Abstract
Background: Lesch–Nyhan disease (LND) is an X-chromosomal disorder of purine metabolism characterized by hyperuricemia, dystonia, and self-mutilation, leading to an extremely high burden of disease in affected patients and families. Although allopurinol therapy can control hyperuricemia, it has no effect on self-mutilation and neurological symptoms. Single reports describe a beneficial effect of S-adenosylmethionine (SAM) on the neurological symptoms, which motivated us to evaluate this alternative treatment.
Methods: We performed a double-blind placebo-controlled trial to analyze the effects of SAM on self-mutilation attempts in a male patient affected by LND. The trial lasted for 282 days and comprised three alternating verum and placebo periods of 50 days each. The mother of the patient recorded attempts of self-mutilation during the entire trial.
Results: While verum and placebo were both well tolerated, a total of 1,762 events of self-mutilation were recorded, of which 1,281 events were in the placebo period and 481 in the verum period. The daily mean of events was 8.6 with placebo and 4.5 with SAM corresponding to a 50 % decrease in self-mutilation events under SAM treatment (p < 0.05).
Conclusion: The results of this double-blind placebo-controlled single-case trial suggest that SAM can have a beneficial effect on self-mutilation in patients with LND, possibly by replenishing the purine pool in affected brain cells.
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References
Anderson LT, Ernst M (1994) Self-injury in Lesch–Nyhan disease. J Autism Dev Disord 24:67–81
Bertelli M, Randi D, Micheli V, Gallo S, Andrighetto G, Parmigiani P, Jacomelli G, Carella M, Lievore C, Pandolfo M (2004) Molecular basis of hypoxanthine-guanine phosphoribosyltransferase deficiency in Italian Lesch–Nyhan patients: identification of nine novel mutations. J Inherit Metab Dis 27:767–773. doi:10.1023/B:BOLI.0000045799.78633.23
Bottiglieri T (2002) S-Adenosyl-L-methionine (SAMe): from the bench to the bedside—molecular basis of a pleiotrophic molecule. Am J Clin Nutr 76:1151S–1157S
Chen BC, Balasubramaniam S, McGown IN, O'Neill JP, Chng GS, Keng WT, Ngu LH, Duley JA (2014) Treatment of Lesch–Nyhan disease with S-adenosylmethionine: experience with five young Malaysians, including a girl. Brain Dev 36:593–600. doi:10.1016/j.braindev.2013.08.013
Criswell H, Mueller RA, Breese GR (1988) Assessment of purine-dopamine interactions in 6-hydroxydopamine-lesioned rats: evidence for pre- and postsynaptic influences by adenosine. J Pharmacol Exp Ther 244:493–500
de Brouwer AP, Williams KL, Duley JA, van Kuilenburg AB, Nabuurs SB, Egmont-Petersen M, Lugtenberg D, Zoetekouw L, Banning MJ, Roeffen M, Hamel BC, Weaving L, Ouvrier RA, Donald JA, Wevers RA, Christodoulou J, van Bokhoven H (2007) Arts syndrome is caused by loss-of-function mutations in PRPS1. Am J Hum Genet 81:507–518. doi:10.1086/520706
De Gregorio L, Nyhan WL, Serafin E, Chamoles NA (2000) An unexpected affected female patient in a classical Lesch–Nyhan family. Mol Genet Metab 69:263–268. doi:10.1006/mgme.2000.2967
Dolcetta D, Parmigiani P, Salmaso L, Bernardelle R, Cesari U, Andrighetto G, Baschirotto G, Nyhan WL, Hladnik U (2013) Quantitative evaluation of the clinical effects of S-adenosylmethionine on mood and behavior in Lesch–Nyhan patients. Nucleosides Nucleotides Nucleic Acids 32:174–188. doi:10.1080/15257770.2013.774012
Duley JA, Christodoulou J, de Brouwer AP (2011) The PRPP synthetase spectrum: what does it demonstrate about nucleotide syndromes? Nucleosides Nucleotides Nucleic Acids 30:1129–1139. doi:10.1080/15257770.2011.591747
Dunnett SB, Sirinathsinghji DJ, Heavens R, Rogers DC, Kuehn MR (1989) Monoamine deficiency in a transgenic (Hprt-) mouse model of Lesch–Nyhan syndrome. Brain Res 501:401–406
Finger S, Heavens RP, Sirinathsinghji DJ, Kuehn MR, Dunnett SB (1988) Behavioral and neurochemical evaluation of a transgenic mouse model of Lesch–Nyhan syndrome. J Neurol Sci 86:203–213
Fu R, Chen CJ, Jinnah HA (2014) Genotypic and phenotypic spectrum in attenuated variants of Lesch–Nyhan disease. Mol Genet Metab 112:280–285. doi:10.1016/j.ymgme.2014.05.012
Glick N (2006) Dramatic reduction in self-injury in Lesch–Nyhan disease following S-adenosylmethionine administration. J Inherit Metab Dis 29:687. doi:10.1007/s10545-006-0229-8
Green RD, Proudfit HK, Yeung SM (1982) Modulation of striatal dopaminergic function by local injection of 5'-N-ethylcarboxamide adenosine. Science 218:58–61
Jinnah HA, Langlais PJ, Friedmann T (1992) Functional analysis of brain dopamine systems in a genetic mouse model of Lesch–Nyhan syndrome. J Pharmacol Exp Ther 263:596–607
Jinnah HA, Wojcik BE, Hunt M, Narang N, Lee KY, Goldstein M, Wamsley JK, Langlais PJ, Friedmann T (1994) Dopamine deficiency in a genetic mouse model of Lesch–Nyhan disease. J Neurosci 14:1164–1175
Jinnah HA, Jones MD, Wojcik BE, Rothstein JD, Hess EJ, Friedmann T, Breese GR (1999) Influence of age and strain on striatal dopamine loss in a genetic mouse model of Lesch–Nyhan disease. J Neurochem 72:225–229
Jinnah HA, De Gregorio L, Harris JC, Nyhan WL, O'Neill JP (2000) The spectrum of inherited mutations causing HPRT deficiency: 75 new cases and a review of 196 previously reported cases. Mutat Res 463:309–326
Jinnah HA, Harris JC, Nyhan WL, O'Neill JP (2004) The spectrum of mutations causing HPRT deficiency: an update. Nucleosides Nucleotides Nucleic Acids 23:1153–1160. doi:10.1081/NCN-200027400
Jinnah HA, Ceballos-Picot I, Torres RJ, Visser JE, Schretlen DJ, Verdu A, Larovere LE, Chen CJ, Cossu A, Wu CH, Sampat R, Chang SJ, de Kremer RD, Nyhan W, Harris JC, Reich SG, Puig JG, Lesch–Nyhan Disease International Study Group (2010) Attenuated variants of Lesch–Nyhan disease. Brain 133:671–689. doi:10.1093/brain/awq013
Kopin IJ (1981) Neurotransmitters and the Lesch–Nyhan syndrome. N Engl J Med 305:1148–1150. doi:10.1056/NEJM198111053051910
Miller AL (2008) The methylation, neurotransmitter, and antioxidant connections between folate and depression. Altern Med Rev 13:216–226
Neychev VK, Jinnah HA (2006) Sudden death in Lesch–Nyhan disease. Dev Med Child Neurol 48:923–926. doi:10.1017/S0012162206002015
Nyhan WL (1976) Behavior in the Lesch–Nyhan syndrome. J Autism Child Schizophr 6:235–252
Puig JG, Torres RJ, Mateos FA, Ramos TH, Arcas JM, Buno AS, O'Neill P (2001) The spectrum of hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency. Clinical experience based on 22 patients from 18 Spanish families. Medicine (Baltimore) 80:102–112
Robey KL, Reck JF, Giacomini KD, Barabas G, Eddey GE (2003) Modes and patterns of self-mutilation in persons with Lesch–Nyhan disease. Dev Med Child Neurol 45:167–171
Schretlen DJ, Ward J, Meyer SM, Yun J, Puig JG, Nyhan WL, Jinnah HA, Harris JC (2005) Behavioral aspects of Lesch–Nyhan disease and its variants. Dev Med Child Neurol 47:673–677. doi:10.1017/S0012162205001374
Stone TW (1981) Physiological roles for adenosine and adenosine 5'-triphosphate in the nervous system. Neuroscience 6:523–555
Acknowledgments
We appreciate the help of the family of our patient in conducting this trial and specifically the excellent recording of self-mutilation events. We also thank Mrs. Ursina Spörri, Zurich, for her help in data analysis.
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Communicated by: Pascale de Lonlay
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Matthias Lauber, Barbara Plecko, Miriam Pfiffner, Jean-Marc Nuoffer, and Johannes Häberle declare that they have no conflict of interest.
This article does contain studies with a human subject. The patient received a medication as compassionate use after approval was obtained from the SwissMedic/Schweizerisches Heilmittelinstitut. As this was a therapeutic trial with a licensed drug in a single patient, there was no need to obtain formal approval by the local ethical board.
Jean-Marc Nuoffer and Johannes Häberle have together planned the study that was performed under the supervision of Johannes Häberle. Analysis and interpretation of data, drafting of the article, and revision were performed by Matthias Lauber, Barbara Plecko, Miriam Pfiffner, Jean-Marc Nuoffer, and Johannes Häberle.
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Lauber, M., Plecko, B., Pfiffner, M., Nuoffer, JM., Häberle, J. (2016). The Effect of S-Adenosylmethionine on Self-Mutilation in a Patient with Lesch–Nyhan Disease. In: Morava, E., Baumgartner, M., Patterson, M., Rahman, S., Zschocke, J., Peters, V. (eds) JIMD Reports, Volume 32. JIMD Reports, vol 32. Springer, Berlin, Heidelberg. https://doi.org/10.1007/8904_2016_571
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DOI: https://doi.org/10.1007/8904_2016_571
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