A1298C mutation, inhibited recycling of BH4, and increased ammonia build-up
 

I recently started exploring the genetics angle more thoroughly using my mom's 23andme raw data. It turns out she has the A1298C mutation, which can interfere with the recycling of tetrahydrobiopterin (BH4), which is an essential cofactor in converting l-tyrosine to l-dopa. BH4 also detoxes ammonia from the body, which also ties into johnt's recent posting about high levels of ammonia in PWP. Having this particular mutation likely means that you have a reduced level of BH4, but not low enough to trigger classic PKU (Phenylketonuria).

For those with their genetic data available, you can check the rs1801131 SNP (single nucleotide polymorphism). If you have CC genotype, then you have this mutation in the MTHFR (methylenetetrahydrofolate reductase) gene.
[http://www.snpedia.com/index.php/Rs1801131]

There are other SNPs that are relevant to the MTHFR gene, which relates to the metabolism of folate, and is critical to dopamine generation (and of course other important biosyntheses).
[http://www.snpedia.com/index.php/MTHFR]

A couple of good links for this dicussion:

http://www.detoxpuzzle.com/bh4.php

http://www.cnsspectrums.com/userdocs...7Stahl2big.jpg

I wanted to share this with the group to:
1. See if others can check their 23andme or other genetic data and see if there is a common pattern amongst PWP.

2. Start a discussion with all the well-informed members of the group about ways to address this inefficiency in the folate metabolic cycle.

My rs1801131 snp shows a genotype of TT.

John

I am heterozygenous with a GT allele

Here is an article of interest:

Inherited Disorders Affecting Dopamine and Serotonin: Critical Neurotransmitters Derived from Aromatic Amino Acids

Laura

MTHFR and autism
 

New Evidence Favors the Folate Hypothesis for Autism
Brian Hoyle


May 31, 2011 (Denver, Colorado) — A new study has documented the presence of a polymorphism in the gene encoding methylenetetrahydrofolate reductase (MTHFR) — essential for the metabolism of vitamin B9 (folate) — which almost doubles the chance of autism spectrum disorder (ASD). The data provide further genetic evidence for a link between folate and autism.

... Dietary supplementation with folate has been anecdotally liked to the improvement of symptoms of ASD, "despite a lack of medical evidence and endorsement," Dr. Schulteis told Medscape Medical News.

... Genetic evidence for a folate connection with autism was first reported in a study of 168 autistic children that chronicled the doubled prevalence of MTHFR polymorphisms in those with autism, compared with those in the control group (J Am Phys Surg. 2004;9[4]:106-108).

Dr. Schulteis and his colleagues established the MTHFR registry in 2002, and used the accumulated data to examine the reported genetic link in detail. The database contains information on patients who have been screened for the 677A→T and 1298A→C MTHFR polymorphisms in connection with other clinical concerns.

[My understanding from SNPedia ::rs1801131 is a SNP in the MTHFR gene, representing an A>C mutation at mRNA position 1298, thus this SNP is also known as A1298C. the risk allele is G or C.
rs1801133 is also a SNP in the MTHFR gene. Homozygous rs1801133(T;T) individuals have ~30% of the expected MTHFR enzyme activity, and rs1801133(C;T) heterozygotes have ~65% activity, compared to the most common genotype, rs1801133(C;C). : non risk : GG or CC (A or T is the risk allele )].
http://www.snpedia.com/index.php/Rs1801133]

Scrutiny of the records of 487 patients younger than 26 years of age revealed that 246 (51%) had 1 of the 2 mutations. The 677A→T mutation was predominate, affecting 67% of the patients. Fourteen of these individuals had ASD, which is appreciably greater than the accepted Centers for Disease Control and Prevention predicted prevalence of 4.43 (or 1 in 110) in young people. The prevalence rate of ADS in the control subjects conformed to the 1 in 110 rate.


"Our results add credence to the folate hypothesis, at least in this select number of ASD cases. These data should not be taken as a recommendation for change regarding folate supplementation...
"Other genes that impair folate transport and metabolism may also contribute to the risk of abnormal neurodevelopment, but MTHFR C677T is also a known risk for placental abruption (miscarriage) under 'normal' folate nutritional status, which is minimized under conditions that enhance maternal folate status during pregnancy."

"Therefore, it is highly likely that the folic acid food fortification/supplementation era has increased the birthrate of individuals with this polymorphism. They require more folic acid for neurodevelopment after birth, and are more susceptible to functional folate deficiency and neurodevelopment disorders, such as autism...

"http://www.medscape.com/viewarticle/743620

Looks like the A1298C MTHFR mutation is now being linked to Parkinson's Disease. I am compound heterozygous being a carrier of both the A1298C and the C677T mutation.

And it is looking like the synthetic Folic Acid that everyone's cardiologist or ob/gyn urges them to take is downright harmful for the many who have these mutations. And folic acid is in every multi-vitamin.

http://mthfr.net/mthfr-a1298c-mutati...ns/2011/11/30/

Actifolate
 

The only product I have found which supplies or replaces the missing enzyme is Actifolate made by metagenics. It supplies both l-mthfr and 5-forml THF which is related to what this gene codes. This preparation reportedly crosses BBB. The MTRR gene codes an enzyme that helps recycle a primary enzyme responsible for converting homocysteine to methionine