lactate 3.6 mmol/l (0.2–2.8). Plasma amino acid concentrations were normal. Ultrasound showed nonspecific hepatomegaly. Echocardiography revealed a hypertrophic left ventricle without hemodynamic compromise. After the initial glucose administration, treatment was continued with a glucose infusion rate of 15 mg/kg/min. Because of the marked hypotonia, carnitine was started at 40 mg/kg/d. Under this regimen the child's consciousness level improved. The dietary treatment, started 24 hours after admission, consisted of six feedings per day with a formula containing medium-chain triglycerides. Essential fatty acids were added to the feedings after 3 days. The hepatopathy persisted for some days, with bilirubin levels up to 4.57 mg/dl. The airway infection was treated with terbutaline and budenoside inhalations. The pretreatment acylcarnitine profile (Dr. P. Vreken, Amsterdam) (see Fig. 1) was severely abnormal, with the accumulation of long-chain acylcarnitines and long-chain hydroxy-acylcarnitines, highly suggestive of LCHAD or multiple trifunctional protein deficiency, and a very low free carnitine concentration (5.4 μmol/l). The diagnosis of LCHAD deficiency was confirmed in fibroblasts (Prof. R. Wanders, Amsterdam). Mutation analysis showed homozygosity for the common G1528C mutation (10). The child was discharged with five feedings of a formula containing medium-chain triglycerides and 10 mg/kg/d oral carnitine. On discharge, echocardiography was normal. Eye examination has shown no pigmentary retinopathy so far. His development has been good. At age 9 months he suffered a second metabolic derangement resulting from another upper airway infection, which was successfully treated. DISCUSSION Both VLCAD and LCHAD deficiency have similar clinical features. In the newborn period, nonspecific signs may be attributed to poor feeding or sepsis. They typically resolve with the intravenous administration of glucose. Within months, however, an acute decompensation usually occurs, marked by hypoketotic hypoglycemia, encephalopathy, hypertrophic cardiomyopathy, hepatomegaly, and liver dysfunction (6,10,11). Patient 1 showed asymptomatic hypoglycemia in the first week of life and at age 2 months decompensated unexpectedly. She had been seen that very day by the pediatrician who had been following her up and showed no abnormal findings, especially no hepatomegaly and no signs of encephalopathy, suggesting that metabolic derangement was fulminant. Patient 2 also decompensated rather unexpectedly, although he had been suffering from an infection for 3 weeks. He also showed hypoketotic hypoglycemia. Although fasting intolerance and infection are the most common precipitants of clinical decompensation, besides a vomiting episode, neither could be proved in patient 1. Unexplained cardiorespiratory arrest and sudden death have also been reported for both diseases (6,7), as was seen in the sibling of patient 1. Approximately 50% of patients with VLCAD deficiency die within 2 months of presentation (6). In a recent study a figure of 43% was reported (4), but numbers up to 80% can be found in the literature (3,6,11,12). Pregnancy complicated by HELLP syndrome has been associated with fetal LCHAD deficiency (13) and was also present in the pregnancy of patient 2. It might be suspected that his older sister had LCHAD deficiency as well, considering the HELLP syndrome present in that pregnancy and the subsequent diagnosis of LCHAD deficiency in the younger brother. Unfortunately, no metabolic investigations were performed, and there are no samples available for retrospective analysis. Several groups have reported successful treatment and outcomes of patients with VLCAD and LCHAD deficiency (6,11,12). Both our patients had encephalopathy (patient 1 with coma) and hepatomegaly, although routine laboratory findings (besides the blood glucose level in patient 2) were only slightly abnormal (i.e., elevated transaminases, creatine kinase, reduced hemoglobin). We did not observe arrhythmias. In an attempt to restore an anabolic state in patient 1 after more than 12 hours of no improvement with glucose alone, caloric intake was increased with an infusion also containing an intravenous fat solution (to achieve higher calories with reasonable fluid intake) and carnitine. This might have triggered a poor outcome, or it might reflect that once certain cardiac damage is caused, a point of no return is reached. Whether this is due to the accumulation of toxic fatty acid β-oxidation metabolites or a lack of cellular energy production, similar to that in patients with defects in the carnitine-dependent transporter, is not understood (6). Patient 2 had a marked muscular hypotonia and a very low level of free carnitine. He clinically improved with a dose of initially 40 mg/kg/d. The administration of fatty acids and carnitine to patients with long-chain fatty acid β-oxidation defects has been controversial. It has been suggested that increased levels of long-chain acylcarnitines mediate ischemic damage, cause arrhythmias, and contribute to impaired postischemic function (14,15). Other authors do not support this theory but claim that the ischemic changes result from the inhibition of long-chain fatty acid oxidation and reduced energy production, not the accumulation of tissue acylcarnitines (16). Further, it is unknown to what extent high concentrations of long-chain fatty acid CoA-esters may represent a toxic risk. Sluysmans et al. (11) reported that high-rate glucose infusion with intravenous carnitine supplementation led to a complete recovery from lethargy, hepatomegaly, and tachycardia with left ventricle hypertrophy in a newborn with VLCAD deficiency. Parini et al (17) stated that increased energy intake and carnitine administration seemed to have been beneficial in their 5-year-old patient with VLCAD deficiency. Gillingham et al. (18) found no toxicity of oral carnitine treatment at a dose of 50 mg/kg/d (energy intake 100 kcal/kg/d) in their LCHAD-deficient patient. Recently, the fact that patients with VLCAD deficiency have lactic acidemia has been reported (19,20). Patient 1 showed an elevated lactate level in plasma and cerebrospinal fluid, possibly pointing to a disturbance in the oxidative phosphorylation or a step in pyruvate oxidation, thus leading to energy deficiency. The lactate increase might suggest that the energy deficiency is an underlying element of metabolic decompensation. In patient 1, a long-chain fatty acid β-oxidation defect was suspected from the first week of life. Patient 2 also had a suggestive family history (consanguinity and HELLP syndrome in former pregnancy). Depending on the clinical state, urinary organic acid analysis in spot urine is not always sufficient to identify all these patients in the first days of life. Patient 1 showed a slight elevation of dicarboxylic acids in urine in the first week of life, and a sunflower oil loading test had been recommended, which would have disclosed the underlying defect sooner. However, sunflower oil loading is not freely performed in very young children because of feared complications. Investigations on fibroblasts usually take a long time to show results. In patient 1, the enzymatic diagnosis was established only by the postmortem skin biopsy. Enzymatic analysis can also be performed in lymphocytes (21), thus saving time and giving an alternative if fibroblasts fail. An easy and quick diagnostic tool is the determination of acylcarnitine profiles in a dried blood spot, plasma, or serum. Even in patients in apparently good condition, elevated long-chain acylcarnitines are considered a constant finding in VLCAD and LCHAD deficiency, at least in plasma or serum (22, P. Vreken, unpublished observation). However, acylcarnitine profiles are not routinely available, but most centers have access to emergency urine organic acid analysis. During the metabolic crisis, this investigation is likely to give an accurate estimate of the diagnosis in only a few hours. The importance of early urine collection in these patients needs to be stressed: a delay in urine collection might cause an important delay in diagnosis, because these patients are usually severely compromised and because of organ failure, urine production may cease. Early diagnosis might improve the poor prognosis of patients with long-chain fatty acid β-oxidation defects. Thus, efforts are being undertaken in several regions to include fatty acid β-oxidation defects in newborn screening programs (i.e., by tandem mass spectrometry). Improved awareness and understanding of the pathogenesis of fatty acid β-oxidation defects will be essential for effective treatment of these patients. With early diagnosis, severe decompensations should be avoided, and thus better outcomes become possible. Acknowledgments: In vitro research of J.O. Sass on fatty acid β-oxidation defects is supported by Milupa GmbH&Co KG (Friedrichsdorf, Germany) and Fresenius Kabi Austria GmbH (Graz, Austria)." @default.
• W2016322898 created "2016-06-24" @default.
• W2016322898 creator A5007202678 @default.
• W2016322898 creator A5040032788 @default.
• W2016322898 creator A5040743356 @default.
• W2016322898 creator A5052370546 @default.
• W2016322898 creator A5057288971 @default.
• W2016322898 creator A5082253782 @default.
• W2016322898 creator A5082760518 @default.
• W2016322898 creator A5086448261 @default.
• W2016322898 date "2000-10-01" @default.
• W2016322898 modified "2023-10-03" @default.
• W2016322898 title "Complications in Early Diagnosis and Treatment of Two Infants With Long-Chain Fatty Acid β-Oxidation Defects" @default.
• W2016322898 cites W1566686893 @default.
• W2016322898 cites W1574255071 @default.
• W2016322898 cites W1968853872 @default.
• W2016322898 cites W1979038368 @default.
• W2016322898 cites W1979660645 @default.
• W2016322898 cites W1985517496 @default.
• W2016322898 cites W2016960939 @default.
• W2016322898 cites W2020123987 @default.
• W2016322898 cites W2021184460 @default.
• W2016322898 cites W2022405812 @default.
• W2016322898 cites W2031070853 @default.
• W2016322898 cites W2062671918 @default.
• W2016322898 cites W2075694342 @default.
• W2016322898 cites W2092077589 @default.
• W2016322898 cites W2104262874 @default.
• W2016322898 cites W2105161385 @default.
• W2016322898 cites W2109835425 @default.
• W2016322898 cites W2111627324 @default.
• W2016322898 cites W2126075295 @default.
• W2016322898 cites W2150710988 @default.
• W2016322898 cites W4253490362 @default.
• W2016322898 doi "https://doi.org/10.1097/00005176-200010000-00023" @default.
• W2016322898 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/11045847" @default.
• W2016322898 hasPublicationYear "2000" @default.
• W2016322898 type Work @default.
• W2016322898 sameAs 2016322898 @default.
• W2016322898 citedByCount "3" @default.
• W2016322898 countsByYear W20163228982015 @default.
• W2016322898 countsByYear W20163228982020 @default.
• W2016322898 crossrefType "journal-article" @default.
• W2016322898 hasAuthorship W2016322898A5007202678 @default.
• W2016322898 hasAuthorship W2016322898A5040032788 @default.
• W2016322898 hasAuthorship W2016322898A5040743356 @default.
• W2016322898 hasAuthorship W2016322898A5052370546 @default.
• W2016322898 hasAuthorship W2016322898A5057288971 @default.
• W2016322898 hasAuthorship W2016322898A5082253782 @default.
• W2016322898 hasAuthorship W2016322898A5082760518 @default.
• W2016322898 hasAuthorship W2016322898A5086448261 @default.
• W2016322898 hasBestOaLocation W20163228981 @default.
• W2016322898 hasConcept C126322002 @default.
• W2016322898 hasConcept C187212893 @default.
• W2016322898 hasConcept C62231903 @default.
• W2016322898 hasConcept C71924100 @default.
• W2016322898 hasConcept C82714985 @default.
• W2016322898 hasConceptScore W2016322898C126322002 @default.
• W2016322898 hasConceptScore W2016322898C187212893 @default.
• W2016322898 hasConceptScore W2016322898C62231903 @default.
• W2016322898 hasConceptScore W2016322898C71924100 @default.
• W2016322898 hasConceptScore W2016322898C82714985 @default.
• W2016322898 hasIssue "4" @default.
• W2016322898 hasLocation W20163228981 @default.
• W2016322898 hasLocation W20163228982 @default.
• W2016322898 hasOpenAccess W2016322898 @default.
• W2016322898 hasPrimaryLocation W20163228981 @default.
• W2016322898 hasRelatedWork W1506200166 @default.
• W2016322898 hasRelatedWork W1995515455 @default.
• W2016322898 hasRelatedWork W2048182022 @default.
• W2016322898 hasRelatedWork W2080531066 @default.
• W2016322898 hasRelatedWork W2604872355 @default.
• W2016322898 hasRelatedWork W2748952813 @default.
• W2016322898 hasRelatedWork W2899084033 @default.
• W2016322898 hasRelatedWork W3031052312 @default.
• W2016322898 hasRelatedWork W3032375762 @default.
• W2016322898 hasRelatedWork W3108674512 @default.
• W2016322898 hasVolume "31" @default.
• W2016322898 isParatext "false" @default.
• W2016322898 isRetracted "false" @default.
• W2016322898 magId "2016322898" @default.
• W2016322898 workType "article" @default.