Background Genistein is a substrate reduction therapy proposed for the treatment of mucopolysaccharidosis type III (MPS III), or Sanfilippo disease. Objectives To assess the efficacy, safety and usefulness of genistein in patients with MPS III in order to evaluate its possible incorporation into the service portfolio of the Spanish National Health System (NHS). Methods Review of the scientific literature based on a pre-specified protocol and following standardized methodological guidelines. The findings were reported in accordance with the PRISMA statement. In January 2018, bibliographic databases, registers of ongoing studies and specific information sources were searched for rare diseases. Studies evaluating the effect of genistein at any dose and presentation, in individuals of any age with MPS III were included, without limitations on design. Two investigators independently selected the studies to be included in the review, and evaluated them critically using a risk of bias assessment tool specific for clinical trials and a methodological quality assessment tool for uncontrolled trials and observational studies. Descriptive data from the studies and the results for the outcomes of interest of the review were extracted. The findings of the review for the main outcomes of interest are compiled in Summary of Evidence tables, which also include a classification of the quality of the evidence. Finally, the conclusions regarding the inclusion of genistein in the Spanish NHS service portfolio are presented and current knowledge gaps are identified. Results The search retrieved 837 references, from which 10 studies were included (two randomized trials, six uncontrolled clinical trials, one uncontrolled observational study and one case report). The studies included a total of 162 individuals with a diagnosis of MPS III. Most studies evaluated a low dose of genistein (between 5 and 15 mg/kg/day) and only two administered a high dose of synthetic pure genistein (150 mg/kg/day). Duration of genistein treatment in the studies varied between six months and three years, and all studies assessed the results immediately after treatment. Low doses of genistein showed improvements on neurocognitive scales of little or no clinical relevance after 12 months of treatment (very low quality of evidence, due to the methodological limitations of the studies and the imprecision of the results). A randomized clinical trial showed no difference on a behavioural scale (or on any of its subscales) between a dose of 10 mg/kg/day of genistein and placebo after six months of treatment. An extension of the study showed that patients treated with genistein presented improvements on the anxiety subscale after one year of followup (low quality of evidence, due to the imprecision of the results and their heterogeneity). Studies of low doses of genistein did not describe adverse effects (low quality of evidence, due to methodological limitations and imprecise results). An uncontrolled clinical trial did not show differences on a disability scale when comparing the change in scores between baseline and after 12 months of treatment with high doses of genistein (very low quality of evidence, due the methodological limitations of the studies and the imprecision of the results). This trial recorded only nine serious adverse events, of which only one was determined as possibly related to genistein. The majority of nonserious adverse events identified were attributed to the underlying disorder (low quality of evidence, due to the imprecision of the results). Conclusions: Low doses of genistein show no clinical relevance, while the data on high doses are insufficient. The consistently negative results for physiological variables with low doses of the treatment argue against the performance of further studies with these doses. The publication of the results of a randomized placebo-controlled clinical trial (EudraCT 2013-001479-18) testing the effects of a genistein dose of 150 mg/kg/day on the level of heparan sulfate in cerebrospinal fluid as the main variable is still pending. If the results of this study are negative, there would be no justification for continuing to investigate the possible benefits of the treatment. Even if the results were positive, additional studies would be needed to evaluate the impact of high doses on patient-important outcomes, such as behavioural or neurocognitive outcomes. Based on the data currently available in the literature, we do not support the inclusion of genistein in the Spanish NHS service portfolio. With regard to clinical practice, we conclude that health professionals should be aware of the limited evidence on the effect of genistein in MPS III; they should inform families of the lack of clinical relevance of low doses of genistein, and of the absence of data on the impact of high doses. This information should serve as a basis for parents to make an informed and individualized decision regarding its use.
Genistein; Sanfilippo disease; National Health System
Roqué-Fíguls M, Solà-Arnau I, Salas-Gama K, Requeijo-Lorenzo C. Eficacia, seguridad y utilidad de la genisteína en pacientes con síndrome de Sanfilippo. Barcelona: Agència de Qualitat i Avaluació Sanitàries de Catalunya; 2018. (Informes de Evaluación de Tecnologías Sanitarias).
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