Genetic Testing

Assessing Risk for Autism: A Brand New Study and Test from GPL


Welcome back to the GPL blog.  I have an exciting announcement: We (GPL) recently conducted a study, and the results demonstrate that the gene ARHGEF6 may play a role in the development of autism.  In the individuals we genotyped, we found that males that had a mutation in this gene are predisposed to develop autism.  Because of this important finding, GPL is now testing for mutations to the ARHGEF6 gene.  Information about this test, the Autism Risk Assessment, including the downloadable brochure can be found here

If you’re a physician with a specialty in pediatric special needs (MD, DO, ND, PA, or NP only) and you’re interested in joining our referral list for ordering and interpreting this new test, please contact your assigned GPL sales representative, send an e-mail to, or call the lab at (913) 341-8949.


The Study:

This study was published in the journal, Hereditary Genetics and can be found online here

The Great Plains Laboratory organized the study utilizing volunteers as well as patient samples from the Autism Genetic Resource Exchange (AGRE), which is a program funded by Autism Speaks. In the study, the researchers genotyped 252 single nucleotide polymorphisms (SNPs) in 35 different genes that had previously been identified as autism risk candidate genes. This study was performed with 247 controls (106 male and 141 female) and 155 patients on the autistic spectrum (134 male and 21 female). They found the most significant marker for autism of the 252 SNPs tested was a genetic variation called rs2295868 in the ARHGEF6 gene on the X chromosome. The odds ratio for males with this SNP was 4.09 with a p value <0.0003, which means nearly 80% would likely develop autism at some point in their lives.  This is higher than any other single SNP previously evaluated for autism risk.  The odds ratio for females (1.02) for the same SNP was not statistically significant and did not indicate that this SNP increased the risk of autism for females.


Since the ARHGEF6 gene is on the X chromosome, this research helps to explain the excess ratio of autism in males, such that males are 4.5 times more affected with autism than females. Males receive an X chromosome only from their mothers while females receive an X chromosome from both their fathers and mothers. Thus, mothers will transmit the affected gene to their sons while both mother and father may transmit the affected gene to their daughters. However, 20% of males with the affected gene do not appear to develop autism, although they may be at risk for schizophrenia and inflammatory bowel disorders. The ARHGEF6 gene SNP was found in 30% of the males with autism spectrum disorders meaning that 70% of cases of autism spectrum disorder in males are due to other causes. A negative result for the ARHGEF6 gene SNP does not rule out a child developing autism from other genes or other non-genetic causes.


Below are some commonly asked questions about the ARHGEF6 gene, along with answers.  If you’re not able to find the answer to your specific question(s) here, please send an e-mail to and either I or one of our other experts will respond to you as soon as possible.


This test is offered exclusively from The Great Plains Laboratory, Inc.  Tests can be ordered through physicians (MD, DO, ND, PA, or NP only) or certified genetic counselors. 

GPL will be building a referral database of physicians who can order and interpret this test.  In the meantime, to find a pediatric special needs physician in your area, visit the Medical Academy of Pediatric Special Needs (MAPS) web site, to find member physicians by state.  Please note these physicians are not guaranteed to be able to order this test.  Physicians will also have their own fees for ordering and interpreting tests.  Please contact them to inquire about fees.

This test is not available in the state of New York. 


Please contact your assigned GPL sales representative, send an e-mail to, or call the lab at (913) 341-8949.


You may seek a genetic counselor through the National Society of Genetic Counselors at or through the American Board of Genetic Counseling at



ARHGEF6 is a gene located on the X chromosome position 26.3 that codes for an enzyme called Guanine Nucleotide Exchange Factor 6. Diseases or non-disease related traits that are transferred through the X-chromosome are termed “sex-linked”. This enzyme is present in the brain, immune system, and the intestine. In the brain, its highest concentration is in the hippocampus CA1 region, which is important for new memory formation. ARHGEF6 is also responsible for normal neuron growth patterns. ARHGEF6 helps to control neurological spine and neurite growth morphologies. Because of its role in neuronal growth, loss of ARHGEF6 activity results in a decrease in the density of cortical pyramidal neurons. These mismanaged growth morphologies can lead to deficits in autophagy (the breakdown and recycling of cellular components) in microglia and impaired synaptic pruning, which have been linked to behaviors similar to those of ASD.

The ARHGEF6 enzyme also plays a role in immunity. It is present in large amounts in the immune system, especially in T-cells. In the intestine it may play a different role. Studies have shown that ARHGEF6 interacts with strains of bacteria that play a role in inflammatory bowel disease.

ARHGEF6’s role in immunity may help explain the link between environmental exposures and the increasing rates of an autism spectrum disorder spectrum disorder. As we are exposed to more toxic chemicals more every day, males with this mutation may be more susceptible to inflammation caused by toxin exposure. Since 20% of males who tested positive for the gene do not have an autism spectrum disorder spectrum disorder spectrum disorder, knowledge about these “resistant” males undoubtedly will help to find out how to protect the 80% of males that are susceptible to the gene.


Males receive an X chromosome from their mothers who have 2 X chromosomes while females receive an X chromosome from both their fathers and their mothers. Thus, mothers will transmit the affected gene to their sons while both fathers and mothers transmit the affected gene to their daughters. 


This mutation is present in about 15% of the population and is present more than twice as often in females than in males because females have two X chromosomes compared to one in males. Our studies so far find no link to the ARHGEF6 mutation and an autism spectrum disorder in females. However our number of female patients was limited. Therefore, no conclusions from this study can be made about how this gene affects human health in females. As we accumulate more data on females we will include it on our website.


Studies have linked many different health issues with ARHGEF6 mutations. In the intestine, mutations in ARHGEF6 have been associated with several types of diseases. ARHGEF6 has been associated with inflammatory bowel disease, ulcerative colitis, and Crohn’s disease. Mutations in ARHGEF6 can cause major structural changes to the brain and have been linked to an autism spectrum disorder spectrum disorder, mental deficiencies, and schizophrenia.



  • Women who are thinking about getting pregnant or who are pregnant

  • Males or females with a history of an autism spectrum disorder in their family

  • Anyone concerned about having a child with an autism spectrum disorder 


If you or child is positive for the ARHGEF6 gene SNP, it is not a definitive diagnosis of an autism spectrum disorder. It simply means there is a greater risk of developing an autism spectrum disorder. There are many things that can be done to potentially counteract various symptoms and common health problems associated with an autism spectrum disorder. The Great Plains Laboratory, Inc. has specialized in these kinds of specialty diagnostics for more than 20 years, and we recommend treatment strategies that are evidence-based and have a high level of efficacy for many patients. We recommend you partner with a healthcare practitioner who thoroughly understands this biomedical approach to an autism spectrum disorder.  You may contact our laboratory to request a list of these kinds of practitioners in your area.

Genetic susceptibility to an autism spectrum disorder may determine who develops this complex disorder, but factors like nutrient deficiencies, food allergies, toxin exposure, and pathogenic intestinal microbial overgrowth strongly influence the severity of symptoms. Yeast (most commonly, Candida) bacteria (particularly Clostridia), and toxins (both metal and non-metal) all have the potential to act as pathogens. Comprehensive laboratory testing can identify the physiological imbalances that contribute to an autism spectrum disorder and point to an individualized treatment approach. Many of the tests are urine tests and can be run on the same urine sample. Treatments are designed to restore the body to balance and optimize function through nutritional support, diet, detoxification, and reduction of toxic environmental influences. For information and resources, go to



An excellent description of the laws in the USA regarding genetic discrimination is found on the website of the National Society of Genetic Counselors:

At the present time, we do not know what safeguards against discrimination based on genetic testing are available in other countries.


Forms that must be completed and submitted are:

  • Test Requisition Form (TRF)

  • Patient/Guardian Informed Consent


  • The sample is collected with a buccal swab which is very similar to a Q-tip®.

  • Rinse your mouth with cold water before you begin collecting your sample and then swallow to remove excess saliva.

  • Collect sample by rubbing the insides of the cheeks of the mouth on all three swabs.

  • Place the swab sleeves containing the dry swabs in the paper envelope included in the kit.

  • Label the envelope with your name and date of sample collection.

  • Ship the test kit back to the laboratory using the shipping mailer provided.

  • More detailed instructions can be found on our website and in the test kits.



Results will be available in about 4 weeks.


Results are kept confidential according to HIPAA requirements and will only be shared with the patient/guardian and designated healthcare practitioner or genetic counselor who authorized the test.  Results are sent via secure portal or secure e-mail. 


Results will only be shared with you as the patient/guardian and healthcare practitioner or genetic counselor who authorized the test. After 60 days, samples will be de-identified in our system and may be used for future research.


In the study by The Great Plains Laboratory, Inc., 80% of males with the ARHGEF6 gene mutation had an autism spectrum disorder while 20% of males with the ARHGEF6 gene mutation did not develop an autism spectrum disorder. Thus, a baby boy with this gene mutation will have four times the risk of developing an autism spectrum disorder compared to a baby boy who is negative for this gene mutation. Since the development of an autism spectrum disorder decreases markedly with age, boys who are positive for this gene mutation would be expected to have decreased risk of an autism spectrum disorder as they age; new development of an autism spectrum disorder is rare after 5 years of age. However, non-autistic men with the ARHGEF6 gene mutation may have a higher rate of depression, colitis, or other bowel disorder.

Males with this gene who produce children do not transfer this gene to their sons but will transfer the gene to all of their daughters. However, our data so far are insufficient to know whether the presence of one or two of the ARHGEF6 gene mutations in female children increases their risk of developing an autism spectrum disorder.



Males who are negative for this gene SNP will not develop an autism spectrum disorder or other illnesses associated with this gene SNP. However, they could develop an autism spectrum disorder or other illnesses due to other untested genetic factors or environmental factors. About 66% of patients with an autism spectrum disorder did not possess the mutant ARHGEF6 gene.


Currently, we have insufficient data to know if females with one or two of the ARHGEF6 gene mutations have an increased risk of developing an autism spectrum disorder or any other illness associated with the ARHGEF6 gene mutations.

Females who have two of the ARHGEF6 gene mutations who bear children have an increased risk of having a boy with an autism spectrum disorder. If a woman with two of the gene mutations (homozygous) is pregnant with a boy child, there is a 100% risk that the boy child will receive the ARHGEF6 gene mutation and an 80% risk that the child will develop an autism spectrum disorder.

Females who have one of the ARHGEF6 gene mutations who bear children have an increased risk of having a boy with an autism spectrum disorder. If pregnant with a boy child, women with one of the ARHGEF6 gene mutations (heterozygous) will have a 50% risk that the boy child will receive the ARHGEF6 gene mutation and a 40% risk that the child will develop an autism spectrum disorder. 

At this time, our data are insufficient to know if women with one or two of the ARHGEF6 gene mutation genes are also at increased risk of having girls with an autism spectrum disorder or other illnesses such as inflammatory bowel disease and depression.


Due to the highly technical and sensitive nature of this test, we ask that you connect with one of our genetic testing experts for any additional questions or concerns.  Please send an e-mail to and one of our experts will respond as soon as possible. 

For a list of references, please visit the Autism Risk Assessment page of our web site here.

If you have any questions about the study or the new Autism Risk Assessment, please contact me at

New Marker Additions to GPL-SNP1000 DNA Sequencing Profile


The number one goal for The Great Plains Laboratory is to provide the best quality results to our clients.  Our GPL-SNP1000 DNA Sequencing Profile has proven to be a great tool in helping provide personalized healthcare to our clients.  The nine pathways we analyze include: methylation, mental health, oxalate metabolism, drug and environmental metabolism/detoxification, gluten sensitivity, cholesterol metabolism, autism risk genes, and transporter gene.  These are crucial biological pathways, which are at the root of many chronic health conditions.  We are now announcing the addition of nine new markers to our already incredibly comprehensive genetic test:

Dopamine Beta Hydroxylase (DBH)
This is an enzyme that catalyzes the oxidation hydroxylation of dopamine to norepinephrine.  DBH can be inhibited by phenolic compounds including those produced by Clostridium species as well as certain organophosphate herbicides and pesticides.  There are two SNPs that can cause decreased activity of DBH.  These are rs2007153 and rs2283123.  These polymorphisms can lead to an increase in dopamine levels and a deficiency in norepinephrine.  Mental health disorders can result because of the imbalance of dopamine and norepinephrine.  Common symptoms can include depression and anxiety.

Paroxonase 1 (PON1)
This is an important enzyme in the metabolism and elimination of many organophosphorus insecticides (PMID: 13032041) and is located mainly in the liver.  PON1 is important in the reduction of atherosclerosis because of its involvement in the protection of high and low density lipoproteins from oxidation.  Individuals with polymorphisms to PON1 are more susceptible to heart disease (PMID: 8675673).  There are two known polymorphisms that can decrease the activity of PON1 and make the individual more susceptible to pesticide exposure, which are Q192R (rs662) and L55M (rs854560).

Hemochromatosis Protein (HFE)
The hemochromatosis gene HFE (high iron) codes for the HFE protein.   This protein is important for regulating the uptake of circulating iron.  This is done by regulating the interaction between transferrin receptor with transferrin.  SNPs to this gene can cause hemochromatosis, a disorder in which the body loads excess iron, which is autosomal recessive.  This means the patient normally needs two bad copies of the gene in order to exhibit symptoms.  There are three SNPs that can lead to hemochromatosis, rs1800562, rs1800730, and rs1799945.  Patients that are homozygous positive for this SNP should have their iron level measured. 

Vitamin K Epoxide Reductase Complex Subunit 1(VKORC1)
This is an enzyme that is necessary for the reduction of vitamin K 2,3-epoxide to its active form, which is important for clotting.  This enzyme is the primary target for the drug warfarin (Coumadin).  The three SNPs that are associated with warfarin sensitivity are rs9923231 (VKORC1*2), rs9934438, and rs8050894.  These polymorphisms can be used in conjuncture with the genotype of Cyp2C9 in order to accurately dose warfarin.

Tryptophan Hydroxylase 2 (TPH2)
This enzyme catalyzes the first and rate-limiting step in the biosynthesis of serotonin. Mutations to this enzyme have been associated with numerous psychiatric diseases including depression, OCD, bipolar disorder, and suicidal behavior.

Major Histocompatibility Complex DQA1 and DQA8
Patients with SNPs to HLA DQA1 and DQA8 have a higher risk of celiac disease.   The HLA-DQA1 and DQA8 are human leukocyte antigen serotype (also called major histocompatibility complex II). The role of this peptide is to present proteins on the surface of cells for identification purposes. This particular serotype presents proteins belonging to a foreign invader on the cells the macrophages, B cells, and dendritic cells in order to activate the helper T cells of the immune system. Proper presentation is critical for immune system activation against pathogens and may possibly be a mediator of autoimmunity.

UDP Glucosyltransferase 1A1 and 1A8 (UGT1A1 and UGT1A8)
These enzymes are important members of the glucuronidation phase II detoxification pathway.  These enzymes catalyze the addition of a glycosyl group from a nucleotide sugar to a small hydrophobic molecule.  The addition of glycosyl groups results in these molecules becoming more water-soluble and easier to excrete. Some of the target molecules for these enzymes include bilirubin, drugs, hormones, and steroids.

Your Body’s Detoxification Pathways

Welcome back to the GPL-BLOG.  Over the past several weeks we’ve been discussing a lot of the environmental toxins that everyone is exposed to on a daily basis.  These toxins must be processed and detoxified.  Most of this is done in the liver through several different processes that include Cytochrome P450 (P450) biotransformation, glutathione conjugation, enzyme hydrolyzing, sulfation, and glucuronidation.

Detoxification is often referred to as a two stage process (phase 1 and phase 2) of metabolism (Figure 1).  Phase 1 metabolism involves the reduction or hydrolysis of the compound (usually caused by the addition of an oxygen molecule).  The addition of oxygen to a compound is referred to as oxidation.  This process is usually performed by the P450 enzymes.

Figure 1

The P450s are a family of enzymes that are found in numerous tissues throughout the body. However, a majority of these are found in the liver.  The P450s are important for the detoxification of many foreign substances, including environmental toxicants and medications.  The P450s are also important in controlling the levels of different molecules produced in the body such as the synthesis and breakdown of hormones, steroids, and multiple other molecules. 

In humans, 58 different P450s have been discovered.  However, only a subset of these is involved in the degradation of xenobiotics (chemicals that come from outside the body).  These enzymes have different substrates, which are determined by the activity pocket of each enzyme.   In regards to detoxification the most important P450s are Cyp1A2, Cyp2A6, Cyp2C9, Cyp2C19, Cyp2D6, Cyp2E1, and Cyp3A4.  Besides detoxification, these enzymes metabolize a majority of medications (figure 2).

Here are some important detoxification enzymes:

Figure 2

Cyp1A2 is important for the metabolism of polycyclic aromatic hydrocarbons (PAHs), which are found in cigarette smoke.  Other substrates include medications, aflatoxin B1, caffeine, and acetaminophen.  The major polymorphism is Cyp1A2*1K, which results in a decrease of activity.

Cyp2A6 is involved in the metabolism of nicotine.  Cyp2A6 is also involved in the metabolism of medications.  The major polymorphic alleles are Cyp2A6*4 and Cyp2A6*9 (which can have between 35% -70% activity depending on if you have one or two polymorphic copies). 

Cyp2C9 is involved with the metabolism of a large number of medications including NSAIDs, warfarin, and tamoxifen.  There are multiple polymorphisms that affect activity of the enzyme. 

Cyp2C19 is involved with the metabolism of multiple medications.  The most common are diazepam, omeprazole, and sertraline.  Cyp2c19 also metabolizes progesterone.   There are two major variants that result in loss of activity.  These are Cyp2C19*2 and Cyp2C19*3.

Cyp2D6 is involved with the metabolism of about 20% of drugs on the market.  It also metabolizes serotonin and neurosteroids.  There are five different polymorphisms that can lead to decreased activity.  Some of the classes of drugs that are metabolized by Cyp2D6 are antidepressants, SSRIs, opioids, and antipsychotics. 

Cyp2E1 is involved with the detoxification of many industrial pollutants, as well as carcinogens.  Cyp2e1 also metabolizes ethanol to acetaldehyde and acetate.  Cyp2e1 is also responsible for bioactivating a number of carcinogens, including cigarette smoke. 

Cyp3A4 is responsible for metabolizing more compounds than most other P450s.  It is responsible for metabolizing sex hormones, caffeine, statins, SSRIs, antifungals, antidepressants, and many other medications.  Some antibiotics can negatively affect its activity. Also, grapefruit and pomegranate juice have been shown to be potent inhibitors. 

Sulfur transferase is a phase 2 enzyme that adds sulfur groups to compounds in order to make them more water soluble and less reactive.  This process is used on a wide variety of toxic molecules including phenols, amines, acetaminophen, and food dyes.  Many chemicals that are able to become airborne are sulfated.  Patients with autism have been found to have impaired sulfation ability, which will make these individuals more sensitive to toxins.

Glutathione transferase is a phase 2 enzyme that catalyzes the conjugation of glutathione to substrates.  The addition of glutathione to toxins prevents these compounds from interacting with proteins in the body and allows them to be excreted via urine or bile.  There are a wide variety of compounds that are conjugated with glutathione.  A partial list includes pesticides, herbicides, carcinogens, acetaminophen, and mycotoxins.   

Glucuronosyltransferase (UGT) is another phase 2 enzyme that is responsible for the glucuronidation of many different toxic chemicals.  This process involves the addition of a glucuronosyl group to substrate molecules making them more polar and more easily excreted by the kidneys. 

Paraoxonase 1 (PON1) is an enzyme that is able to perform paraoxonase activity on substrates.  This enzyme is able to hydroylse and detoxify many different types of organophophate molecules.  PON1 is one of the major pathways that protects people from these types of compounds.  Mutations to PON1 could lead someone to be more sensitive to pesticides.  Infants do not have a lot of PON1 activity.  PON1 becomes active between birth and seven years of age. 

These are the major pathways that you should be aware of when you are thinking about detoxification.  Please see Table 1 to help you understand which pathway is mostly responsible for detoxifying these common toxicants.  Also see Figure 1 to help you understand what you can do to help support type 1 and type 2 detoxification pathways.  Detoxification of compounds by glutathione can be assisted by the supplementation of additional glutathione.  Next week I will discuss some additional methods to help with detoxification.  

Email if you have any questions about this blog post.

DNA Methylation Pathway

In my post last week I briefly talked about the methylation pathway, also called the MTHFR cycle and how disruptions in this pathway may appear on an Organic Acid Test (OAT).  Today, I will go more in-depth into this pathway. Since most practitioners have at least some knowledge of this its function, I’ve decided to focus on the more important polymorphisms (SNPs) common to these genes and on the treatments that work the best for these mutations.  Patients should talk to their healthcare practitioner before starting any treatment. 

The important role of methylation is gaining in popularity among functional medicine groups these days because mutations are quite common and lead to many different chronic conditions. Practitioners interested in treating the root cause of illness are especially interested in learning about this pathway because nucleotide synthesis, neurotransmitter function, detoxification, and numerous other processes are greatly improved once these mutations have been compensated for, leading to much better patient outcomes.

If you’re not already familiar, the methylation pathway is a process by which carbons are added onto folic acid from amino acids and redistributed onto other compounds throughout the body.  This process is responsible for the formation of methionine, S-Adenosyl methionine (SAM), and thymidylate monophosphate (dTMP).  Mutations in this pathway usually lead to the reduction of methionine which leads to the absence of S-adenosyl methionine (SAM). This compound facilitates virtually every methylation reaction in the body. These reactions include the promotion of several neurologically important agents, histamine breakdown, CoQ10 synthesis, and tissue-specific gene expression. The accumulation of homocysteine, which is caused by mutations in this pathway, has been directly linked to oxidative stress which influences multiple factors of disease.      

When we designed the GPL-SNP1000 test, we knew that most other genetic tests were only reporting about 35 SNPs of the common methylation pathway enzymes. When we did our literature research, we found 105 different methylation SNPs that could potentially cause health conditions and included all of these to provide a more useful tool for practitioners.


Methylenetetrahydrofolate reductase (MTHFR) is an enzyme that converts 5,10-methylenetetrahydrofolate to 5,methyltetrahydrofolate, which is the active form of folate.  Mutations in this gene cause the accumulation of homocysteine and a lack of available folate for cellular functions. Both of these factors have been linked to oxidative stress, vascular disease (including cardiovascular), neural tube defects, neurological disorders (including schizophrenia and bipolar disorder), cancer, preeclampsia, hypotonia, and seizures.  Common mutations are rs1801133 (C677T), rs1801131 (A1298C), and rs2274976 (G1793A).  The C677T polymorphism is present in about 39% of caucasians as heterozygotes and 17% as homozygotes.  Table 1 provides data on how much activity your MTHFR enzyme would possess with different combinations of the C677T and the A1298C.



Patients with polymorphisms in MTHFR may consider supplementing with methyl-B12 (also called methylcobalamin) and methyl-folate.  We recommended starting at a very low doses and building up.


Methionine synthase (MTR) is also known as 5-methyltetrahydrofolate-homocysteine methyltransferase.  This enzyme facilitates the transfer of a methyl group from 5-methyltetrahydrofolate to homocysteine using cobalamin (B12) and MTRR enzyme as a catalyst. The end products of this reaction are the amino acid methionine and the vitamin tetrahydrofolate.  Mutations in this gene lead to a lack of methionine and the accumulation of homocysteine in the body (hyperhomocysteinemia).  The pathological consequence of the gene mutation depends on how profoundly these methylation pathways are affected and the degree of homocysteine accumulation in the body.  The most common polymorphism is rs1805087 (A2756G), which most genetic tests do analyze.  However, we decided to look at seven different SNPs including the rs121913581 (R52Q) polymorphism.  This is a rare polymorphism; however it could dramatically affect the activity of patients with MTR polymorphisms, who should also consider methyl-B12, as well as S-adenosyl methionine (SAM) supplementation.  ).


Methionine synthase reductase (MTRR) is also known as 5-methyltetrahydrofolate-homocysteine methyltransferase reductase.   MTRR is important for the methylation of cobalamin and subsequent activation of methionine synthase (MTR).  Mutations in this gene lead to a lack of methionine and the accumulation of homocysteine in the body (hyperhomocysteinemia). Some common mutations in this pathway are RS1801394 and RS10380.  Patients who are heterozygous for MTHFR mutations and concomitant mutations to MTRR have a greater loss of function and increased levels of homocysteine. Patients with MTRR polymorphisms should consider methyl-B12 and SAMe supplementation. 


Adenosylhomocysteinase (AHCY) is also known as S-adenosylhomocysteine hydrolase.  AHCY is an enzyme involved in the degradation of the amino acid methionine.  AHCY converts the methionine substrate S-adenosylhomocysteine (SAH) to adenosine and homocysteine. This reaction is an important part of the regulation of methyl groups which are added to DNA, RNA, proteins, and lipids (fats).  Methyl groups help regulate what parts of the genome are active and control protein activity.  Mutations to the AHCY gene can cause methionine to accumulate in the blood, which is called hypermethioninemia (MET).  Two common mutations are Trp112X which causes tryptophan to be replaced with a premature stop signal and Tyr143Cys.  MET  can manifest in neurological problems, delays in motor skills, muscle weakness, and liver problems.  Patients with MET should consult with a dietician to avoid the amino acid methionine.


Betaine-homocysteine methyltransferase (BHMT) and BHMT2 are the only enzymes that can metabolize betaine.  This reaction is considered the alternate or short route for methylation.  BHMT uses zinc as a co-factor to catalyze the transfer of a methyl group from betaine to homocysteine.  There are several mutations in the human population that decrease the activity of this enzyme.  BHMT mutations can result in fatty liver and hepatocellular (liver) carcinomas.  BHMT mutations in mothers increase the risk of Down syndrome for their children.  Patients with BHMT polymorphisms are recommended to take betaine and zinc.


Cystathione beta-synthase (CBS) is a pyridoxal-5’-phosphate (vitamin B6) dependent enzyme that converts L-serine and L-homocysteine into L-cystathionine.   L-cystathionine is later converted into the amino acid cysteine.  Mutations to the CBS gene are the most common cause of hereditary hyperhomocysteinemia.   The adverse effects of homocysteine accumulation in the body are related to the substitution of homocysteine for methionine in protein synthesis. The resulting complications include an increase in immune response, increase in cell death, and protein damage. The degree of homocysteinemia is relative to the mutation.  Hyperhomocysteinemia has been linked to multiple mutations to the CBS gene.  The most common of these are the Ile278Thr and the Gly307Ser, which cause homocysteine to build up in the blood.  Complications of hyperhomocysteinemia include mental retardation, seizures, and vascular disease. One of the most common causes of death for patients with homocystinuria (CBS deficiency) is heart attack.   Patients with CBS polymorphisms are recommended to take glutathione and B6.  There are reports that the CBS polymorphisms A360A (rs1801181) and N212N (rs2298758) can lead to an increase in CBS activity.  Some claim that these mutations lead to a buildup of ammonia and decrease in glutathione. Since ammonia is a very unstable compound that must be measured STAT for accurate results, the better marker for increased ammonia is orotic acid which is very stable and accumulates when excessive amines are filtered through the urea cycle. I recommend that patients with this mutation do an Organic Acid test (OAT) and look at marker 60 (orotic acid) for ammonia and markers 58-59 (Pyroglutamic and 2-hydroxybutyric acid) for glutathione synthesis and cysteine accumulation respectively.


Serine hydroxymethyltransferase (SHMT1) is important for linked reactions.  The first is the conversion of tetrahydrofolate to 5,10-methylenetetrahydrofolate.  The second is the conversion of L-serine to glycine.  It also has a role in mediating the synthesis of dTMP and SAM. It preferentially selects for dTMP biosynthesis which is the precursor to the nucleic acid thiamine. Mutations in this enzyme may cause elevations in uracil which can build up when dTMP synthesis in impaired.  Uracil is marker 40 in the OAT.  


Sulfite oxidase (SUOX) is an enzyme that is located in the mitochondria of cells.  The enzyme oxidizes sulfite to sulfate.  The physiological damage that occurs as a result of enzyme deficiency may be due to the accumulation of toxic levels of sulfite, from the absence of sulfate, or both. Sulfite is a reactive product of cysteine metabolism found in high concentrations in the brain. Its toxicity is exacerbated by glutathione depletion. Sulfate plays an important role in detoxification and deactivation of toxic compounds. Sulfate deficiency has been linked to autism, Parkinson’s disease, and Alzheimer’s disease.  Individuals with SUOX genetic mutations may benefit from a reduction in dietary methionine and cysteine.


Vitamin D receptor (VDR) is a nuclear hormone receptor for vitamin D3.  Vitamin D3 interacts with this receptor to influence multiple biological activities by regulating gene transcription.  Vitamin D3 is associated with maintenance of calcium distribution. More recently, it has been implicated in inflammatory processes, vascular integrity, and collagen formation. Mutations in VDR have been linked to metabolic syndrome.  Individuals with VDR mutations have greater propensity for insulin insensitivity, higher triglycerides, and lower HDL levels.  Vitamin D receptor mutations can also lead to vitamin-D-dependent rickets type 2.  Patients with VDR polymorphisms are recommended to take 1000 units/day for children or 5000 units/day for adults. 

I hope this information is helpful.  I know many of these pathways can be very intimidating, but hopefully we can work together to produce useful treatment plans for everyone.  Next week I plan on talking about the mental health genes MAO and COMT.

Email if you have any questions about this blog post.