Efficacy of dietary suppletion genestein in patients with the MPS III (A follow-up study)

Sanfilippo syndrome (MPS III) is a rare lysosomal storage disorder,
characterized by progressive mental and motor deterioration and premature
death. MPS III is caused by a deciency in the degradation of heparansulphate
(one of the glucosaminoglycans) with subsequent accumulation of
heparansulphate. Until now no causal therapy is available.

Genestein is a isoflavone from soy occuring in the natural diet. Genestein is
widely used as a food additive (*nutriceutical*). Several potentially
beneficial health effects have been attributed to genestein.

In vitro research demonstrated genestein inhibits the synthesis of GAG's,
probably through inhibition of an epidermal growth factor. Since accumulation
of GAG's (heparansulphate) is a key symptome in Sanfilippo syndrome, dietary
supplementation of genestein could potentially have clinically relevant
beneficial effects in children with MPS III. In a recent small open-label pilot
study in children with MPS III positive results on GAG excretion in the urine,
cognitive function measured by questionairs and hairmorphology were
demonstrated after oral treatment with genestein.

The positive results of the Polish study gave hope to many parents and in
several countries parents already started to give their children genestein,
which is available as a dietary supplement, despite of proven efficiency.

In June 2009 a double blind placebo controlled study on the effect of genestein
was initiated in the Netherlands. Thirty patients with MPS III type A, B or C
are included in this study and receiving either placebo or genestein (10 mg/kg)
during two 6 month periods in a cross-over design
results will be expected at the end of this year. Our study will be a follow-up
study of previous mentioned study en will examine the efficacy of genestein as
nutriceutical in patients with MPS III.

The objective of the study is to establish the effect of genestein in patients
with MPS III on urinary and serum GAGs levels, hair morphology, GAG
accumulation in skinbiopsy, cognitive functions and behavior (Piotrowska et al,
2008). MPS III is a devastating disorder for which until now no treatment is
available. Results will be used in the management of patients with MPS III.
When genestein proves to be effective it can be used as dietary supplementation
in the treatment of MPS III. When genestein has no effect, the use of genestein
can be discouraged.

Given that this study is a follow-up study, the effect of genestein, mainly on
neurocognitive functioning could be examined over a longer time period.

Study design is a follow up study of the double-blind randomised controlled
trial with cross-over design. This follow-up study is an open-label study.
Patients will receive Genestein 10 mg/kg for a period of 12 months.

All participating patients will receive genestein capsules (10mg/kg) for a
period of 12 months.

The effects of genestein on development of breast cancer, prostate cancer,
plasma lipid levels ed have been extensively studied. Until now, no short time
negative effects have been reported. In the Polish pilot study no adverse
events occured. Use of genestein appears to be save. Besides genestein occurs
in the natural diet, and infants fed soy-based formulas even ingest 5-9 mg/kg
isoflavines a day (Setchell et al 1997). A possible negative effect of
genestein is a decreased fertility and this is compared to the symptoms of MPS
III a neglegible risc. The riscs and burden of the study for the patients are
relatively small: 2x venapuncture, 1x skinbiopsy, 2x collection urine, 1x
assessing hairmorpholgy, 1 x questionairs for patients, and 2x assessment of
cognitive function (In subset of patients with developmental age > 1 years).
Invasive procedures, including venapuncture, skinbiopsy and hairmorphology at 6
and/or 12 months will only be done when results of placebo controlled trial
demonstrate a postive effect of genestein in these patients.