Familial Dysautonomia: The Connection between Genes and Environment
Over the course of writing our book, Thiamine Deficiency Disease, Dysautonomia, and High Calorie Malnutrition, I came across many examples of genetic malleability. A particularly striking example involves a devastating condition called Familial Dysautonomia. Familial dysautonomia, also known as “Riley-Day Syndrome” is a relatively rare condition affecting approximately 1 in 3700 individuals of Ashkenazic Jewish heritage. It presents in infancy and carries with it a high mortality rate. Infants carrying the underlying mutation have a increased susceptibility to infection and sudden death. Some of the symptoms associated with familial dysautonomia include:
- A failure to grow despite normal growth hormone
- Difficulty in feeding, choking, and defective swallowing coupled with a failure to thrive
- Severe episodes of vomiting
- The absence of fungiform papillae and taste buds on the tongue
- Excessive sweating, especially on the head during sleep
- A failure to produce tears
- Vasomotor instability with frequent but transient morbilliform rash when eating or excited
- Decreased sensitivity to pain
- Absence of deep tendon reflexes
- Inappropriate emotional responses (in older children)
- A high prevalence of scoliosis
Familial dysautonomia is caused by a mutation in a gene called IKBKAP (inhibitor of kappa light polypeptide gene enhancer in B-cells). IKBKAP affects the splicing of a protein referred to as either IKAP (IκB kinase complex–associated protein), or ELP (elongator protein). The mutation results in the errant development and survival of the sensory neurons that receive information from the environment and transmit it back to brain. Disruptions in the autonomic nervous system result.
Given the severity of the potential disturbances associated with an effectively disconnected autonomic system, it would seem unreal that something as simple as food, or more specifically, the nutrients in foods, could modify, perhaps even override the consequences of familial dysautonomia, but it does. Both the original expression of the mutation and it’s continued influence on health are mediated by food, likely via interactions with the mitochondria. From the book (Chapter 5, pp 205-207):
“Recall from Chapter 3 that the majority of the ∼1500 proteins required for proper mitochondrial functioning are transcribed from nuclear genes and translated in the cell cytosol before being transported into the mitochondria; a contingent reciprocity when one considers that transcription and translation processes are themselves ATP dependent. When we explore IKBKAP, the gene encoding the IKAP/ELP proteins responsible for familial dysautonomia, we find that the IKAP/ELP proteins play a critical role in cellular response to stress, particularly nutrient stressors, but also temperature and chemical stressors. This is in addition to their role in transcription/chromatin remodeling, teleomere silencing, DNA damage response signals, and cell division. In other words, the IKAP/ELP proteins contribute significantly to what researchers call the mitochondrial regulome, acting as “environmental” sensors that respond to and affect epigenetic modifications. Though the mechanisms remain to be elucidated fully, in the HeLa cell line, at least, the ELP protein complex influences mitochondrial signal transduction directly. Similarly, researchers have identified both enzymatic and nonenzymatic mitochondrial processes regulated by the ELP protein complex, mostly via its role in lysine acetylation processes.
Most notably for our purposes, the IKAP/ELP nutrition/starvation stressor-sensing capability extends the possibility that, at least evolutionarily, the splicing error was in response to dietary constraints; one that may yet be modified by overriding those conditions. Indeed, some research suggests this is the case. Specifically, the soy isoflavones genistein and daidzein (phytoestrogens), in addition to tocotrienol (vitamin E), the flavinoid epigallocatechin gallate (EGCG; an antioxidant found in green tea), and the plant cytokinin kinetin (a component of coconut milk), all favorably modulate IKBKAP splicing in familial dysautonomia-derived cells. That is, these compounds, alone or together, increase the proportional number of wild-type to mutated proteins. The combination of EGCG plus genistein restored the ratio of wild-type to mutated proteins equivalent to those in normal cells.
While not directly related to thiamine, the notion that compounds found in consumed foods regulate the transcriptional activity of proteins involved in nutrient sensing with direct and indirect ties to mitochondrial function suggests the inherent modifiability of processes that we heretofore considered hardwired. It is not such a big jump to think that there may be other nutrient compounds capable of supporting healthy development and/or functionally overriding genetic errors.”
Wow. Both the original splicing error and it’s continued persistence may be due to dietary constraints, via cell-based environmental sensors. The implications of this research are staggering. If this proves to be true, it means that some, maybe many or all genes have stressor-sensing capabilities. That is an enormously important discovery, one that shifts the entire paradigm of genetics. Even more interesting, the possibility that genetic errors may be overridden with nutrients. The therapeutic possibilities are endless.
The flip side, of course, is that the lack of nutrients in the typical western diet and the regular exposure to environmental toxicants may have genetic ramifications well beyond our lifetimes. Our behaviors now will affect the health of our grandchildren and their grandchildren. The medications we take, the foods we eat, the chemical exposures are all subtly and not so subtly changing our DNA; changes that may not manifest in any significant way for us, but will become obvious in subsequent generations. That is an awesome responsibility. One that none of us seems too keen to admit. Perhaps that is why the immutability of genetics continues to hold sway.
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