- Email: [email protected]
A novel explanation for potential toxic effects of valproic acid on creatine: Implications for autism
Molecular Genetics and Metabolism 101 (2010) 304
Contents lists available at ScienceDirect
Molecular Genetics and Metabolism j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / y m g m e
Letter to the Editor A novel explanation for potential toxic effects of valproic acid on creatine: Implications for autism Dear Editor: Ammonia may cause creatine deficiency in brain cells [1–3]. Creatine has protective effects in various neurodegenerative processes. Creatine co-treatment with ammonia exposure protected brain cells from some of the toxic effects of ammonia [1]. On the other hand, divalproex is effective in the treatment of irritability in individuals with ASD [4]. Herein, we consider a possible role for creatine in autism; a novel explanation for an association between valproic and autism will be provided. Then, a possible clinical implication of creatine is provided. Exposure to valproic acid in pregnancy is a significant risk factor for autism spectrum disorders [5,6]. Already, this behavioral phenotype is related to alterations in plasticity-related genes [7]. There are reports indicating that valproic acid causes hyperammonia [4,6,12] and ammonia causes creatine deficiency in brain [1–3]. Most individuals with creatine biosynthetic disorders such as guanidinoacetate methyltransferase deficiency have behavioral disorders including autistic behaviors [8,9]. Considering the association of ammonia and valproic acid [10–12], the association of autism and exposure to valproic acid [8,9], creatine deficiency due to hyperammonia [1–3], and the association of creatine deficiency and autistic behaviors [8,9], it is hypothesized that creatine deficiency due to valproic acid is a novel explanation for the increased rate of autism after exposure during pregnancy. In addition, considering the causative role of valproic acid for autism, the role of creatine decrease by hyperammonia, and hyperammonia caused by valproic acid, it is worth considering possible negative longterm outcomes of valproic acid administration in individuals with autism. More studies are required to be conducted to advise whether valproic acid is appropriate for individuals with autism. Administering creatine for individuals taking valproic acid to prevent the possible side effects should be investigated.
References [1] O. Braissant, Ammonia toxicity to the brain: effects on creatine metabolism and transport and protective roles of creatine, Mol. Genet. Metab. 100 (Suppl 1) (2010) S53–58. [2] O. Braissant, L. Cagnon, F. Monnet-Tschudi, O. Speer, T. Wallimann, P. Honegger, H. Henry, Ammonium alters creatine transport and synthesis in a 3D culture of developing brain cells, resulting in secondary cerebral creatine deficiency, Eur. J. Neurosci. 27 (2008) 1673–1685. [3] L. Cagnon, O. Braissant, Hyperammonemia-induced toxicity for the developing central nervous system, Brain Res. Rev. 56 (2007) 183–197. [4] E. Hollander, W. Chaplin, L. Soorya, S. Wasserman, S. Novotny, J. Rusoff, N. Feirsen, L. Pepa, E. Anagnostou, Divalproex sodium vs placebo for the treatment of irritability in children and adolescents with autism spectrum disorders, Neuropsychopharmacology 35 (2010) 990–998. [5] A. Ornoy, Valproic acid in pregnancy: how much are we endangering the embryo and fetus? Reprod. Toxicol. 28 (2009) 1–10. [6] A.D. Rasalam, H. Hailey, J.H. Williams, S.J. Moore, P.D. Turnpenny, D.J. Lloyd, J.C. Dean, Characteristics of fetal anticonvulsant syndrome associated autistic disorder, Dev. Med. Child Neurol. 47 (2005) 551–555. [7] F.I. Roullet, L. Wollaston, D. Decatanzaro, J.A. Foster, Behavioral and molecular changes in the mouse in response to prenatal exposure to the anti-epileptic drug valproic acid, Neuroscience (2010) Jul 17. [Epub ahead of print]. [8] F. Nasrallah, M. Feki, N. Kaabachi, Creatine and creatine deficiency syndromes: biochemical and clinical aspects, Pediatr. Neurol. 42 (2010) 163–171. [9] S. Stockler, P.W. Schutz, G.S. Salomons, Cerebral creatine deficiency syndromes: clinical aspects, treatment and pathophysiology, Subcell. Biochem. 46 (2007) 149–166. [10] S.A. Hamed, M.M. Abdella, The risk of asymptomatic hyperammonemia in children with idiopathic epilepsy treated with valproate: relationship to blood carnitine status, Epilepsy Res. 86 (2009) 32–41. [11] M.M. Mehndiratta, P. Mehndiratta, P. Phul, S. Garg, Valproate induced non hepatic hyperammonaemic encephalopathy (VNHE)—a study from tertiary care referral university hospital, north India, J. Pak. Med. Assoc. 58 (2008) 627–631. [12] A. Verrotti, R. Greco, G. Morgese, F. Chiarelli, Carnitine deficiency and hyperammonemia in children receiving valproic acid with and without other anticonvulsant drugs, Int. J. Clin. Lab. Res. 29 (1999) 36–40.
Ahmad Ghanizadeh Research Center for Psychiatry and Behavioral Sciences, Department of Psychiatry, Shiraz University of Medical Sciences, Hafez Hospital, Shiraz, Iran E-mail address: [email protected].
Conflict of Interest 29 July 2010 The author declares that there is no conflict of interest.
1096-7192/$ – see front matter © 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.ymgme.2010.07.019
Contents lists available at ScienceDirect
Molecular Genetics and Metabolism j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / y m g m e
Letter to the Editor A novel explanation for potential toxic effects of valproic acid on creatine: Implications for autism Dear Editor: Ammonia may cause creatine deficiency in brain cells [1–3]. Creatine has protective effects in various neurodegenerative processes. Creatine co-treatment with ammonia exposure protected brain cells from some of the toxic effects of ammonia [1]. On the other hand, divalproex is effective in the treatment of irritability in individuals with ASD [4]. Herein, we consider a possible role for creatine in autism; a novel explanation for an association between valproic and autism will be provided. Then, a possible clinical implication of creatine is provided. Exposure to valproic acid in pregnancy is a significant risk factor for autism spectrum disorders [5,6]. Already, this behavioral phenotype is related to alterations in plasticity-related genes [7]. There are reports indicating that valproic acid causes hyperammonia [4,6,12] and ammonia causes creatine deficiency in brain [1–3]. Most individuals with creatine biosynthetic disorders such as guanidinoacetate methyltransferase deficiency have behavioral disorders including autistic behaviors [8,9]. Considering the association of ammonia and valproic acid [10–12], the association of autism and exposure to valproic acid [8,9], creatine deficiency due to hyperammonia [1–3], and the association of creatine deficiency and autistic behaviors [8,9], it is hypothesized that creatine deficiency due to valproic acid is a novel explanation for the increased rate of autism after exposure during pregnancy. In addition, considering the causative role of valproic acid for autism, the role of creatine decrease by hyperammonia, and hyperammonia caused by valproic acid, it is worth considering possible negative longterm outcomes of valproic acid administration in individuals with autism. More studies are required to be conducted to advise whether valproic acid is appropriate for individuals with autism. Administering creatine for individuals taking valproic acid to prevent the possible side effects should be investigated.
References [1] O. Braissant, Ammonia toxicity to the brain: effects on creatine metabolism and transport and protective roles of creatine, Mol. Genet. Metab. 100 (Suppl 1) (2010) S53–58. [2] O. Braissant, L. Cagnon, F. Monnet-Tschudi, O. Speer, T. Wallimann, P. Honegger, H. Henry, Ammonium alters creatine transport and synthesis in a 3D culture of developing brain cells, resulting in secondary cerebral creatine deficiency, Eur. J. Neurosci. 27 (2008) 1673–1685. [3] L. Cagnon, O. Braissant, Hyperammonemia-induced toxicity for the developing central nervous system, Brain Res. Rev. 56 (2007) 183–197. [4] E. Hollander, W. Chaplin, L. Soorya, S. Wasserman, S. Novotny, J. Rusoff, N. Feirsen, L. Pepa, E. Anagnostou, Divalproex sodium vs placebo for the treatment of irritability in children and adolescents with autism spectrum disorders, Neuropsychopharmacology 35 (2010) 990–998. [5] A. Ornoy, Valproic acid in pregnancy: how much are we endangering the embryo and fetus? Reprod. Toxicol. 28 (2009) 1–10. [6] A.D. Rasalam, H. Hailey, J.H. Williams, S.J. Moore, P.D. Turnpenny, D.J. Lloyd, J.C. Dean, Characteristics of fetal anticonvulsant syndrome associated autistic disorder, Dev. Med. Child Neurol. 47 (2005) 551–555. [7] F.I. Roullet, L. Wollaston, D. Decatanzaro, J.A. Foster, Behavioral and molecular changes in the mouse in response to prenatal exposure to the anti-epileptic drug valproic acid, Neuroscience (2010) Jul 17. [Epub ahead of print]. [8] F. Nasrallah, M. Feki, N. Kaabachi, Creatine and creatine deficiency syndromes: biochemical and clinical aspects, Pediatr. Neurol. 42 (2010) 163–171. [9] S. Stockler, P.W. Schutz, G.S. Salomons, Cerebral creatine deficiency syndromes: clinical aspects, treatment and pathophysiology, Subcell. Biochem. 46 (2007) 149–166. [10] S.A. Hamed, M.M. Abdella, The risk of asymptomatic hyperammonemia in children with idiopathic epilepsy treated with valproate: relationship to blood carnitine status, Epilepsy Res. 86 (2009) 32–41. [11] M.M. Mehndiratta, P. Mehndiratta, P. Phul, S. Garg, Valproate induced non hepatic hyperammonaemic encephalopathy (VNHE)—a study from tertiary care referral university hospital, north India, J. Pak. Med. Assoc. 58 (2008) 627–631. [12] A. Verrotti, R. Greco, G. Morgese, F. Chiarelli, Carnitine deficiency and hyperammonemia in children receiving valproic acid with and without other anticonvulsant drugs, Int. J. Clin. Lab. Res. 29 (1999) 36–40.
Ahmad Ghanizadeh Research Center for Psychiatry and Behavioral Sciences, Department of Psychiatry, Shiraz University of Medical Sciences, Hafez Hospital, Shiraz, Iran E-mail address: [email protected].
Conflict of Interest 29 July 2010 The author declares that there is no conflict of interest.
1096-7192/$ – see front matter © 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.ymgme.2010.07.019