MTHFR: mutation not insult Angela DeLaria, MS, CRNA

Disclosure statement Conflict of Interest Disclosure Statement MoANA Fall Meeting 2018 I have no financial relationships with any commercial interest related to the content of this activity.

objectives Describe MTHFR deficiency and what causes it Identify the pathways which are affected by MTHFR Deficiency Explain Anesthetic complications related to MTHFR Deficiency

MTHFR Methylene tetrahydrofolate Reductase Rate limiting enzyme in the methyl cycle Catalyzes conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate Required for homocysteine remethylation to methionine MTHFR first came to my attention in 2014 when I was diagnosed with as homozygous for the MTHFR mutation. Since then I’ve had a particular interest in following the literature as it comes out. It is a bit of a taboo topic as many medical physicians will say it is not a problem and you don’t need to modify your lifestyle and others who have some holisitic training or naturopathic backgrounds think this is a public health crisis. Michael actually brought this up in his pharmacogenomics lecture yesterday so I hope I can add some more here that you’ll find interesting and useful. MTHFR is the abbreviation for methylenetetrahydrofolate reductase

Methylene tetrahydrofolate Reductase… It is the - Rate limiting enzyme in the methyl cycle, Catalyzes conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, and is Required for homocysteine remethylation to methionine - I want you to specifically remember this last note about methionine and we’re to come back to it. The cycle starts with Tetrahydrofolate, which we ingest in our diet. It is also known as folate or folic acid.

How does one become deficient? MTHFR is a gene that codes for the enzyme Variants C677T and A1298C Heterozygous vs homozygous This is a genetic mutation that one acquires at conception. Patient’s can be hetero or homozygous. The NIH states that there are at least 40 identified mutations. The two major variants that are tested for and followed are the C677T and A1298C. They are located on the short arm of chromosome 1 at position 36.22 It is believed that homozygous individuals are at much higher risk for related health conditions and that the C677T variant leaves one more deficient that the A1298C variant.

The importance of methionine An essential amino acid Precursor to cysteine and taurine Cysteine sulfahyrdrl group – protein structure Taurine – conjugation of bile acids, antioxidation, osmoregulation, membrane stabilization, modulation of calcium signaling Acts as an antioxidant A building block for many proteins and hormones Carnitine Adrenaline Choline Melatonin Serotonin So what is the big deal about methylating homocysteine to methionine? Methionine is an essential amino acid – that means our bodies have to make it, we cannot ingest it from another source. And we know that methionine is a critical part of other amino acid, protein, and hormone synthesis. Specifically methionine is required for cysteine and taurine synthesis, as well as catecholamines, and Serotonin. Without a functioning MTHFR enzyme, that leads to elevated homocysteine and no methionine.

complications Neural Tube Defects Homocystinuria Anencephaly and Spina bifida Homocystinuria Heart disease, hypertension, preeclampsia, glaucoma, psychiatric disorders, cancer, vascular disease, abnormal clotting, skeletal abnormalities, and cognitive problems Alzheimer's and Autism If we go back to the slide at the beginning with the methyl cycle, it all starts with tetrahydrofolate which we ingest in our diet. Aka folic acid. The lack of the mthfr enzyme leads to the inability to methylate folic acid or folate. This is obviously a serious issue for pregnant women and can lead to neural tube defects. So if there is parturient seeking tertiary level care, a perinatologist for spina bifida and they keep pushing her to take more folic acid, it would make so much more sense to do a simple blood draw and test her for mthfr and get her proper supplementation. According to the NIH, homocystinuria or elevated homocysteine, develop eye problems, abnormal blood clotting, skeletal abnormalities, and cognitive problems. The body is capable of excreteting homocysteine in the urine but not all of it. There are a number of sources that also link MTHFR to age realated hearing loss, alopercia, heart disease, stoke, hypertension, preeclampsia, glaucoma, psychiatric disorders, and some cancers. There is even a growing base on the interent that MTFHR is linked to autism and alzheimers. Unfortunately a lot of the research is inconclusive so there have not been any definitive statements regarding these two conditions.

treatment Down the rabbit hole… http://mthfr.net/mthfr-c677t-mutation-basic-protocol/2012/02/24/

Or perhaps supplement... OTC Prescription L-methylfolate

Anesthetic implications NITROUS oxide inhibits vitamin B12 by irreversibly oxidizing the cobalt atom of B12  Methionine synthase is located at the juncture of two pathways - homocysteine remethylation and the folate cycle. It requires B12 as a cofactor. Inhibition of methionine synthase via oxidation results in a sustained increase of plasma homocysteine concentrations and lack of biologically active folate. What are the considerations for these patients? NITROUS oxide inhibits vitamin B12 by irreversibly oxidizing the cobalt atom of B12. This leads to a subsequent inhibition of enzymes requiring cobalamin in its coenzyme form. Methionine synthase is located at the juncture of two pathways - homocysteine remethylation and the folate cycle. It requires B12 as a cofactor to become activated. Inhibition of methionine synthase via oxidation results in a sustained increase of plasma homocysteine concentrations and lack of biologically active folate that can be used for the conversion of homocysteine to methionine.

The journal of the American society of anesthesiologists Nagele et al (2008) hypothesized exposure to Nitrous Oxide is MTHFR deficiency patients would lead to increased and sustained levels of homocysteine. Prospective cohort study in which all patients received 66% nitrous oxide. Patients were unaware of their MTHFR genotype before the study and genotyping was performed after completion of the study. Patients with homozygosity for MTHFR 677T or MTHFR 1298C developed significantly higher plasma total homocysteine concentrations after nitrous oxide anesthesia than wild-type patients. Nagele et al hypothesized exposure to Nitrous Oxide is MTHFR deficiency patients would lead to increased and sustained levels of homocysteine. Prospective cohort study in which all patients received 66% nitrous oxide. Patients were unaware of their MTHFR genotype before the study. Plasma total homocysteine concentrations were measured as the main outcome variable before and after nitrous oxide anesthesia. Genotyping was performed after completion of the study, patients and research staff were blinded to the MTHFR genotype. Patients with homozygosity for MTHFR 677T or MTHFR 1298C developed significantly higher plasma total homocysteine concentrations after nitrous oxide anesthesia than wild-type patients.

A long story with a short and sweet ending… Avoid nitrous oxide! Be mindful of anticoagulants and the possible need for bridge therapy The moral of this genetics story is to avoid nitrous! And to be aware of anticoagulants as these patients may be undergoing anticoagulation therapy for vascular disease.

references NIH Genetic and Rare Disease Information Center. (2018). MTHFR gene variant. GARD. Retrieved from https://rarediseases.info.nih.gov/diseases/10953/mthfr- gene-mutation NIH. (2018). MTHFT gene. Genetics Home Reference. Retrieved from https://ghr.nlm.nih.gov/gene/MTHFR#location Peter Nagele, M.D., Barbara Zeugswetter, B.S., Caspar Wiener, B.S., Hansjörg Burger, M.D., Michael Hüpfl, M.D. (2008). Influence of Methylenetetrahydrofolate Reductase Gene Polymorphisms on Homocysteine Concentrations after Nitrous Oxide Anesthesia. Anesthesiology. 109, 36-43.