leukotriene-c4 and Metabolism--Inborn-Errors

A 32-year-old man with glutathione synthetase deficiency developing an acute metabolic crisis is described. During this acute episode, intracellular glutathione content in erythrocytes was below the detection limit (<0.3 mmol/L). Leukotriene C4 in CSF and urinary leukotriene E4 were massively decreased, indicating an imparied synthesis of cysteinyl leukotrienes. Clinical recovery after one week was accompanied by a clear improvement of these biochemical parameters. The highly disturbed glutathione synthesis is postulated to be the reason for a deficient synthesis of cysteinyl leukotrienes, which may at least in part be responsible for the severe clinical symptoms.

Topics: Acute Disease; Adult; Glutathione; Glutathione Synthase; Humans; Leukotriene C4; Male; Metabolism, Inborn Errors

Cysteinyl leukotrienes (LTC(4), LTD(4), LTE(4)) are potent lipid mediators derived from arachidonate in the 5-lipoxygenase pathway. Recently, the first inborn error of leukotriene synthesis, LTC(4)-synthesis deficiency, has been identified in association with a fatal developmental syndrome. The absence of leukotrienes in cerebrospinal fluid was one of the most striking biochemical findings in this disorder. We analysed leukotrienes in cerebrospinal fluid of patients with a broad spectrum of other well-defined inborn errors of metabolism, including glutathione synthetase deficiency (n=2), Zellweger syndrome (n=3), mitochondrial disorders (n=8), fatty acid oxidation defects (n=7), organic acidurias (n=7), neurotransmitter defects (n=5) and patients with non-specific neurological symptoms, as a reference population (n=120). The concentrations of leukotrienes were not related to age. Representative percentiles were calculated as reference intervals of each leukotriene. In all patients with an inborn error of metabolism concentration of cysteinyl leukotrienes and LTB(4) did not differ from the reference group. Our results indicate that absence of cysteinyl leukotrienes (<5 pg/ml) in association with normal or increased LTB(4) (50.0-67.3 pg/ml) is pathognomonic for LTC(4)-synthesis deficiency. The unique profile of leukotrienes in cerebrospinal fluid in this new disorder is primarily related to the defect and represents a new diagnostic approach.

Topics: Adolescent; Case-Control Studies; Child; Child, Preschool; Humans; Infant; Infant, Newborn; Leukotriene B4; Leukotriene C4; Leukotriene D4; Leukotriene E4; Leukotrienes; Metabolism, Inborn Errors; Reference Values

Topics: Cells, Cultured; Fatal Outcome; Female; gamma-Glutamyltransferase; Glutathione Transferase; Humans; Infant; Leukotriene C4; Leukotriene D4; Leukotriene E4; Metabolism, Inborn Errors; Monocytes

Leukotrienes are potent oxygenated metabolites derived from the 5-lipoxygenase pathway of arachidonic acid metabolism. They comprise the cysteinyl leukotrienes (LTC4, LTD4, LTE4) and LTB4. The rate limiting step in the formation of cysteinyl leukotrienes is the conversion of LTA4 to LTC4 catalyzed by the enzyme LTC4 synthase. Recently, the first inborn error of leukotriene synthesis, LTC4-synthesis deficiency, has been identified in a patient with a fatal developmental syndrome. We report on an additional infant presenting with severe muscular hypotonia, symmetrical extension in the lower extremities and psychomotor retardation who died at the age of 6 months. Despite intensive investigations no specific diagnosis could be made. Leukotrienes were subsequently analyzed in the cerebrospinal fluid. Concentrations of LTC4, LTD4 and LTE4 were below the detection limit (< 5 pg/ml) whereas LTB4 was found to be in the upper normal range. The absence of cysteinyl leukotrienes with normal LTB4 concentration in cerebrospinal fluid is unique and seems to be pathognomonic for LTC4-synthesis deficiency. Our patient most likely represents the second case described so far with this condition. This report provides further evidence that LTC4-synthesis deficiency represents a new neurometabolic disorder.

Topics: Fatal Outcome; Female; Humans; Infant; Leukotriene C4; Metabolism, Inborn Errors; Muscle Hypotonia; Psychomotor Disorders

Cysteinyl leukotrienes (LTC4, LTD4, LTE4) are potent lipid mediators derived from arachidonic acid in the 5-lipoxygenase pathway that exert profound biological effects. We investigated synthesis and metabolism of leukotrienes in an infant who presented with muscular hypotonia, psychomotor retardation, failure to thrive, and microcephaly. The course of the disease was rapidly progressive and the infant died aged 6 months.. Cysteinyl leukotrienes and LTB4 were analysed in cerebrospinal fluid, plasma, urine, and stimulated monocytes by EIA. We measured [3H]-LTC4 formation from [3H]-LTA4 in monocytes and platelets by radio-high-pressure liquid chromatography.. Concentrations of LTC4 and its metabolites were below the detection limit in the cerebrospinal fluid, plasma and urine. LTC4 could not be generated in stimulated monocytes, whereas LTB4 synthesis was increased. [3H]-LTC4 could not be made from [3H]-LTA4 in the patient's monocytes or platelets.. In this patient, inability to synthesise LTC4 suggests a deficiency of LTC4 synthase. This defect is a new inborn error of human eicosanoid metabolism and may be associated with the clinical disorder. Leukotriene analysis should be done in all patients with neurological symptoms who are candidates for metabolic diseases.

Topics: Abnormalities, Multiple; Case-Control Studies; Consanguinity; Failure to Thrive; Female; Glutathione Transferase; Humans; Infant, Newborn; Leukotriene C4; Metabolism, Inborn Errors; Microcephaly; Muscle Hypotonia; Psychomotor Disorders

Glutathione synthetase deficiency (GSD) is an inborn error of glutathione (GSH) metabolism. As a consequence of the block in the gamma-glutamyl cycle, the enzyme defect leads to a generalized intracellular GSH deficiency. The cysteinyl leukotrienes (LTs), LTC4, LTD4 and LTE4, are potent lipid mediators generated in the 5-lipoxygenase pathway. LTC4 is derived from the unstable epoxide LTA4 by conjugation with GSH, and therefore GSH is required for LTC4 synthesis. In the circulation LTC4 is rapidly metabolized to LTE4 which is excreted in the urine. In the present study, LT metabolites were separated in a patient with biochemically established GSD and intracellular GSH deficiency (0.5 mM in erythrocytes, normal range 2.0-2.5 mM) by reversed-phase high-performance liquid chromatography, and quantified by enzyme immunoassays. Our results revealed that in GSD LTC4 synthesis is significantly decreased in calcium ionophore A23187-activated monocytes as well as in neutrophils (11-14% and 7-10%, respectively, of the levels detected in the parents or healthy controls). Additionally, urinary LTE4 was also found to be abnormally decreased in GSD (0.4 nmol/mol creatinine as compared to 15-46 nmol/mol creatinine in parents and controls). GSD represents the first described disorder with decreased synthesis of cysteinyl LTs and may serve as a unique model for the linkage between LT synthesis and GSH metabolism in vivo. Moreover the impaired synthesis of cysteinyl LTs might be involved in the pathophysiology of GSD.

Topics: Cysteine; Female; Glutathione; Glutathione Synthase; Humans; Infant, Newborn; Leukotriene C4; Leukotriene E4; Leukotrienes; Metabolism, Inborn Errors; Monocytes; Neutrophils