Genistein in Sanfilippo disease: A randomized controlled crossover trial

Objective: Sanfilippo disease (mucopolysaccharidosis type III [MPS III]) is a rare neurodegenerative metabolic disease caused by a deficiency of 1 of the 4 enzymes involved in the degradation of heparan sulfate (HS), a glycosaminoglycan (GAG). Genistein has been proposed as potential therapy but its efficacy remains uncertain. We aimed to determine the efficacy of genistein in MPS III. Methods: Thirty patients were enrolled. Effects of genistein were determined in a randomized, crossover, placebocontrolled intervention with a genistein-rich soy isoflavone extract (10mg/kg/day of genistein) followed by an openlabel extension study for patients who were on genistein during the last part of the crossover. Results: Genistein resulted in a significant decrease in urinary excretion of total GAGs (p 0.02, slope = 0.68mg GAGs/mmol creatinine/mo) and in plasma concentrations of HS (p 0.01, slope = 15.85ng HS/ml/mo). No effects on total behavior scores or on hair morphology were observed. Parents or caregivers could not predict correctly during which period of the crossover a patient was on genistein. Interpretation: Genistein at 10mg/kg/day effectively reduces urinary excretion of GAGs and plasma HS concentration in patients with MPS III. However, the absolute reduction in GAGs and in HS is small and values after 12 months of treatment remain within the range as observed in untreated patients. No clinical efficacy was detected. Substantially higher doses of genistein might be more effective as suggested by recent studies in animal models. ANN NEUROL 2012; 71: 110-120