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22. PROSPECTIVE STUDY OF MULTIPLE SUPRATHERAPEUTIC ACETAMINOPHEN DOSES IN FEBRILE CHILDREN

Author

Kozer, E, Barr, J, Lahat, E, Bulkowstein, M, Avgil, M, Greenberg, R, Matias, A, and Berkovitch, M

Subjects
Children -- Health aspects, Liver -- Abnormalities, Acetaminophen -- Dosage and administration, Convulsions in children -- Causes of, Environmental issues, Health, Pharmaceuticals and cosmetics industries
Abstract

Background: Repeated doses of acetaminophen given for therapeutic reasons have been reported to cause hepatotoxicity in adults and children. We studied the effects of repeated Acetaminophen (APAP) overdoses administered for therapeutic purposes. Methods: Forty four children, aged 2 months to 10 years, who were referred to the Emergency Department with a fever of [is greater than] 38.5 [degrees] for more than 48 hours, and received APAP in a dosage [is greater than] 60 mg/kg/day. AST, ALT and APAP blood levels were measured. Results: The mean total daily dose of APAP was 92 [+ or -] 26 (63-171) mg/kg. There were no cases of severe liver injury. In 4 children (9.1%) an elevation of AST and ALT was found. One patient had a slight elevation of AST only. Among children with AST and ALT levels of [is greater than or equal to] 45 IU/L, those who received APAP in a dosage of [is greater than] 100 mg/kg/day had marginally significantly higher levels of AST (p = 0.05) and ALT (p = 0.07) as compared to those who received 60-100 mg/kg/day. APAP blood levels ranged from 0 to 23 mcg/mL. No correlation was found between the time since the last dose of APAP and the drug level in the serum. Conclusions: This study shows that in ill children receiving repeated supratherapeutic doses of acetaminophen, abnormalities in liver function may occur. Both the medical and the pharmaceutical industries should be responsible for providing adequate, accurate and easily understood information to parents and patients on the judicious use of this common medication., Kozer E, Barr J, Lahat E, Bulkowstein M, Avgil M, Greenberg R, Matias A, Berkovitch M. Department of Pediatric Emergency Medicine, Clinical Pharmacology and Toxicology Unit, Clinical Biochemistry, Assaf Harofeh [...]

Published
2001

23. B56delta-related protein phosphatase 2A dysfunction identified in patients with intellectual disability

Author

Houge, G., Haesen, D., Vissers, L.E.L.M., Mehta, S., Parker, M.J., Wright, M., Vogt, J., McKee, S., Tolmie, J.L., Cordeiro, N., Kleefstra, T., Willemsen, M.H., Reijnders, M.R.F., Berland, S., Hayman, E., Lahat, E., Brilstra, E.H., Gassen, K.L. van, Zonneveld-Huijssoon, E., Bie, C.I. De, Hoischen, A., Eichler, E.E., Holdhus, R., Steen, V.M., Doskeland, S.O., Hurles, M.E., FitzPatrick, D.R., Janssens, V., Houge, G., Haesen, D., Vissers, L.E.L.M., Mehta, S., Parker, M.J., Wright, M., Vogt, J., McKee, S., Tolmie, J.L., Cordeiro, N., Kleefstra, T., Willemsen, M.H., Reijnders, M.R.F., Berland, S., Hayman, E., Lahat, E., Brilstra, E.H., Gassen, K.L. van, Zonneveld-Huijssoon, E., Bie, C.I. De, Hoischen, A., Eichler, E.E., Holdhus, R., Steen, V.M., Doskeland, S.O., Hurles, M.E., FitzPatrick, D.R., and Janssens, V.

Abstract

Contains fulltext : 154618.pdf (publisher's version ) (Open Access), Here we report inherited dysregulation of protein phosphatase activity as a cause of intellectual disability (ID). De novo missense mutations in 2 subunits of serine/threonine (Ser/Thr) protein phosphatase 2A (PP2A) were identified in 16 individuals with mild to severe ID, long-lasting hypotonia, epileptic susceptibility, frontal bossing, mild hypertelorism, and downslanting palpebral fissures. PP2A comprises catalytic (C), scaffolding (A), and regulatory (B) subunits that determine subcellular anchoring, substrate specificity, and physiological function. Ten patients had mutations within a highly conserved acidic loop of the PPP2R5D-encoded B56delta regulatory subunit, with the same E198K mutation present in 6 individuals. Five patients had mutations in the PPP2R1A-encoded scaffolding Aalpha subunit, with the same R182W mutation in 3 individuals. Some Aalpha cases presented with large ventricles, causing macrocephaly and hydrocephalus suspicion, and all cases exhibited partial or complete corpus callosum agenesis. Functional evaluation revealed that mutant A and B subunits were stable and uncoupled from phosphatase activity. Mutant B56delta was A and C binding-deficient, while mutant Aalpha subunits bound B56delta well but were unable to bind C or bound a catalytically impaired C, suggesting a dominant-negative effect where mutant subunits hinder dephosphorylation of B56delta-anchored substrates. Moreover, mutant subunit overexpression resulted in hyperphosphorylation of GSK3beta, a B56delta-regulated substrate. This effect was in line with clinical observations, supporting a correlation between the ID degree and biochemical disturbance.

Published
2015

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