Quantitative Evaluation of the Clinical Effects of<i>S</i>-Adenosylmethionine on Mood and Behavior in Lesch-Nyhan Patients

Dolcetta, Diego; Parmigiani, Pietro; Salmaso, Luigi; Bernardelle, Roberta; Cesari, Ugo; Andrighetto, Gilberto; Baschirotto, Giuseppe; Nyhan, William L.; Hladnik, Uroš

doi:10.1080/15257770.2013.774012

Cited by 23 publications

(18 citation statements)

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“…A less rigorous but similarly positive description was reported for a young LNS patient shortly thereafter [Dolcetta et al, 2013]. However, Dolcetta et al [2013] conducted a study where SAM was administered to 13 LNS patients; 4 showed significant positive improvement, but the majority of patients experienced worsening of their symptoms. Chen et al [2014] administered SAM to 5 related LNS patients and found a significant reduction of self-harm and aggressive behavior in all 5 patients.…”

Section: Treatment With S-adenylmethioninementioning

confidence: 99%

Lesch-Nyhan Syndrome: Models, Theories, and Therapies

et al. 2016

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Lesch-Nyhan syndrome (LNS) is a rare X-linked disorder caused by mutations in HPRT1, an important enzyme in the purine salvage pathway. Symptoms of LNS include dystonia, gout, intellectual disability, and self-mutilation. Despite having been characterized over 50 years ago, it remains unclear precisely how deficits in hypoxanthine and guanine recycling can lead to such a profound neurological phenotype. Several studies have proposed different hypotheses regarding the etiology of this disease, and several treatments have been tried in patients, though none have led to a satisfactory explanation of the disease. New technologies such as next-generation sequencing, optogenetics, genome editing, and induced pluripotent stem cells provide a unique opportunity to map the precise sequential pathways leading from genotype to phenotype.

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Section: Treatment With S-adenylmethioninementioning

confidence: 99%

Lesch-Nyhan Syndrome: Models, Theories, and Therapies

et al. 2016

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“…SAM treatment has previously been reported in only few patients Dolcetta et al 2013;Glick 2006); in some of these, supplementation with SAM led to a drastic reduction in self-mutilation events and very good clinical outcome. This was investigated with (Dolcetta et al 2013) or without Glick 2006) formal assessment tools, and we decided here to base effect on parental judgment and documentation.…”

Section: Discussionmentioning

confidence: 99%

“…Purine depletion in tissue culture models and selective vulnerability of basal ganglia in HPRT-deficient mice was shown in several studies (Dunnett et al 1989;Finger et al 1988;Jinnah et al 1992Jinnah et al , 1994Jinnah et al , 1999, and SAM could act on this by replenishing adenosyl stores in LND. Other authors discuss a role of SAM in neurotransmitter synthesis and metabolism (Dolcetta et al 2013;Miller 2008), but this clearly needs more studies.…”

Section: Discussionmentioning

confidence: 99%

“…This was investigated with (Dolcetta et al 2013) or without Glick 2006) formal assessment tools, and we decided here to base effect on parental judgment and documentation.…”

Section: Discussionmentioning

confidence: 99%

“…With S-adenosylmethionine (SAM, depicted in blue), an adenosine donor, the lack of purines in LND can be recovered by turning adenosine to adenosine monophosphate (AMP) by adenine phosphoribosyltransferase (APRT) and then to IMP. ADA adenosine deaminase, ADSL adenylosuccinate lyase, AK adenosine kinase, AMPRT amido phosphoribosyltransferase, ATP adenosine triphosphate, GTP guanosine triphosphate, IDH isocitrate dehydrogenase, PNP purine nucleoside phosphorylase, PPRP phosphoribosylpyrophosphate et al 2011), has been beneficial for treatment of selfmutilation in a single LND patient who initially received SAM for liver detoxification and elevated transaminases (Bottiglieri 2002;Glick 2006) and was tested in 14 patients from the Italian LND cohort with unequivocally opposite effects on patients (Dolcetta et al 2013). A recent study in four additional patients ) demonstrated a positive effect of SAM on the neurological symptoms, mainly self-mutilation.…”

Section: Introductionmentioning

confidence: 99%

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The Effect of S-Adenosylmethionine on Self-Mutilation in a Patient with Lesch–Nyhan Disease

et al. 2016

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Background: Lesch-Nyhan disease (LND) is an Xchromosomal 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 Sadenosylmethionine (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 selfmutilation events under SAM treatment (p < 0.05).Conclusion: The results of this double-blind placebocontrolled 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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S‐Adenosyl Methionine in the Therapy of Depression and Other Psychiatric Disorders

Kuželički

2016

Drug Development Research

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Preclinical Research S-adenosyl methionine (SAM) is a major methyl donor and as such exerts its influence on CNS function through methylation reactions, such as methylation of several catecholamine moiety-containing neurotransmitters, epigenetic changes through methylation of DNA, RNA, RNA-binding proteins and histones, and phospholipid methylation. Based on available evidence, SAM is currently recommended as a next-step (second-line) treatment option following inadequate treatment response to a first-line antidepressant. It shows significant promise in the treatment of pediatric and perinatal depression, as well as Alzheimer's disease, but to make this a recommendation further clinical trials are needed. SAM is safe to use in most patients, but is contraindicated in those with bipolar disorder. Concerns considering the possible increase of homocysteine levels (and cardiovascular complications) due to long-term SAM therapy need to be further addressed in clinical trials taking into account individual`s ability to metabolize homocysteine and his/her folate status. Drug Dev Res 77 : 336-346, 2016. © 2016 Wiley Periodicals, Inc.

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Quantitative Evaluation of the Clinical Effects ofS-Adenosylmethionine on Mood and Behavior in Lesch-Nyhan Patients

Abstract: Four patients tolerated the drug and reported beneficial effects. The majority experienced worsened behavior. The 2 assessment tools demonstrated effectiveness in quantitatively evaluating the self-injurious behavior.

Cited by 23 publications

References 29 publications

Lesch-Nyhan Syndrome: Models, Theories, and Therapies

Lesch-Nyhan Syndrome: Models, Theories, and Therapies

The Effect of S-Adenosylmethionine on Self-Mutilation in a Patient with Lesch–Nyhan Disease

S‐Adenosyl Methionine in the Therapy of Depression and Other Psychiatric Disorders

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