January 2010

Dear Members of the FD community,

Before sharing with you our most recent research results, I would like to reflect on a variety of issues. Firstly, I would like to thank Ann Slaw, the President of FD Now, the members of the Board of Directors of FD Now and all of the individuals in this organization who have worked very hard to provide funding that enables Dr. Sylvia Anderson to continue to work on a research program that focuses on improving the lives of those with FD. For Sylvia, this is a passion that grows from a deep compassion for your children. The walls of Sylvia’s office are covered with pictures of children with FD. The pictures that greet Sylvia each morning remind her of those who are awaiting the next breakthrough. I wish to thank FD-NOW for their steadfast support of our research program and for providing the lion’s share of support for our research program, through their funding of Sylvia’s salary. Funds for the purchase of many of the reagents and supplies for our work have primarily come from two foundations that have a long-term and unwavering commitment to the work we are doing. These organizations are the Eric Alterman Foundation for F.D. Cure and the Cure FD Foundation. Without the commitment of the individuals that make up these three organizations, the research that is going on in our lab would not be taking place.

Over the years, our research laboratory has provided those with FD with new therapeutic modalities that target the deficit caused by the FD-causing mutation – but our work has not been limited to a study of splicing or gene regulation. We have focused on what is needed to improve the lives of those with FD and it is as a result of this focus that we discovered and reported on the ability of tyramine and related molecules to trigger dysautonomic crises. This observation has provided valuable insight into the reason the children went into what had until that time been “unexplained” episodes of dysautonomic crises. Below, I share with you our recent discovery of a new therapeutic modality and, over the next few months, I will share with you some thoughts about FD-related issues that have grown out of the ever-present perspective that Sylvia and I share, which is “what more can we do for the children with FD?” Before discussing the new results, I would very much like to thank Dr. Neal Gittleman, a pediatrician in Lakewood, New Jersey, who has embraced the therapeutic programs that we have developed and has been willing to take my phone calls at the oddest hours to discuss a thought or a perspective that has occurred to us. Dr. Gittleman brings an extensive medical perspective and important insight to these conversations. He has become an extremely valuable resource in our search to improve the lives of those with FD.

Finally, before I share with you our latest results, I would like to remind the community that I am not a physician. I am a researcher at Fordham University whose research topic is FD. I will provide my perspective on our findings, but I ask that you please contact the physician that treats your child to see if this new therapeutic modality is appropriate for your child.

The two therapeutic modalities that we have published on to date are tocotrienols and epigallocatechin gallate (EGCG). Both of these compounds are relatively benign and I have not been able to find any literature that reflects on any danger associated with taking these substances. Initially, there was concern in the FD community that tocotrienols could compromise clotting time, but the studies done in patients who are taking as many as 12 tocotrienols (600mg) per day indicate that there is no negative impact on the clotting activity of their blood. If your child is taking the tocotrienols and you are concerned about this, I suggest that you ask your physician to perform the appropriate test to evaluate this.

The excessive intake of the new compound that I will describe in this report can be toxic in high doses and therefore the amounts taken should reflect what has been reported in the literature. We are in the process of preparing a manuscript that demonstrates that vitamin A, as well as the related provitamin A forms, such as beta-carotene, increase the production of the functional IKAP transcript in FD-derived and normal cell lines. These vitamin A forms increase functional IKAP levels in a similar manner to that which occurs in response to the tocotrienols. In fact we have observed that the simultaneous treatment of cells with vitamin A and the tocotrienols results in a greatly enhanced production of functional IKAP. When one reports on the effect of a compound on gene expression in cell lines, the question always arises as to whether this effect occurs in people who take the compound. To address this question, in addition to being the “researchers”, Sylvia and I were the “guinea pigs”. We have taken Vitamin A and the provitamin beta-carotene and have seen a clear increase in the amount of IKAP produced in our blood cells. These results reveal that these compounds enter the blood stream where they mediate the same effects seen in the laboratory cell lines. While we don’t have definitive proof that the vitamin A compounds will affect IKAP levels in the nerve cells of our bodies, we have evaluated the impact of these compounds on neuronal cells in the lab and they respond very well. Before going “public” with our findings, we often will ask parents of some of the local children if they would be willing to have their child ingest a supplement and report back to us any effects noted. The results have been VERY encouraging. Parents have reported significantly increased autonomic stability and increased cognitive function. The commercial products that Sylvia and I have been testing in the lab and have been ingesting are the “Non-Oily Dry A” product produced by Vitamin Shoppe (http://www.vitaminshoppe.com/store/en/browse/sku_detail.jsp?id=VS-1261) and the “Dry Beta-carotene” product made by Solgar (http://www.iherb.com/Solgar-Dry-Beta-Carotene-10-000-IU-250-Tablets/15060?at=0).

Allow me to provide some background information on vitamin A. Vitamin A is obtained by our bodies either in the form of vitamin A or as a provitamin A such as beta carotene or similar molecules. The ingestion of excessive amounts of vitamin A can be toxic. The Dietary Supplement Fact Sheet provided by the National Institutes of Health (http://dietary-supplements.info.nih.gov/factsheets/vitamina.asp) presented below provides guidance on the Upper Intake Limits for vitamin A, depending on the age of the individual. According to this information, a child that is between 9 and 13 years of age can take 5610 units of vitamin A. An individual between the ages of 14 and 18 can take 9,240 units of vitamin A. How much should you give your child? Clearly age is not necessarily a good measure when it come to FD children as they tend to be smaller that unaffected children. As a guide to how much vitamin A to give your child, I would suggest that a 19 year old healthy female may weigh 100 pounds and her upper limit would be 10,000 units. It would therefore seem reasonable to extrapolate that a 50 pound FD child could receive 5000 units of vitamin A each day. Further extrapolations should be easy for each of you to perform according to the weight of your child. It is important to keep in mind that if your child is receiving vitamin A from another supplement or from a formula, the total amount of vitamin A that you can give him/her should not exceed the upper limit. When calculating how much vitamin A to give your child, please consult your physician.

Tolerable Upper Intake Levels (ULs) for retinol

retinol table

Contrary to the impact of the ingestion of vitamin A, the ingestion of large amounts of beta-carotene are not toxic, as the body will only use the beta-carotene if the body is not being provided with a sufficient amount of vitamin A. What this means is that there is more leeway when ingesting the beta-carotene. For our studies, Sylvia and I have been ingesting either one “Dry A” capsule or one beta carotene pill. In us, a clear effect of these treatments was apparent when we ingested either the “Dry A” capsule that contains 5000 IU of vitamin A (in the form of retinyl acetate) and 5000 IU of beta-carotene, or the tablet ( Dry Beta-Carotene) that contains 10,000 IU of the beta-carotene. What we suggest is that you consult with your child’s physician regarding this matter and that you arrive at a dose that is deemed appropriate for your child. What you should keep in mind is that the beta carotene is considered non-toxic and, as such, a higher dose of this provitamin A is not believed to have any negative effects. To provide a perspective, LifeExtension produces a product that is 65,000 IU per dose. I should mention that the ongoing ingestion of an excessive amount of beta-carotene can cause the skin to turn somewhat orange in color. This color change disappears when the supplementation is stopped.

There are many interesting and sometimes contradictory studies in the literature that are worth noting. There is a study that suggests that ingestion of large amounts of vitamin A may cause osteoporosis and there is a study that indicates that the ingestion of beta-carotene is associated with improved cognitive function. While these studies, in my view, are not conclusive, I would suggest that if you provide your child with an increased amount of vitamin A, you also provide calcium supplementation.

Best Wishes,

BerishSig crop

Berish Rubin