Interesting CBS mutation rebuttal
- Subject: Interesting CBS mutation rebuttal
- Date: Sun, 6 Jan 2008 05:11:29 -0500
- Yahoo! Message Number: 218588
- Onibasu Link: http://onibasu.com/archives/am/218588.html
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.
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