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A Personal Story about Cancer, Autism, & DPD Deficiency

For the last few years, my mother has been battling colorectal cancer. In 2012, the primary tumor was removed, all lymph nodes appeared clear, and the pathologist, surgeon, and oncologist all agreed it looked like an early stage II tumor and therefore didn’t insist on chemo. Given the Clostridium difficile infection she picked up during her surgical stay that took over 6 months to overcome, that was probably a good call.

Fast forward to last summer, when we find that she has a tiny nodule growing on her upper left lung and the thoracic surgeon insists on taking it out. The nodule turns out to be a metastasis from the earlier colorectal cancer, which had otherwise been clean the previous 3 years. Apparently her stage II colorectal cancer, despite all other indications, was actually a stage IV. The oncologist strongly advises chemotherapy, a double-whammy of oxaliplatin (IV) and xeloda (pills) for 6 months.

Fast forward two weeks into treatment and my mother is currently in the hospital, hooked up to fluids, unable to eat because she’s so nauseous, and weaker than a newborn kitten. (In fact, I’m writing this blog in the hospital right now.) And now, being the constant scientist, I find myself reading up on something called “Dihydropyrimidine Dehydrogenase (DPD) Deficiency” to pass the time and satisfy my need for understanding. We’re still waiting for the fancy expensive lab tests to come back, telling us whether my mother suffers from DPD or some other mystery disorder that causes her to react so severely to xeloda. But in the meantime, I’m learning a good deal about DPD deficiency– a condition which, up until a week and a half ago, was just a number on a list in one of my research studies.

For the last year, I’ve been researching various genetic forms of intellectual disability (ID) and their comorbidities with autism and epilepsy. Ironically, I’ve been glancing over DPD deficiency in this ongoing study, without ever realizing its potential relevance to my family situation. While I’ve been studying DPD deficiency in its homozygous or compound heterozygous forms, which lead to complete deficiency and often congenital neurological symptoms such as ID, epilepsy, and even autism, complete deficiency only exists in about 0.2% of the population. Meanwhile, partial deficiency, usually due to single heterozygous mutations, is often asymptomatic until– you guessed it– a cancer patient with partial deficiency is prescribed a medication like xeloda. And then WHAMMO! All hell breaks loose.

About 4-10% of the population have a partial DPD deficiency. And because xeloda is a widely-used form of chemo for both breast and colorectal cancers, two of the most common cancer types in the United States, study of DPD deficiency has received a boom of attention recently, focusing on genetic identification of at-risk individuals and the development of protocols to prevent adverse reactions [1].

How does a DPD deficiency cause xeloda toxicity? Xeloda, otherwise known as capecitabine, is metabolized by the body into 5-fluorouracil (5-FU). 5-FU in turn is what is known as a “pyrimidine analog”, which means it tricks the body into thinking that it is a type of DNA nucleotide known as a pyrimidine, taking its place. In doing so, it prevents the body from producing the nucleotide, thymine, which ultimately triggers pathways that can promote cell death [2]. Cells that are metabolically active are more vulnerable to these effects, e.g., cancer cells, immune cells, and hair follicles.

DPD is an enzyme highly expressed in the liver that helps to metabolize 5-FU. Individuals with a completely deficiency are incapable of metabolizing this enzyme, a situation that can often be lethal. People with partial deficiency on the other hand are capable of metabolizing the drug but at a much slower rate. This effectively increases the half-life of the drug, causing what is essentially a drug overdose. There is growing evidence to suggest that chemo drug protocols need to be revised for DPD partially deficiency individuals who are prescribed some variant of 5-FU, starting at very low dosages and then slowly working upwards, all the while checking blood levels of the drug.

Unfortunately, this practice still requires further study, and improved methods of identification are needed as well (metabolic and genetic). For right now, clinics and hospitals generally only check for a DPD deficiency if an individual has had a severe adverse reaction, a practice that, while lethal for an unlucky few, certainly hinders further medication compliance for many more with partial deficiency. For now, my mother is battling with whether continuing treatment is worth the risk.

#Cdiff #genetics #epilepsy #clostridiumdifficile #chemotherapy #dihydropyrimidinedehydrogenase #pyrimidine #colorectaladenocarcinoma #cancer #breastcancer #autism #5fluorouracil #xeloda #DPDdeficiency #5FU #colorectalcancer #thymine #dihydropyrimidinedehydrogenasedeficiency #intellectualdisability #mentalretardation #capecitabine #Cdifficile


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