In January, 2001, the discovery of the two mutations which cause Familial Dysautonomia (FD) rocked the scientific community. Research in the field of FD moved quickly and a scant two years after the identification of the mutations, treatment options aimed at the actual disease rather than its symptoms became available for children with FD for the first time.

How does FD work? The FD mutation occurs in a gene that makes IKAP protein. This mutation causes cells to cut out (or "skip") an essential part of the gene (called exon 20), which results in a shortened form of IKAP. The truncated protein does not work well. In order to "fix" FD. the cell must be manipulated to ignore the mutation and make nor­mal IKAP protein (with exon 20 included), rather than the shortened form. While science has not reached this ultimate cure, the advancements made by researchers throughout the world have taken us closer and closer to that eventuality and have provided the children a significant treatment in the interim.

There are several areas of potential investigation, many of which are being pursued by dedicated scientists. There are labs working to clone the mutation in mice to create "FD mice", labs working towards understanding what the gene does, labs trying to understand how the mutation causes exon 20 to be skipped, and labs working to find substances which can cause nerve cells to ignore the mutation. The first research following the identity of the FD mutation compared the make-up of the human IKAP gene to that of rats, mice, and rabbits. Because more research can be carried out in these lab animals than in humans, this research was an important step to understanding both what the protein does and how the gene works.

Researchers also began to explore more about the "tissue specificity" of FD (i.e., why some cells can make mostly normal IKAP protein, while others make predominantly ab­normal IKAP protein). In other words, all cells can (and do) ignore the mutation, but some cell types (in particular, nerve cells) do this less often than others.

Both of the labs which had identified the mutation in 2001 (Drs. Rubin and Anderson at Fordham University and Drs. Slaugenhaupt and Gusella at Mass General Hospital) cited this unique aspect of Familial Dysautonomia in their original papers and in 2003, Slaugenhaupt, et al published a paper confirming the tissue specificity.

The tissue specific pattern of gene expression in FD is a vitally important clue in the search for a cure. By manipulating nerve cells to behave like other cell types that ignore the mutation and make mostly normal IKAP protein, a cure could be developed.

In September, 2003, Rubin and Anderson published a second paper describing the effect of EGCG (epigallocatechin gallate) on IKAP gene expression. EGCG, a constituent of green tea, was found to increase the ratio of normal to mutant IKAP protein in FD cells. In combination with tocotrienol, EGCG has the potential to significantly improve the amount of normal IKAP protein made by nerve cells. Children continued on both of these supplements have had significant improvement in symptoms.

In February 2004, Slaugenhaupt published an article which showed that kinetin, a plant cytokinin, significantly improved the ratio of normal to mutant IKAP protein in FD cells. Unfortunately, kinetin is currently approved only for use topically as a skin anti-aging cream, and not for internal use. Some studies suggest that it can significantly increase bleeding time.

While these two labs have been researching substances which can alter the way the FD mutation affects IKAP gene expression, Dr. Gil Ast and his colleagues at Tel Aviv Uni­versity seek to understand how the mutation causes its effect. Through research funded entirely by FD Hope, Ast has been working towards his ultimate goal: to identify ways in which to get FD cells to produce normal IKAP protein as a matter of course. By understanding why the mutation causes exon 20 to be cut out of the final IKAP protein, a strategy can be devised to prevent the deletion.

In addition to funding topnotch research, FD Hope seeks to raise awareness of FD among the scientific community. FD Hope initiated and helped organize the National Institutes of Health sponsored symposium on FD and inherited dysautonomias in October, 2002. Researchers in the fields of dysautonomia and genetics came together for the two-day workshop to collaborate on ways to make science applicable and beneficial for kids with FD. An article outlining the needs for future research was published as a result of the conference.