Meet the Researchers

(left) Dr. Berish Rubin, Head, and (right) Dr. Sylvia Anderson,
Director, Laboratory for Familial Dysautonomia Research,
Fordham University

Dr. Berish Rubin and Dr. Sylvia Anderson’s research currently focuses on the molecular biology of Familial Dysautonomia (FD). FD, also known as hereditary sensory neuropathy Type III, and previously known as Riley-Day Syndrome, is an autosomal recessive disorder that affects the development and survival of sensory, sympathetic and some parasympathetic neurons. Individuals with FD are affected with a variety of symptoms which include decreased sensitivity to pain and temperature, cardiovascular instability, recurrent pneumonias, vomiting crises, blood pressure swings, an absence of overflow emotional tears and gastrointestinal dysfunction. This disorder is primarily confined to individuals of Ashkenazi Jewish descent.

In the summer of 2001, Dr. Rubin’s laboratory directed its efforts to identifying the genetic cause of FD. The mutations responsible for FD were found to occur in a gene encoding a protein termed IKAP. These findings were published in the American Journal of Human Genetics [Anderson, S.L., Coli, R., Daly, I.W., Kichula, E.A., Rork, M.J. Volpi, S.A., Ekstein, J. and Rubin, B.Y. (2001) Familial Dysautonomia is caused by mutations of the IKAP gene. Am. J. Hum. Genet. 68:753-758]. With the identification of the mutations responsible for FD, genetic testing has been established by several academic and commercial laboratories and couples can now be screened to determine their carrier status and their risk of having children with FD. Large scale studies done to date demonstrate that the carrier frequency for FD is approximately the same as that of Tay Sachs in those of Ashkenazi Jewish descent. It is expected that, with time, there will be a reduction in the number of children born with FD.

While studying cells derived from individuals with FD, members of Dr. Rubin’s laboratory noted that these cells are able to produce some functional IKAP protein. This finding demonstrated that the FD-causing mutation does not completely block the production of the functional IKAP protein. This observation prompted an intense screening program to evaluate the ability of naturally- derived compounds to modulate the amount of functional IKAP produced in FD-derived cells. After screening hundreds of compounds, these researchers identified two compounds capable of increasing the amount of functional IKAP protein produced in these cells. The two compounds identified are a form of vitamin E called tocotrienol and a chemical component of green tea termed epigallocatechin gallate (EGCG). These findings have since been published: Anderson, S.L., Qiu, J. and Rubin, B.Y. (2003) Tocotrienols induce IKBKAP expression: a possible therapy for Familial Dysautonomia. Biochem. Biophys. Res. Comm. 306:303-309; and Anderson, S.L., Qiu, J., and Rubin, B.Y. (2003) EGCG corrects aberrant splicing of IKAP mRNA in cells from patients with Familial Dysautonomia. Biochem. Biophys. Res. Comm. 310:627-633. The availability of these compounds in health food stores has allowed individuals with FD to take these supplements on a daily basis. Individuals taking these compounds have seen a dramatic reduction in the symptoms associated with FD and have had a dramatic improvement in their quality of life.

A third breakthrough came in 2005 when the laboratory reported that individuals with FD not only have low levels of IKAP protein, but also do not have enough of an enzyme called MAO (monoamine oxidase), which is responsible for breaking down a potentially toxic substance in certain foods such as aged cheeses, smoked and processed meats and fish and certain fruits and vegetables. The researchers also found that the tocotrienols increased both IKAP and MAO levels in the blood. The avoidance of tyramine in the diet is helping to avoid life-threatening autonomic crises that used to occur frequently in individuals with FD [Anderson, S.L. and Rubin, B.Y. (2005) Tocotrienols reverse IKAP and monoamine oxidase delficiencies in familial dysautonomia. Biochem. Biophys. Res. Comm. 336:150-156; Rubin, B.Y., Anderson, S.L. and Kapas, L. (2008) Can the therapeutic efficacy of tocotrienols in neurodegenerative familial dysautonomia patients be measured clinically? Antioxid. Redox Signal. 10:837-841].

Studies underway in the laboratory are aimed at continuing to identify compounds that will increase the amount of functional IKAP produced in individuals with FD and to understand the role IKAP plays in the pathophysiology of FD.