Interesting CBS mutation rebuttal

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CBS Upregulation, Myth or Reality?

By Mark London

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Upregulation of the CBS enzyme via two genetic polymorphisms has been

theorized to be possibly detrimental for some conditions, based on the

work by Dr. Amy Yasko in autism. These two polymorphisms were studied

in 2000, and in that study, the Post Methionine Load (PML) test was

used to determine the effects of different CBS polymorphism genotypes.

That loading test can detect subtle defects in the transsulfuration

pathway, which is the metabolic process that is affected by the CBS

enzyme. The polymorphism with the greatest effect, as shown by the

PML test, was found to be 699CàT (Y233Y). People with the TT (+/+)

genotype of that polymorphism, and to a lesser degree CT (-/+),

produce lower levels of homocysteine levels in response to the PML

test, when compared with the CC (-/-) genotype. Lower homocysteine

levels from that test infers greater CBS activity. By the way, none

of these genotypes are rare. About 40% of the population has CC, 40%

has CT, and 20% have TT. Thus, all the genotypes of this polymorphism

are quite common. The study also looked at the CBS polymorphism

1080CàT (A360A), but that was found to have less a significant effect.

The TT genotype of that polymorphism only showed a significant

decrease in homocysteine in the PML test, if 2 other polymorphisms

were also excluded. Thus, 699TT seems to have the most significant

affect on CBS activity.

On the other hand, a similar study in 2003 on these polymoprhisms did

not show a significant difference in homocysteine levels due to the

different genotypes, in response to the PML test. One difference with

this new study is that it was done on a different ethnic group, which

is sometimes a factor in genetic studies. Also, while the mean age

was the same in both studies, this new study had a much smaller range

of ages, and did not include anyone younger than about 40 years old.

This might be a factor, since CBS activity is known to decrease as a

person gets older.

Even more interestingly, is that a study on pregnant women in 2003

surprisingly showed an increase in basal homocysteine levels from the

TT genotype, the same genotype that had the lowest homocysteine level

in the 2000 study. This study did not give any possible reason for

this result.

In any event, even in studies which showed increased CBS activity

effects from the TT genotype, such as the one from 2000, and a more

recent one from 2007, only small changes in homocysteine levels were

observed. For example, in the latest study, which used a very large

population of 10000, the basal homocysteine levels only differed by

2.7%, between the TT genotype, which has the highest CBS activity,

compared to the CC genotype, which has the lowest CBS activity.

This minor decrease in homocysteine levels is in contrast to that

which is seen in Down's syndrome, where CBS upregulation is definitely

known to occur. In one study on Down's syndrome children, basal

homocysteine levels were reduced by 25%, and plasma levels of

cystathionine, which is produced by the transsulfuration pathway, was

increased by 3.8 fold.

On the other hand, a later study on Down's syndrome adults did not

show decreased homocysteine levels. This surprising result was

theorized to be due to the fact that adults have a much lower

requirement for folic acid. When folic acid was given to the Down's

syndrome children, their homocysteine levels rose significantly.

Thus, age may become a factor when considering the effects from CBS

upregulation. Dr. Yasko claims that these CBS polymorphisms can have

significant effects for autistic children. Even if that claim is

true, it is possible that it only has relevancy for children. Also,

the claim may have no relevancy for other conditions, due to the fact

that autism has many other metabolic disturbances that are not found

in other conditions.

It's also been claimed that increased urinary taurine and ammonia can

help diagnose CBS upregulation. While it's true that CBS upregulation

can cause increased taurine and ammonia production, there's no

evidence that this increased production can be detected by measuring

their urinary levels.

Urinary taurine is an unreliable test for CBS upregulation, due to

fact that urinary taurine is dependent on many factors, including age,

genetics, gender, renal function, clinical conditions, and especially

dietary intake. Thus, even though a study on Down's syndrome found a

significant increase in plasma taurine, another study on Down's

syndrome found that urinary taurine levels were normal. Urinary

inorganic sulfur was also not significantly different, which doesn't

confirm Dr. Yasko's prediction of excess sulfur byproducts from CBS

upregulation .On the other hand, urinary thiosulfate was

significantly increased. Thiosulfate is a metabolite of hydrogen

sulfide, and CBS is one of only three enzymes known to be able to

produce hydrogen sulfide. Thus, significant CBS upregulation was

likely occurring, even though urinary taurine and sulfur levels were

normal.

Urinary ammonia is an even less reliable method for testing for CBS

upregulation. This is because most of the ammonia (NH4+) in urine is

produced by the kidneys for ph regulation. The ammonia that is

produced elsewhere in the body, is usually detoxified by being

converted to urea, which is then excreted. This process mainly occurs

in the liver, and the liver is quite capable of handling the large

amount of ammonia that is produced in the body, which occurs due to

the metabolization of amino acids. The liver has to be able to do

this, because the nervous system can only tolerate very low levels of

ammonia. Excess ammonia, i.e., hyperammonia, only usually occurs

either when liver functioning has been greatly reduced, or where a

genetic defect in the urea cycle exists. Only by testing serum

ammonia, can such a condition be diagnosed.

In conclusion, the medical literature states that these CBS

polymorphisms have only very mild effects on CBS activity. And even

if there is significant CBS upregulation, there is no evidence that it

can significantly cause any negative effects, such as overproduction

of ammonia. Furthermore, the medical literature doesn't support the

claim that elevated levels of urinary ammonia or taurine is indicative

of CBS upregulation.

Dr. Yasko claims that CBS upregulation can lead to " a lack of

glutathione. " However, while glutathione is reduced in Down's

syndrome, medical researchers do not believe that this is due to the

CBS upregulation. Instead, they believe it is due to the

overexpression of the superoxide dismutase (SOD) gene, which also

occurs in Down's syndrome: " The reduced plasma glutathione observed in

the children with DS most likely reflects an adaptive antioxidant

response to chronic oxidative stress, resulting from SOD

overexpression. " This conclusion is possibly confirmed by a lab study

on CBS overexpression in mice, where even though homocysteine levels

were significantly reduced by the CBS upregulation, gluathione levels

were unchanged.

Thus, while some of the aspects of Dr. Yasko's treatment plan may have

usefulness, there is no support that CBS upregulation can have any

negative effects.