CBS Upregulation (C699T) Can Lead to Sulfur Sensitvity - Amy Yasko

[Guest guest]

Rich and those who are sulfur intolerant,

I have barely scratched the surface of Yasko's books and articles,

but I am intrigued by her discussion of CBS Upregulation. The CBS

gene produces the CBS enzyme that is used to convert homocysteine to

cysteine. When too much CBS enzyme is produced, too much cysteine is

produced. This *reduces* the production of glutathione and triggers

the production of a lot of sulfate and taurine, instead.

CBS Upregulation can lead to too much sulfur in the body BUT at the

same time cause *glutathione deficiency* and *drain methylation*

cycle products. This caught my attention because I am sulfur

intolerant.

Yasko says, " Sensitivity to sulfur products and sulfur containing

antibiotics is often symptomatic of this mutation. "

Also regarding glutathione supplementation, she says:

" While the temptation may be to add glutathione (due to low

glutathione levels), this can potentially create additional issues

due to sulfur excess in the body. The CBS upregulation is generating

so many sulfur products that adding glutathione, another sulfur

containing product, may be a problem for these individuals.

At the same time that CBS upregulation produces excess taurine,

sulfite, and sulfate, it also produces ammonia, H2S, and Alpha

Ketoglutaric Acid. These latter 3 substances cause brain fog and

other harmful effects.

Yasko says, " Individuals with CBS upregulations may not see high

ammonia levels until they are supplementing the pathway to address

other imbalances in this pathway. Other mutations in the methylation

cycle can prevent the methylation pathway from functioning properly.

Once the pathway is supplemented to function properly the

intermediates of the cycle can be drained through the CBS enzyme

activity into taurine, sulfur compounds and ammonia. Again, the

reason you may not recognize this initially, is that other blocks in

the pathway can mask the presence of this mutation until you

supplement to bypass other mutations. "

Here is more of Yasko's discussion:

Beginning on Page 48

" The net effect of excess CBS activity is to take sulfur groups and

nitrogen groups that are complexed in the methionine cycle and free

them up. Having relatively free sulfur and nitrogen moieties has

downstream consequences which can lead to elevations in adrenaline

and depletion of dopamine and norepinephrine. A constant state

of " flight or fight " as a result of chronic high levels of sulfur can

also cause sympathetic versus parasympathetic overload. This cortisol

response has a wide range of secondary effects in the body, including

changes in magnesium/calcium, decreased levels of serotonin and

dopamine, effects on the methylation cycle via phosphatidylserine

levels, changes in gaba and glutamate as well as potentially

depleting G6PDH and causing clood sugar issues. "

" Another possible consequence of the accelerated breakdown of

homocysteine by overactive CBS enzyme is that increased levels of

alpha ketoglutarate will be generated in the body. Under ideal

conditions, glutamine, glutamate, GABA and alpha keto glutarate will

be generated in the body. Under ideal conditions, glutamine,

glutamate, GABA and alpha keto glutarate can interconvert to form the

intermediates that the body requires at any given time. However,

aluminum and mercury inhibit some of the enzymes involved in these

conversions. Aluminum inhibits the activity of glutamate synthase.

GAD is the enzyme that converts glutamate to GABA, however its

activity can be compromised by a wide range of mutations as well as

the presence of auto antibodies against this enzyme. "

" Antibodies against GAD are seen in several viral and disease

states. This combination of mutations, infectious diseases and toxic

metals can create a possible scenario where excess alpha keto

glutarate is being generated by breakdown of homocysteine but it

cannot convert properly to form GABA. However this excess alpha KG

can combine with the excess ammonia to form more glutamate. I have

previously discussed at length the relationship between glutamate,

excitotoxins and nerve damage. "

" Individuals with CBS upregulations may not see high ammonia levels

until they are supplementing the pathway to address other imbalances

in this pathway. Other mutations in the methylation cycle can

prevent the methylation pathway from functioning properly. Once the

pathway is supplemented to function properly the intermediates of the

cycle can be drained through the CBS enzyme activity into taurine,

sulfur compounds and ammonia. Again, the reason you may not recognize

this initially, is that other blocks in the pathway can mask the

presence of this mutation until you supplement to bypass other

mutations. "

" Methylation is needed to silence virus, to myelinate nerves, to make

new T cells (so that we are not making auto antibodies, to respond

properly to infectious agents and to reduce allergic inflammation),

to make new DNA (that is, to repair the gut lining), for

neurotransmitters, for DNA regulation, detoxification of

environmental toxins and the list goes on. It is critical to support

any mutations in the methylation pathway so that it will function

properly. However, for those individuals with CBS up regulations

this is a " catch 22 " . As the pathway is supplemented you generated

breakdown products that are a problem. Once you have supplemented

with nutrients to bypass the CBS upregulation you are then in a

better position to supplement the remainder of the methylation

pathway for optimal function. "

" The sulfite oxidase enzyme (SUOX) is downstream from the CBS enzyme

in this pathway. Molybdenum helps the body to process neurotixic

sulfite to sulfate via the enzyme sulfite oxidase. This reaction

will be heavily taxed in individuals with CBS C699T upregulations and

you will often see low levels with molybdenum in the body in spite of

constant supplementation. If molybdenum is too low then the more

toxic sulfite will not convert to the sulfate form. "

" By virtue of the fact that the methylation cycle is needed for

synthesis of carnitine and COQ10, both important energy components of

mitochondria, individuals with CBS mutations will likely be energy

depleted. As a consequence of energy depletion, homocysteine

produced is metabolized to alpha KG, NH3 (ammonia) and H2S (hydrogen

sulfide). This suggests that another consequence of increased

activity of the CBS enzyme is elevated levels of hydrogen sulfide in

the brain. "

" Research has shown that hydrogen sulfide is able to induce a state

of " tupor " , or a state of semi hibernation. This may help to explain

the " brain fog " that is often used to describe autistic children who

carry the C699T+ mutations. "

Beginning On Page 226, Yasko says:

CBS C699T + ++

The heterozygonous CBS C699T mutation will allow for any added

methylation cycle supplements to be depleted through the trans

sulfuration pathway to generate additional ammonia and excess sulfur

compounds. This creates a " catch 22 " . It is important to supplement

the methylation cyle in order to address viral infection in the body,

toxic metal burdens, as well as to support neurotransmitters and

immune function and myelination of nuerves.

On the other hand, until the CBS upregulation is under control, there

is a risk of any added methylation cycle support creating additional

problems for the body. The added ammonia that is generated due to

enhanced breakdown due to methylation cycle intermediates will put a

burden on the Urea cycle and will deplete BH4 that is needed for

serotonin, dopamine, conversion of phenylalanine to tyrosine, and

language related function.

The excess sulfur can trigger the stress/cortisol response in the

body as well as potentially causing a decrease in the enzyme glucose

6 phosphate dehydrogenase (G6PDH). "

CBS C699T and MTHFR A1298C

.......

" Until now, it has been felt that [the A1298C mutation of the MTHFR

gene] may not be of serious consequence. Literature suggests that the

MTHFR enzyme can drive the reverse reaction leading to the formation

of BH4. The A1298C mutation would then be associated with an

inability to convert BH2 to BH4. Between these two mutations (CBS

C699T and MTHFR A1289C) it may cause exceedingly low BH4 levels. This

in turn will affect dopamine levels as well as the levels of

serotonin and urea cycle function. The COMT and VDR Bsm/Taq status

will play a role in affecting overall BH4 levels as any needed

synthesis of dopamine to replenish dopamine stores will require BH4. "

" Individuals who are COMT ++ or VDR Bsm/Taq – have an advantage in

this area: the COMT ++ and VDR Bsm/Taq status will help to compensate

to a certain extent for the effect for the MTHFR A1298C mutation.

MTHFR A1298C mutations limit the supply of BH4. "

" Low levels of BH4 are also associated with more severe parasitic

infections, diabetes, as well as hypertension and atheroschlerosis.

Serotonin synthesis as well as ammonia detoxification also require

BH4. The CBS C699T leads to more ammonia that needs to be

detoxified. Elevated levels of ammonia are sufficient to cause

flapping and other over stimulatory behaviors. Excess ammonia in the

gut may alter the local PH and aggravate imbalances in microbial

flora. Each molecule of ammonia requires two molecules of BH4 for

ideal detoxification. It is clear to see how several of these

mutations may act together to impact ammonia detoxification as well

as optimal BH4 levels for neurotransmitter synthesis. "

" Keeping the CBS C699T + mutation under control is of paramount

importance for overall health and wellness. Any excess ammonia

generated by the CBS C699T + mutation can drain stores of BH4. This

will impact on serotonin levels and to a certain extent cause fluxes

in dopamine (which translates into mood swings). Therefore, keeping

the CBS C6599T + mutation under control is of paramount importance to

getting the body back in balance. Also helping to restore adequate

levels of BH4 should aid in serotonin synthesis, maintaining dopamine

levels in a more stable manner, as well as ammonia detoxification. "