Leukotriene C4-synthesis deficiency: a new inborn error of metabolism linked to a fatal developmental syndrome.
BACKGROUND
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Mayatepek
E
E
Department of General Paediatrics, Children's Hospital, University of Heidelberg, Germany. ertan_mayatepek@ukl.uni-heidelberg.de
Flock
B
B
D000015:Abnormalities, Multiple / Q000235:genetics / Q000378:metabolism*; D016022:Case-Control Studies; D003241:Consanguinity; D005183:Failure to Thrive / Q000235:genetics; D005260:Female; D005982:Glutathione Transferase / Q000172:deficiency*; D006801:Humans; D007231:Infant, Newborn; D017997:Leukotriene C4 / Q000096:biosynthesis / Q000172:deficiency* / Q000502:physiology; D008661:Metabolism, Inborn Errors / Q000235:genetics / Q000378:metabolism*; D008831:Microcephaly / Q000235:genetics; D009123:Muscle Hypotonia / Q000235:genetics; D011596:Psychomotor Disorders / Q000235:genetics
D017997:Leukotriene C4; D005982:Glutathione Transferase; C041116:leukotriene-C4 synthase