Personalized Medicine

Transcription

Implications of
Genetic Testing for
Alternative Healthcare
Dr. Amy Yasko
May 2005
Many factors influence our susceptibility to
disease. These include our stress load,
our environment and the toxins we absorb
from it, the total number of infectious
agents we are exposed to as well as our
underlying genetic susceptibility to these
diseases. It is important in this day and
age to address all the contributing factors
to these multifactorial diseases.
A given individuals
the risk of
Multifactorial Disease
is dependent on a number of factors
•Environmental
•Genetic
•Infectious
•Stress
DISEASE
Stress + Infectious agents + Toxins +
Underlying genetic susceptibility =
Disease
Examples
of Multifactorial Disease
Atherosclerosis vs.. Autism
• Genetic
• MTHFr
• Infectious
• Chlamydia pneumonia
• Streptococcus
• Stress
• Inflammatory Mediators
• Glutamate
• Improper Calcium
Regulation
• Improper CO2 Regulation
• Environmental
• Cholesterol
• Cardiovascular
Inflammatory Disease
• Genetic
• MTHFr
• Infectious
• Viral: MMR, Herpes
• Bacterial
• Stress
• Inflammatory Mediators
• Glutamate
• Improper Calcium
Regulation
• Improper CO2 Regulation
• Environmental
• Heavy Metals
• Neuroinflammatory
Disease
Alzheimer’s Disease
• Associated with age
• While APOE2 is an underlying risk factor
• Risk is heterogeneous and independent of
APOE
• Risk may be related to “other genes or
environmental factors that can be
investigated” JAMA September 15, 2004
The combination of components that
interact to cause multifactorial
diseases may be different in every
individual. There may be slight or
enormous changes in the relative
contributions of each of these
components to disease.
Genetic Testing as a Way to
Evaluate the Genetic
Contribution of Multifactorial
Disease
Genetic Screening is the
wave of the future for both
Alternative Healthcare as
well as Allopathic medicine
F.D.A. Issues a Guide to Gathering Genetic Data
By ANDREW POLLACK
Published: March 23, 2005
The Food and Drug Administration took a significant step yesterday toward the development
of so-called personalized medicine, in which drugs would be tailored to individuals based on their
genetic profiles.
The agency issued guidelines for pharmaceutical companies intended to encourage them to
gather and submit information about how genetic variations affect the way people respond to their
drugs.
Drug companies have been somewhat reluctant to do this, agency officials said, from fear that the
government might use the information to limit the market for their drugs. Drug makers have also worried that
the F.D.A. might block approval if, say, a drug was shown in a laboratory test to activate a gene that might be
involved in cancer.
To reassure drug companies, the F.D.A. has said that most of the genetic information will not be
considered in regulatory decisions. Instead, the agency said, the information will be used to help the agency
learn about the new science of tying genetic variations to drug response, a field called pharmacogenomics or
pharmacogenetics.
"Companies either weren't doing that work because they weren't understanding its regulatory status
or they weren't submitting it to us," Janet Woodcock, the F.D.A. acting deputy commissioner for
operations, said in an interview. She added, "I can't tell you how important it is for medicine that we
move into this paradigm."
Edward Abrahams, executive director of the Personalized Medicine Coalition, a Washington group
of companies, academic institutions and others that aim to promote the new field, hailed the F.D.A. guidelines
as a milestone. "The government is now the advocate for personalized medicine in an official way."
Pharmacogenomics is still in its infancy. It is well known that a particular drug might work
for some people but not for others, or might cause side effects in some people but not in others. But so
far there has been little testing of patients for genetic variations that could predict such reactions,
which would allow drugs to be given to appropriate patients and reduce side effects.
Both disciplines (Alternative and
Allopathic Medicine) will take advantage
of the strides made in the Human
Genome Project that allow us to utilize
simple genetic tests to look at our genetic
weaknesses.
The goal of the Human Genome Project
was to identify all the approximately
30,000 genes in human DNA and to
determine the sequences or “spelling” of
the 3 billion chemical base pairs that
make up human DNA. This project was
completed in June of 2000.
As a direct consequence of having the
complete sequence of the human
genome, research has focused on
identifying particular genes that are
involved with specific diseases. The
challenge is to identify disease causing
genes and clarify their roles. “The advent
of microarray technology has accelerated
the pace of gene expression analysis,
allowing the simultaneous analysis of
thousands of genes.” (Salowsky, R.,
BioPharm International, May 2004).
The Ultimate Gene Gizmo: Humanity on a Chip
Commercial genomics reached a landmark last week, and several companies are
jostling to share the limelight. Affymetrix Inc. of Santa Clara, California, announced that it
is now selling the first research device that contains a complete set of 50,000 candidate
genes covering the entire human genome. The GeneChip, as this microarray is called, can
be used to measure the activity of all known human genes
in a biological sample. Meanwhile, another California
company, Agilent Technologies Inc. of Palo Alto, has
begun distributing its own human genome array as an
Experimental prototype, and since June NimbleGen
Systems Inc. of Madison, Wisconsin, has been using yet
Another whole-genome setup to support a DNA-scanning
Service at a lab in Iceland.
These arraymakers use a variety of techniques to
attach minuscule dots of DNA onto glass slides, silicon
wafers, or nylon membranes. When exposed to a mix of
RNAs from a biological sample, each DNA latches onto
the RNA that matches its sequence. The RNA carries a
fluorescent tag, marking the place where it attaches.
Based on the location and intensity of the signal,
researchers can tell which gene is the source and how
active it is.
Fear Of Genetic Testing
• Inability to address the condition
• Insurance
• Job Discrimination
Genetic testing falls short of public
embrace.
NY Times (Print). 1998 Mar 27;:A16. No abstract available.
PMID: 11647298 [PubMed - indexed for MEDLINE]
Ethical aspects of genetic testing.
Whittier Law Rev. 1998 Winter;20(2):411-22. No abstract available.
Refusal of employment or insurance.
Am J Hum Genet. 1997 Oct;61(4):A56. No abstract available.
Is knowledge always good?
Genethics News. 1996 May-Jun;No. 12:6-7. No abstract available.
Screened out of coverage?
Genetic discrimination in health insurance is emerging as companies deny coverage to people
whose genes give them a greater chance of getting sick later on. Genetic predisposition, the
argument goes, is a pre-existing condition.
With the health insurance system as attentive to the bottom line as it is, some observers predict
that unless safeguards are put in place, genetic screening could become routine for coverage or
for continued coverage. It seems certain that some will be shut out of the health-care system.
What mechanisms will protect those forced out, and who will pay the cost? Will society have the
will--and the opportunity--to decide?
In the workplace, genetic discrimination is beginning to surface as employers refuse to consider
people with predispositions to illnesses. Employees who may become ill later on could cost a
company in higher health insurance rates and lost productivity.
Medical privacy is a closely related issue. Last spring two Marines were court martialled because
they refused to submit to DNA classification, claiming it violated their privacy. Though the
Pentagon said the information would be used only to help identify the casualties of war, many
see a danger in genetic data routinely collected and stored.
Civil libertarians fear that genetic test results obtained for one purpose may be used against the
person later on. What if genetic screening of an 18-year-old soldier revealed the gene linked to
Huntington disease, an incurable degenerative condition that strikes in middle age? When the
soldier was back in civilian life, would an insurance company or employer have access to the
data?
And what if people do not want to learn of their genetic predisposition, lest they find out they are
at risk of developing an incurable condition?
One Illinois man committed suicide after learning he carried the gene for
Huntington disease.
Anticipating these problems, the Evangelical Lutheran Church in America
is working to prepare pastors and congregations to sort out the issues
and work to minimize the damage--both locally and throughout society.
The Division for Church in Society is developing congregational study
materials on genetics, planned for distribution in fall 1997.
"We are going to help illuminate this controversial and urgent topic that's
going to have profound consequences in ordinary people's lives," says
Mary Solberg, project leader. A professor of religion at Haverford [Pa.]
College, she worked for five years as the editor of the Encyclopedia of
Bioethics.
However, despite the promise of lifesaving medical
breakthroughs, some implications of the research
have raised concerns within the Jewish community
-- and not only for the diseases themselves. These
concerns are primarily about genetic discrimination
in insurance or employment.
Since the breast cancer research results first appeared, Hadassah has understood that fear of
genetic discrimination might keep individuals from undergoing genetic testing to gain health
information. We have heard this fear expressed, throughout the United States, in our
Hadassah-sponsored community health forums and via frantic telephone calls received by our
Health Education Department in New York.
Individual stories are easy to find. One of our own Hadassah Board Members who has a strong
family history of breast cancer will not take a genetic test, for fear her daughter may be at risk
for discrimination. Such stories are reported regularly in the Jewish press.
Major national newspapers also report evidence of this fear. About a month ago The New York
Times featured a story entitled, "Genetic Testing Falls Short of Public Embrace,"
which detailed the current status of what was to be a potentially $100
million-a-year commercial genetic testing market. The article claimed
biotechnology companies that had developed tests to identify genetic
mutations -- like the ones found for breast cancer in the Jewish community - had expected a deluge of clients. Instead, the companies reported that
they had not seen much business in the past year. Individuals interviewed in the
story stated that fear of discrimination played a key role in their decision not to take a test, even
where they believed it could provide critical medical information.
A more disturbing article ran in Ha'aretz, the Hebrew language daily in Israel. The title of the
story was "Come to Israel to test your genes." It read, "A new kind of tourism is
developing at Israel's oncology clinics which specialize in genetic testing ..."
It described the phenomenon of Americans traveling to Israel for genetic
testing, where they are not afraid that insurance companies can get access
to the results. Mr. Chairman, it is a terrible Catch-22 that individuals who are simply seeking
information to better care for their health may be denied the health insurance coverage they
need to do so. It is particularly unfair with genetic information. The presence of a genetic
mutation does not necessarily mean the individual carrying it will ever get the disease. A
significant percentage of those carrying a B-R-C-A1 mutation will never get breast or ovarian
cancer. Nor does the lack of a genetic alteration indicate that an individual is risk-free.
We need a way not only to
diagnose Genetic Susceptibility
but also to way to treat it
Four basic steps have been outlined to work from
information in our genes to developing
personalized medicine.
• Defining the functional elements of the human
genome
• Determining which genes or pathways are
altered in a disease state
• Discovering inherited sequence patterns
contributing to disease
• Applying genomics information to improve
clinical practices”
• (Wills, R, Modern Drug Discovery, June 2004).
The long term goal of both molecular
medicine as well as molecular
nutrition is to have personalized
medicine that takes into account an
individuals genetic, environmental and
infectious disease profile.
Personalized medicine enables
your cells get the specific
communication that they need to be
balanced. “individualized
healthcare, once a seemingly
utopian fantasy, is steadily gaining
ground as a rational approach…”
(Nature Medicine, June 2004).
Molecular medicine will use
sophisticated drugs that are concerned
with precise mechanisms of action to
accomplish this task.
“We’re saying if we know what changes
in genetic make-up drive a particular
disease, then we can design a drug
tailored for the individual requirements of
that patient.”
(Burke, M., BioPeople Sept., 2004).
In addition
Molecular medicine will use
genetics to help to define which
individuals can benefit from
existing phamaceuticals
Improved diagnostics permit better drug dosing to
identify the percentage of patients that will respond to
customized treatments.
“Though the cost and logistics of implementing
individualized therapy may appear to be prohibitive…the
value of targeted therapy ..and the appeal of customized
therapy is evident.”
(Nature Medicine, June 2004).
This is underscored by the recent finding that only
patients with a certain genetic makeup gain any benefit
from particular commonly prescribed drugs. The study
helps to support the concept of personalized medicine,
the choice of drugs that work best for an individual
patient based on genetic testing.
(Chasman, D., JAMA, Sept. 2004)
Special section on human genetics: With your genes?
Take one of these, three times a day
Truly 'personalized' medicine remains a distant goal. But researchers are now thinking
about how to use genomic data to avoid prescribing drugs that may kill, or won't work.
By Alison Abbott
Nature 425, 760 - 762 (23 October 2003); doi:10.1038/425760a
It causes at least 100,000 deaths each year in the United States, and is responsible for more than 10% of
hospital admissions in some European countries. But this isn't some terrifying emerging infection, it's
the annual toll inflicted by adverse reactions to prescription drugs. What's more, millions of people are
being treated with drugs that, for them, will never do much good. Beta-blockers, given to reduce blood
pressure, are ineffective in one-third of patients; many antidepressants don't work in half of the people
who take them.
The blame lies largely with our genes, which help to determine the way in which we react to drugs.
Small genetic variations between people — or polymorphisms — can alter the behaviour of proteins that
carry a drug to its target cells or tissues, cripple the enzymes that activate a drug or aid its removal from
the body, or alter the structure of the receptor to which a drug is supposed to bind. Variation in immunesystem genes can also influence how particular drugs are tolerated. Together, these subtle genetic
variations mean that the dose at which a drug will work may vary hugely from person to person. And
with today's 'one-size-fits-all' prescribing, that can lead to life-threatening adverse reactions or to a drug
completely failing to do its job.
Molecular nutrition uses natural products to
effect cellular and molecular processes.
“Most chronic diseases are related to cellular
alterations which can, in part, be influenced by
nutrients. “
(International Society for Molecular Nutrition and Therapy).
RNA based therapies should be a key factor in
helping develop personalized nutrition based on
the results of the completed Human Genome
Project.
A new field of Bioinformatics is developing and
information about millions of nucleotides is now
stored in huge databases that new medicine will
be based on.
It would appear that RNA’s function might be as
the “mother of all information networks”
(Zweigler, G., Transducing the Genome McGraw Hill, 2000).
One area or variable that has been sorely
overlooked is enhancing our natural cell:
cell communication. As we attempt to
facilitate the communication between our
cells we can reduce some of our
underlying genetic susceptibility to
disease.
We are all familiar with the game of “telephone”
where one child whispers a message to the child
sitting next to him, who in turn whispers the
message to the child sitting next to her, who in
turn whispers the message to yet a fourth child
and so on until the message has been
whispered to the last child in the circle. By the
time the message reaches its destination, the
final child, it has undergone significant changes.
Think of RNA as the mediator that ensures
that the initial message is not distorted.
RNA helps to facilitate our cell:cell
communication by ensuring that the
messages in our genes (our DNA) are
accurately converted into the structural
building blocks for our body (our proteins)
in spite of the stresses, the toxins and the
infectious diseases in our lives.
Specific RNAs can help us to
address proper cell: cell
communication that is necessary
to address multifactorial disease.
RNA Based Support
Knowledge is power. Armed with this knowledge and
genetic profile analysis we can select precise natural RNA
formulas that will aid in cell : cell communication to help to
address the genetic susceptibilities that are involved in a
variety of health conditions. (Stress, Health Foundation,
Heart Support, Methylation Support, Nerve Calm, Mood S,
Mood D, Mood Focus, Respiratory Support, Brain Support,
CSF Support, Lipid Support ,Kidney Support, Healthy
Microbial Balance, Organ Support, Bone Support and
ProLongevity RNA NutriSwitch™ Formulas among others).
For while we cannot change our genes, we can help to
enhance the expression of these genes.
DNA for testing
RNA for balancing
Relationship between specific
genetic mutations and
biochemical pathways and what
we can do to address these
mutations
Specific Mutations of Interest
CBS cystathionine beta synthase
COMT catechol-O-methyltransferase
MTHFR A1298C methylene tetrahydrofolate reductase
MTHFR C677T methylene tetrahydrofolate reductase
MS(MTR)A2576G methionine synthase
MSR(MS_MTRR) A66G methionine synthase reductase
NOS nitric oxide synthase
SOD super oxide dismutase
VDR vitamin D receptor
Consequences of these mutations
Increased Homocysteine
Decreased Methylation
Decreased BH4
Elevated Ammonia
Homocysteine is elevated in the
following pathological states:
•
•
•
•
•
•
•
•
•
Renal failure
Thyroid dysfunction
Heart transplantation
Cardiovascular events
Diabetes
Neural tube defects
Downs syndrome
Alzheimer’s disease
Autism
Decreased BH4 is associated with
the following:
•
•
•
•
•
•
•
Diabetes
Atypical phenylketonuria (PKU)
Decreased dopamine levels
Decreased serotonin levels
Hypertension
Atherosclerosis
Decreased NOS, endothelial dysfunction
States associated with
undermethylation
•
•
•
•
•
Cancer
Aging
Cardiovascular disease
Neurological function
Retroviral transmission
Ammonia toxicity
•
Disorientation, “brain fog", confusion
•
Flapping tremors of extended arms
•
Hyperactive reflexes
•
Activation of N-methyl-D- aspartate receptors leading to glutamate
excitotoxicity
•
Tremor of the hands
•
Paranoia, panic attacks
•
Memory loss
•
Hyperventilation (caused by respiratory alkalosis of high ammonia levels that
stimulate the respiratory center; respiratory alkalosis is often associated with
decreased CO2)
•
CNS toxicity affecting glial and nerve cells a, leading to altered CNS
metabolism and function.
AMMONIA
AMMONIA
“When the need is for energy and not for cysteine,
homocysteine is metabolized to Alpha KG, NH3 and H2S.”
Textbook of Biochemistry with Clinical Correlations ,Devlin 2002
How do you know if you have
any of these mutations?
Testing for Mutations
• Saliva tests
• Blood tests
• Both MTHFR mutations
A1298C
C677T
Interpreting the Results
•
•
•
•
A1298C+/A1298C+
A1298C-/A1298CA1298C+/A1298CA1298C-/A1298C+
homozygous
no mutation
heterozygous
heterozygous
Punnett Square
A Punnett square is a chart which shows/predicts all possible gene
combinations in a cross of parents (whose genes are known). Punnett squares
are named for an English geneticist, Reginald Punnett. He discovered some
basic principles of genetics, including sex linkage and sex determination.
The standard way of working out what the possible offspring of two parents
will be is the Punnett Square. Consider a single gene. Since each individual has one
pair of each chromosome, they have two copies of each gene (one on each
chromosome). A Punnett square is a simple graphical way of figuring out how the
genes from each parent might combine to produce an offspring. The Punnett square
duplicates the observation that the reproductive cells (eggs and sperm) get only half
the normal number of chromosomes. When an egg is made, it receives one of each
pair of chromosomes, not both. Likewise with sperm.
Since eggs and sperm each carry only one of each chromosome instead of
a pair of each, they carry only one copy of each gene instead of two. Thus a female
who carries two different flavors (alleles) for a particular gene, produces some eggs
reproductive cells that carry one flavor, and some eggs that carry the other. A male
with two different alleles for the same gene likewise produces some sperm carrying
one allele and some sperm carrying the other.
A1288C +
A1288C +
A1288C +
A1298C +
A1288C +
A1288C +
A1288C +
A1288C +
A1288C +
A1288C +
A1288C +
A1288C +
A1288C -
A1288C -
A1288C -
A1298C -
A1288C –
A1288C –
A1288C -
A1288C -
A1288C –
A1288C –
A1288C -
A1288C -
A1288C -
A1288C +
A1288C +
A1298C -
A1288C –
A1288C –
A1288C +
A1288C +
A1288C –
A1288C –
A1288C +
A1288C +
A1288C +
A1288C -
A1288C +
A1298C -
A1288C +
A1288C –
A1288C -
A1288C -
A1288C +
A1288C –
A1288C +
A1288C +
Supplementation based on
specific mutations
Methylation Cycle Supplementation
•
¼ Folapro
•
¼ Intrinsic B12
•
¼ Nucleotides
•
Methylation Support RNA
•
TMG and /or phosphatidyl serine
•
Sublingual B12 and /or B12 injections
COMT + + : hydroxy cobalamin
COMT - -: methyl cobalamin
Regardless of COMT status: cyano cobalamin (eyes)
•
Methionine
SAMe for COMT - Methionine COMT + +
•
Optional methyl donors for COMT - - and COMT + MSM, TMG, DMG, curcumin, methyl B12, melatonin, FgF, caffeinated tea
AMMONIA
COMT
COMT is the enzyme that inactivates
dopamine and norepinephrine by adding a
methyl group to these compounds.
• COMT has an allelic variation with high activity,
which decreases dopamine
• COMT has an allelic variation with low activity,
leads to less of a decrease of dopamine
COMT
In the case of COMT the amino acid change is from a valine to a
methionine. This is what is being tested for in the COMT genetic test.
The labs are able to look at the DNA to determine which amino acid
your version of COMT has. If you have the version with a methionine
in it is written as COMT + meaning the genetic test is positive for the
methionine version. If the result is COMT- it means that you do not
have methionine in that spot of the enzyme and have valine there
instead. Since the valine in that spot is considered the “norm” the
methionine represents the variation, so it is + for a variation being
present.
The form of the COMT with the variation (the methionine in it at a
particular location) is a less efficient form of the enzyme. When the
methionine is present it does not do as good a job of breaking down
the dopamine. So an individual with the COMT+ will not break
dopamine down as easily. An individual with COMT-(with the valine in
that spot) will break dopamine down more efficiently.
The reason that we have two ++ or two - - or + - is that we all have
two copies of the DNA for the COMT enzyme; one from each parent.
Another way to represent COMT + + is as COMT met/met.
Another way to represent COMT - - is as COMT val/val.
COMT
val/val - -
•
The dopamine pathway is tied to the folate and methionine cycles.
•
Individuals who are COMT - - will inactivate dopamine (and norepinephrine)
more rapidly and as such will be depleting methyl groups from the
methylation cycle in the process.
Consider supplementation to help to maintain healthy dopamine levels.
•
Mood D (1/4 dropper once to twice a day)
Mood Focus (1/8 to 1/4 dropper once a day)
Quercetin supplementation
•
•
S adenosyl homocysteine (SAH) acts to slow down the activity of COMT. As
a result consider supplementation with SAMe. This will support methylation
as well as generate SAH.
SAH also is reported to have antiviral activity.
•
Individuals who are COMT - - tend to have a higher viral and metals load,
and require higher doses of Metals RNA to facilitate detoxification.
•
Compounding mutation : MTHFR A1298C
COMT
met/met + +
•
Individuals who are COMT + + seem to have less of a viral and metal load,
are more sensitive to supplements, recover language more easily (or never
lost it), require a lower dose of the Metals RNAs for detoxification, and are
more likely to exhibit "mood swing" type behaviors if you are not careful with
food , supplementation, and also during detoxification.
•
Supplementation with quercetin, Mood D, Mood Focus is not advised.
•
Supplementation with additional methyl donors such as MSM, TMG, DMG,
curcumin, methyl B12, melatonin, FgF, caffeinated tea is not advised.
•
Caution should be used with high dopamine content foods.
High Dopamine Foods
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
Alcoholic beverage (some, not all
alcohol)
Homemade yeast breads
Crackers containing cheese
Sour cream
Bananas
Red plums
Avocados
Figs
Raisins
Aged game
Liver
Canned meats
Yeast extracts
Commercial meat extracts
Stored beef liver
Chicken livers
Salami
Sausage
•
•
•
•
•
•
•
•
•
Aged cheese (including Blue, Boursalt,
Brick, Brie, Camembert, Cheddar,
Colby, Emmental, Gouda, Mozzarella,
Parmesan, Provolone, Romano,
Roquefort, and Stilton)
Salted dried fish (herring, cod), pickled
herring
Italian broad beans
Green bean pods
Eggplant
Yeast concentrates or products made
with them
Marmite
Soup cubes
Commercial gravies- anything with soy
sauce, and an protein that has not
been stored properly or has some
degree of spoilage (i.e., all but those
that have been freshly prepared).
Vitamin D Receptor
Environmental Medicine
Amyotrophic Lateral Sclerosis, Lead, and Genetic Susceptibility: Polymorphisms in the
-Aminolevulinic Acid Dehydratase and Vitamin D Receptor Genes
Freya Kamel,1 David M. Umbach,1 Teresa A. Lehman,2 Lawrence P. Park,3 Theodore L. Munsat,4 Jeremy M.
Shefner,5 Dale P. Sandler,1 Howard Hu,6 and Jack A. Taylor1
1National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA; 2Bioserve
Biotechnologies, Rockville, Maryland, USA; 3Westat, Durham, North Carolina, USA; 4New England Medical Center, Boston,
Massachusetts, USA; 5SUNY Upstate Medical University, Syracuse, New York, USA 6Harvard Medical School and Harvard
School of Public Health, Boston, Massachusetts, USA
Abstract
Previous studies have suggested that lead exposure may be associated with increased risk of
amyotrophic lateral sclerosis (ALS). Polymorphisms in the genes for -aminolevulinic acid
dehydratase (ALAD) and the vitamin D receptor (VDR) may affect susceptibility to lead
exposure. We used data from a case-control study conducted in New England from 1993 to
1996 to evaluate the relationship of ALS to polymorphisms in ALAD and VDR and the effect of
these polymorphisms on the association of ALS with lead exposure. The ALAD 2 allele (177G
to C; K59N) was associated with decreased lead levels in both patella and tibia, although not
in blood, and with an imprecise increase in ALS risk [odds ratio (OR) = 1.9; 95% confidence
interval (95% CI), 0.60-6.3]. We found a previously unreported polymorphism in ALAD at an
Msp1 site in intron 2 (IVS2+299G>A) that was associated with decreased bone lead levels
and with an imprecise decrease in ALS risk (OR = 0.35; 95% CI, 0.10-1.2). The VDR B allele
was not associated with lead levels or ALS risk. Our ability to observe effects of genotype on
associations of ALS with occupational exposure to lead or with blood or bone lead levels was
limited. These findings suggest that genetic susceptibility conferred by polymorphisms in
ALAD may affect ALS risk, possibly through a mechanism related to internal lead exposure.
Key words: -aminolevulinic acid dehydratase, amyotrophic lateral sclerosis, genetic
susceptibility, lead, vitamin D receptor. Environ Health Perspect 111:1335-1339 (2003).
doi:10.1289/ehp.6109 available via http://dx.doi.org/ [Online 1 April 2003]
Vitamin D Receptor
AMMONIA
VDR Mutations
•
•
•
•
•
•
Vitamin D levels are closely tied to neurological conditions.
Supplement with at least 1000 IU of supplemental vitamin D daily.
Supplement with ¼ dropper of ProLongevity RNA daily.
Vitamin D is also related to blood sugar regulation.
Consider supplementation with Vitamin K1/K2 to help with potential
blood sugar issues.
The relationship between Vitamin D and insulin levels can also
affect weight control as well as eating habits. Consider
supplementation with :
Ora pancreas
chromium picolinate
gymnema sylvestre
Digestive enzymes containing pancreatic extract
VDR Mutations
•
•
•
•
Bsm
Taq
Fok
Compensatory effect of lack of Bsm and
Taq mutations
• Relationship between elevated vitamin D
and dopamine levels
AMMONIA
Vitamin D and Dopamine
Brain Res Mol Brain Res. 1996 Feb;36(1):193-6.Related Articles, Links
Vitamin D increases expression of the tyrosine hydroxylase gene in adrenal
medullary cells.
Puchacz E, Stumpf WE, Stachowiak EK, Stachowiak MK.
Laboratory of Molecular Neurobiology, Barrow Neurological Institute, Phoenix, AZ 85013, USA.
We examined expression of the 1,25-dihydroxyvitamin D3 [1,25-(OH)2 D3]
receptors in chromaffin cells of the adrenal medulla and the effects of 1,25(OH)2
D3 on expression of the tyrosine hydroxylase (TH) gene. Accumulation of
1,25(OH)2 D3 in the nuclei of adrenal medullary cells, but not in the adrenal
cortex, was observed in mice intravenously injected with radioactively labeled
hormone. 1,25(OH)2 D3 produced concentration-dependent increases in the TH
mRNA levels in cultured bovine adrenal medullary cells (BAMC). The maximal
increases (2-3-fold) occurred at 10(-8) M 1,25(OH)2 D3. Combined treatment with
1,25(OH)2 D3 and 20 microM nicotine had no additive effect on TH mRNA levels
suggesting that transsynaptic (nicotinic) and vitamin D (hormonal) stimulation of
TH gene expression are mediated through converging mechanisms. Induction of
TH mRNA by 1,25(OH)2 D3 was not affected by calcium antagonist TMB-8. By
increasing expression of the rate limiting enzyme in the catecholamine
biosynthetic pathway, 1,25-(OH)2 D3 may participate in the regulation of
catecholamine production in adrenal chromaffin cells. This regulation provides
mechanisms through which 1,25(OH)2 D3 may control response and adaptation
to stress.
AMMONIA
The magnitude of the genetic
association is substantial with those
in the "TT" group having a 50-60%
reduction in risk compared with the
"tt" group with heterozygotes in
between.
TT = Bsm/Taq - The Taq-1 polymorphism is located within
1.1 kb 3' of the polymorphic Bsm-1 site and is
in strong linkage disequilibrium with the
previously reported Bsm-1 polymorphism such
that there is up to 97% concordance of
genotype. Because of this strong linkage and
the presence of an internal control in the Taq1 RFLP, only the Taq-1 RFLP was determined
in the present study population. Presence (t)
and absence (T) of the polymorphic Taq-I
restriction endonuclease site are in linkage
with the absence (B) and presence (b)
respectively of the polymorphic Bsm-I site.
• High Vitamin D is associated with lower rates of
osteoarthritis
• Previous study showed that the absence of the
Taq and Bsm sites were associated with lower
levels of osteoarthritis
• Implies that lack of Taq and Bsm lead to higher
levels of Vitamin D
• High Vitamin D increases dopamine
• Fits with observation that Bsm - - and Taq - may mitigate other mutations in autism severity
• Fits with observation that Bsm - - and Taq - COMT + + children are the most sensitive to
dopamine and methyl groups
MTHFR A1298C
•
The A1298C mutation has been mapped to the SAMe regulatory region of the
gene.
•
Mutations in the A1298C do not lead to increased levels of homocysteine; as such
it has been felt that this mutation may not be of serious consequence.
•
Literature suggests that the MTHFR enzyme can drive the reverse reaction leading
to formation of BH4.
•
Dr. Yasko has suggested that the A1289C mutation is associated with a defect in
the reverse reaction leading to the formation of BH4.
•
The A1298C mutation would then be associated with an inability to convert BH2 to
BH4. This would impact levels of dopamine, serotonin, norepinephrine , and
phenylalanine.
•
The availability of BH4 helps to determine whether nitric oxide, peroxy nitrite or
super oxide are formed as a function of the urea cycle; two molecules of BH4 are
required for formation of nitric oxide, one molecule of BH4 leads to the formation of
peroxy nitrite and the absence of BH4 leads to super oxide formation.
AMMONIA
MTHFR
A1298C
++
•
MTHFR gene with the A1298C mutation may decrease the formation of BH4.
•
This mutation impacts dopamine levels as well as the levels of serotonin and the
urea cycle.
•
Supplementation for optimal methylation cycle function should be followed.
•
Methylation cycle supplementation should be adapted to the relevant COMT
status.
•
Consider supplementation to help to maintain healthy dopamine and serotonin
levels. The specific supplementation utilized should be dependent on the COMT
status.
•
Compounding mutation : CBS C699T + +
•
Dr. Yasko has found that more severe autistic children have
A1289C + +,CBS + + COMT - -.
High Dopamine Foods
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Alcoholic beverage (some, not all
alcohol)
Homemade yeast breads
Crackers containing cheese
Sour cream
Bananas
Red plums
Avocados
Figs
Raisins
Aged game
Liver
Canned meats
Yeast extracts
Commercial meat extracts
Stored beef liver
Chicken livers
Salami
Sausage
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Aged cheese (including Blue, Boursalt,
Brick, Brie, Camembert, Cheddar,
Colby, Emmental, Gouda, Mozzarella,
Parmesan, Provolone, Romano,
Roquefort, and Stilton)
Salted dried fish (herring, cod), pickled
herring
Italian broad beans
Green bean pods
Eggplant
Yeast concentrates or products made
with them
Marmite
Soup cubes
Commercial gravies- anything with soy
sauce, and an protein that has not
been stored properly or has some
degree of spoilage (i.e., all but those
that have been freshly prepared).
High Tryptophan Foods may
increase Serotonin
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Spirulina (seaweed)
Soy Nuts
Chicken Liver
Pumpkin Seeds
Turkey
Chicken
Tofu
Watermelon Seeds
Almonds
Peanuts
Brewer’s Yeast
Cottage Cheese
Milk
Yoghurt
AMMONIA
Brain Res. 2002 May 10;935(1-2):47-58
Glutathione depletion in nigrostriatal slice cultures: GABA loss, dopamine
resistance and protection by the tetrahydrobiopterin precursor sepiapterin.
Gramsbergen JB, Sandberg M, Moller Dall A, Kornblit B, Zimmer J.
Anatomy and Neurobiology, Institute of Medical Biology, SDU-Odense University,
Winsloewparken 21, DK-5000 C Odense, Denmark. [email protected]
Dopaminergic neurons in culture are preferentially resistant to the toxicity of
glutathione (GSH) depletion. This effect may be due to high intrinsic levels
of tetrahydrobiopterin (BH(4)). Here we studied the effects of manipulating GSH
and/or BH(4) levels on selective neurotoxicity in organotypic nigrostriatal slice
cultures. Following treatments with L-buthionine sulfoximine (BSO, 10-100
microM, 2 days exposure, 2 days recovery), either alone or in combination with the
BH(4) precursor L-sepiapterin (SEP, 20 microM), or the BH(4) synthesis inhibitor
2,4-diamino-6-hydroxypyrimidine (DAHP, 5 mM), toxic effects were assessed by
HPLC analysis of medium and tissues, cellular propidium iodide (PI) uptake,
lactate dehydrogenase (LDH) efflux, as well as stereological counting of tyrosinehydroxylase (TH) positive cells. Thirty micromolar BSO produced 91% GSH and
81% GABA depletion and general cell death, but no significant effect on medium
homovanillic acid (HVA) or tissue dopamine (DA) levels. SEP prevented or
delayed GABA depletion, PI uptake and LDH efflux by BSO, whereas DAHP in
combination with BSO caused (almost) complete loss of medium HVA, tissue DA
and TH positive cells. We suggest that under pathological conditions with
reduced GSH, impaired synthesis of BH(4) may accelerate nigral cell loss,
whereas increasing intracellular BH(4) may provide protection to both DA
and GABA neurons.
Brain Res. 2002 May 10;935(1-2):47-58
J Neurochem. 2000 Jun;74(6):2305-14.
Preferential resistance of dopaminergic neurons to the toxicity of glutathione depletion is
independent of cellular glutathione peroxidase and is mediated by tetrahydrobiopterin.
Nakamura K, Wright DA, Wiatr T, Kowlessur D, Milstien S, Lei XG, Kang UJ.
Department of Neurology, University of Chicago, IL 60637, USA.
Depletion of glutathione in the substantia nigra is one of the earliest changes observed in
Parkinson's disease (PD) and could initiate dopaminergic neuronal degeneration.
Nevertheless, experimental glutathione depletion does not result in preferential toxicity to
dopaminergic neurons either in vivo or in vitro. Moreover, dopaminergic neurons in
culture are preferentially resistant to the toxicity of glutathione depletion, possibly owing
to differences in cellular glutathione peroxidase (GPx1) function. However,
mesencephalic cultures from GPx1-knockout and wild-type mice were equally susceptible
to the toxicity of glutathione depletion, indicating that glutathione also has GPx1independent functions in neuronal survival. In addition, dopaminergic neurons were more
resistant to the toxicity of both glutathione depletion and treatment with peroxides than
nondopaminergic neurons regardless of their GPx1 status. To explain this enhanced
antioxidant capacity, we hypothesized that tetrahydrobiopterin (BH(4)) may function as an
antioxidant in dopaminergic neurons. In agreement, inhibition of BH(4) synthesis
increased the susceptibility of dopaminergic neurons to the toxicity of glutathione
depletion, whereas increasing BH(4) levels completely protected nondopaminergic
neurons against it. Our results suggest that BH(4) functions as a complementary
antioxidant to the glutathione/glutathione peroxidase system and that changes in
BH(4) levels may contribute to the pathogenesis of PD.
MTHFR
COMT
A1298C
val/val
++
--
•
•
•
This mutation impact dopamine levels as well as the levels of serotonin and the urea cycle.
•
Methylation cycle supplementation should be adapted to the relevant COMT status.
•
Consider supplementation to help to maintain healthy dopamine and serotonin levels. The
use of Mood S, Mood D and Mood Focus may put less of a drain on limited supplies of BH4
so that there is sufficient BH4 to drive the urea cycle.
Mood S (1/4 dropper once to twice a day)
Mood D (1/4 dropper once to twice a day)
Mood Focus (1/8 to 1/4 dropper once a day)
•
Compounding mutation : CBS + +
•
Dr. Yasko has found that more severe autistic children have
A1289C + +,CBS + + COMT - -
AMMONIA
MTHFR
A1298C
COMT met/met + +
•
•
•
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•
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•
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This may not impact dopamine levels as severely as a result of the COMT
mutation which may compensate in terms of dopamine levels.
It may be prudent to add Mood S to help to support healthy serotonin levels.
Between the use of Mood S and the presence of the COMT mutations it may
put less of a drain on limited supplies of BH4 so that there is sufficient BH4
to drive the urea cycle.
Individuals who are COMT + + seem to have less of a viral and metal load,
are more sensitive to supplements, recover language more easily (or never
lost it), require a lower dose of the Metals RNAs for detoxification, and are
more likely to exhibit "mood swing" type behaviors if you are not careful with
food , supplementation, and also during detoxification.
status.
Compounding mutation : CBS A699T + +
AMMONIA
MTHFR
•
•
•
•
C677T
++
C677T mutation leads to less efficient activity of the enzyme through
the methionine and folate pathways.
The body is less able to make 5 methyl folate. The addition of
Folapro as well as other methylation cycle supplementation should
help to compensate for this mutation.
Supplementation for optimal methylation cycle function should be
followed.
Methylation cycle supplementation should be adapted to the relevant
COMT status.
•
The C677T mutation had been associated with an increased risk of
heart disease
•
Compounding mutation : MSR (MS__MTRR) A66G
Arch. Neurol. April 2005
• Subjects with the highest folate intake had twice
the rate of mental decline over six years as
those with the lowest folate intake.
• Elevated homocysteine and the relationship to
Alzheimer’s
• Screening for the ability to use plain folate
• Implication for C677T mutations in the
population at risk for Alzheimer’s
Dietary Folate and Vitamin B12 Intake and Cognitive Decline Among
Community-Dwelling Older Persons
Martha Clare Morris, ScD; Denis A. Evans, MD; Julia L. Bienias, ScD; Christine C. Tangney, PhD; Liesi E.
Hebert, ScD; Paul A. Scherr, PhD, ScD; Julie A. Schneider, MD
Arch Neurol. 2005;62:641-645.
Background Deficiencies in folate and vitamin B12 have been associated with neurodegenerative disease.
Objective To examine the association between rates of age-related cognitive change and dietary intakes of folate and vitamin B12.
Design Prospective study performed from 1993 to 2002.
Setting Geographically defined biracial community in Chicago, Ill.
Participants A total of 3718 residents, 65 years and older, who completed 2 to 3 cognitive assessments and a food frequency
questionnaire.
Main Outcome Measure Change in cognitive function measured at baseline and 3-year and 6-year follow-ups, using the average z
score of 4 tests: the East Boston Tests of immediate and delayed recall, the Mini-Mental State Examination, and the Symbol Digit
Modalities Test.
Results High folate intake was associated with a faster rate of cognitive decline in mixed models adjusted for multiple risk factors.
The rate of cognitive decline among persons in the top fifth of total folate intake (median, 742 µg/d) was more than twice that of
those in the lowest fifth of intake (median, 186 µg/d), a statistically significant difference of 0.02 standardized unit per year
(P = .002). A faster rate of cognitive decline was also associated with high folate intake from food (P for trend = .04) and with folate
vitamin supplementation of more than 400 µg/d compared with nonusers ( = –.03, P<.001). High total B12 intake was associated
with slower cognitive decline only among the oldest participants.
Conclusions High intake of folate may be associated with cognitive decline in older persons. These unexpected findings call for
further study of the cognitive implications of high levels of dietary folate in older populations.
Author Affiliations: Rush Institute for Healthy Aging (Drs Morris, Evans, Bienias, and Hebert), Departments of Internal Medicine
(Drs Morris, Evans, Bienias, and Hebert), Preventive Medicine (Dr Morris), and Clinical Nutrition (Dr Tangney), and Rush Alzheimer’s
Disease Center (Dr Schneider), Rush University Medical Center, Chicago, Ill; and Division of Adult and Community Health, Centers
for Disease Control and Prevention, Atlanta, Ga (Dr Scherr).
AMMONIA
MS (MTR)
A2576G
•
This mutation is reported to increase the activity of the methionine synthase
enzyme.
•
While this may result in lower homocysteine levels, it may also deplete
intermediates from the methylation cycle.
•
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status.
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This mutation may also be correlated with an elevated risk for Down’s
Syndrome.
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The effect of this mutation may be compounded by a CBS mutation which
also acts to deplete intermediates of the methylation cycle.
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Compounding mutation : CBS C699T + +
MSR(MS_ _MTRR) A66G + +
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The function of MSR is to regenerate B12 for the MS to utilize.
This mutation reduces the ability of MSR to regenerate methylcobolamin.
Methylation cycle supplementation should be adapted to the relevant COMT status.
Supplementation with small amounts of methyl B12 and SAMe should be considered
even for individuals who are COMT + +.
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Supplement with additional with B12 beyond basic levels
COMT + + : hydroxy cobalamin
COMT - -: methyl cobalamin
Regardless of COMT status: cyano cobalamin (eyes)
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There is a second pathway to generate methionine via the BHMT enzyme that will
bypass the MSR mutation. This pathway uses phosphatidyl serine and /or TMG as
donors for the reaction.
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This mutation can an lead to elevated homocysteine levels
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Compounding mutation: MTHFR C677T
B12
• Low levels of B12 are associated with
lower bone density
• Risk of breaking a hip after a fall was 80%
lower in those supplemented with
adequate levels of vitamin B12 and folate
• Pernicious anemia
• Energy
AMMONIA
CBS
C699T
++
•
The C699T mutation in the CBS enzyme causes this enzyme to work at a higher efficiency. This
will drain the homocysteine from the methylation cycle so that we further deplete methyl groups
and methyl donors in this pathway.
•
Methionine, SAMe and carnitine aid in addressing excess ammonia; however CBS C699T and
other methylation cycle mutations deplete this pathway making it difficult to maintain adequate
levels of methionine and SAMe. SAMe is necessary for carnitine synthesis.
•
Consider supplementing with SAMe, methionine, carnitine, charcoal or bentonite to decrease
ammonia.
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Ammonia intoxication can be reduced by restricting the growth of ammonia-producing bacteria and
limiting the amount of protein in the diet.
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Suggest keeping protein in the diet to a minimum.
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Consider Ammonia Support RNA
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Recommend against the use of high levels of taurine or additional sulfur donors (broccoli etc) as it
may create problems with excess sulfur groups.
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Too much added glutathione can be a problem due to sulfur excess as a result of the CBS
mutation.
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Compounding mutation : MTHFR A1298C
AMMONIA
Specimen Marker
Before Low Protein/Ammonia
Support RNA
After Low
Protein/Ammonia
Support RNA
Reference Range
Ammonia Level
52,500
15,000
7,000-36,000uM
Taurine
3610
880
200-1000
Cysteine
35
20
15-54
Arginine
6.3
33
5-35
Homocysteine
1.6
2.5
<3
Sarcosine
7.9
5
<5
Beta alanine
160
28
<10
Carnosine
320
25
<100
GABA
<dl
2.5
<5
Ornithine
3.2
15
1.5-20
Science News April 23, 2005
Inducing a “topor like” state with hydrogen
sulfide gas. The gas competes with oxygen
in mitochondria, slowing the metabolic
activity.
Topor is an extreme state of metabolic
slowdown in which the heart rate drops,
breathing slows and body temperature
plunges.
AMMONIA
CBS
C699T
- -
•
If there is no mutation to up regulate the CBS enzyme the intermediates in
the methionine cycle should not be depleted to the extent that they are with a
CBS C699 T mutation.
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There should not be an excess of sulfur containing groups as a result of
excessive conversion of homocysteine to cysteine and taurine.
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Sulfur donors should be well tolerated.
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The lack of the CBS up regulation can lead to elevated homocysteine levels.
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Forward mutations in the MTHFR, C677T can lead to elevated homocysteine
levels.
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Compounding mutations : MTHFR C677T, MSR(MS__MTRR) A66G
AMMONIA
Combinations of
Genetic Variations
November
ACAM Meeting
CBS
MTHFR
C699T + +
A1298C + +
•
The C699T mutation in the CBS enzyme causes this enzyme to work at a
higher efficiency. This will drain the homocysteine from the methylation
cycle so that we further deplete methyl groups and methyl donors in this
pathway. The conversion of homocysteine via this enzyme also generates
ammonia.
•
Dr. Yasko believes that individuals with the A1298C mutation have
problems with the reverse reaction through the MTHFR which drives the
reaction of BH2 to BH4 . This impacts the levels of serotonin, dopamine,
norepinephrine and the urea cycle (getting rid of ammonia)
•
Limited BH4(due to A1298C) will create issues with the urea cycle and the
ability to use this cycle properly to eliminate ammonia in a less toxic
fashion.
CBS
MTHFR
•
C699T + +
A1298C + +
The amount of BH4 also plays a direct role in the urea cycle
With no BH4 the cycle will still function, however super oxide will be
generated which causes
oxidative damage, neuronal damage and
microglial activation.
With one molecule of BH4 for each turn of the urea cycle the damaging
peroxy nitrite will be produced.
It requires two molecules of BH4 in order to make citrulline and nitric oxide
(NO) properly
•
The depletion of BH4 due to excess ammonia generated by the CBS C699T
mutation can be partially compensated by a COMT++ status. With COMT++
it will slow the breakdown of dopamine and so it will require less BH4 to
make more dopamine and leave more of the limited BH4 to make serotonin
and convert arginine to citrulline in the urea cycle. This may be why children
who are COMT-- and A1298C ++ may have the greater difficulties.
CBS
MTHFR
C699T + +
A1298C + +
• Methionine, SAMe and carnitine aid in addressing
excess ammonia; however CBS C699T and other
methylation cycle mutations deplete this pathway
making it difficult to maintain adequate levels of
methionine and SAMe. SAMe is necessary for
carnitine synthesis.
• SAH which is an intermediate in this pathway helps to inhibit
COMT so that if you are COMT-- but can make sufficient
SAH it will help to slow down the degradation of dopamine
and help to compensate for the COMT- -.
• BH4 reaction is inhibited by aluminum.
A1298C/ CBS/
Protein
• Increased ammonia puts strain on the
urea cycle.
• Decreases BH4.
• May either generate excessive Nitric
Oxide or not enough NO.
• Also generates peroxy nitrite and
superoxide. Excess superoxide in turn
affects SOD.
The urea cycle is an endergonic process that ultimately requires the hydrolysis of
3 ATP's for each molecule of urea produced
In the first reaction, which occurs in mitochondria, bicarbonate (HCO3¯) is
combined with NH4+ to form carbamoyl phosphate
http://www.lander.edu/flux/301_aminoacid_catabolism.htm
Functions of Nitric Oxide
•
•
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NO inhibits platelet aggregation, keeping inappropriate clotting from interfering with
blood flow.
Release of NO around the glomeruli of the kidneys increases blood flow through
them thus increasing the rate of filtration and urine formation.
The wavelike motions of the gastrointestinal tract are aided by the relaxing effect of
NO on the smooth muscle in its walls.
NO affects secretion from several endocrine glands.
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it stimulates
the release of Gonadotropin-releasing hormone (GnRH) from the hypothalamus;
the release of pancreatic amylase from the exocrine portion of the pancreas;
the release of adrenaline from the adrenal medulla.
Some motor neurons of the parasympathetic branch of the autonomic nervous
system release NO as their neurotransmitter.
NO is released by neurons in the CA1 region of the hippocampus and stimulates the
NMDA receptors there that are responsible for long-term potentiation (LTP) — a type
of memory (and learning).
Mice whose genes for nNOS have been knocked out are healthy but display
abnormal behavior, e.g., they kill other males and try to mate with nonreceptive
females.
Nitric oxide plays an integral role in the airway; nonadrenergic, noncholinergic
(NANC) parasympathetic relaxant nerves are the primary relaxant nerves innervating
airway smooth muscle.
Studies indicate that muscarinic cholinergic inhibition of beta-adrenergic cardiac
responses may be modulated in part by nitric oxide (NO)
Consequences of Excessive Nitric Oxide
•
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Leaky blood brain barrier
Neuro degeneration
Demyelination
Degradation of mucin (protective for the gut)
Increases intestinal permeability
Inhibits gall bladder contraction
Mediates slow transit constipation
McGinnis, W. Oxidative Stress in Autism, Alternative Therapies 10(6), 2004.
AMMONIA
Glutathione S Transferase
Glutathione conjugation: Glutathione is a tripeptide (gglutamylcyteinylglycine, with the amino acid residues color
coded in the structures below). It is used in cells as a recyclable
anti-oxidant as well as a conjugating agent. When used in
conjugation it is initially conjugated by a glutathione-Stransferase, or sometimes as a simple chemical reaction.
Generally the conjugation occurs as a nucleophilic attack by the
-SH group on a reactive electrophilic center. Conjugation is often
followed by metabolic cleavage of the peptide to leave only the
cysteinyl residue, which may then be acetylated to give a
mercapturic acid.
Of course not all glutathione derivatives are further metabolized,
some may be excreted as is. However, if the derivative is
excreted via the bile, it may be metabolized by the gut fauna and
the toxin may be reabsorbed.
Example:
1. Glutathione S-transferase:
2. g-glutamyltranspeptidase:
3. cysteinyl glycinase:
4. N-acetyl transferase:
www.humboldt.edu/.../C451LecNotesar10.html
GSTM1
GSTP1
GSTT1
•
GST enzymes bind glutathione to products of detoxification reactions to aid in
excretion from the body.
•
Mutations in the GST enzyme pathway may be liberally supplemented with sulfur
donors as well as with glutathione, except for individuals with CBS C699T + +
mutations.
Glutathione supplementation would include the use of topical glutathione, oral
glutathione, IV glutathione could be considered with the addition of NADH.
Also supplementation with NAC (500mg per day), vitamin C with rose hips (500mg two
to three times per day), vitamin E with mixed tocopherols, and selenium. These
supplements will help to maintain and regenerate healthy glutathione levels.
Consider Thione sublingual glutathione.
Consider LipoFlow glutathione which is encapsulated in liposomes to enhance
delivery.
Consider supplementation with sulfur donors, these would include taurine, broccoli
extract, glucosamine and/or chondroitin.
•
•
•
•
•
•
•
•
High levels of cysteine lead to the formation of taurine rather than glutathione.
Reduced levels of cysteine favor the formation of glutathione
CBS mutations lead to decreased levels of glutathione. Yet may create greater
sensitivity to glutathione and other sulfur containing compounds.
•
Complicating mutation : CBS C699T + +
AMMONIA
SOD
Superoxide dismutases are an ubiquitous family of enzymes that function to
efficiently catalyze the dismutation of superoxide anions. Three unique and highly
compartmentalized mammalian superoxide dismutases have been biochemically
and molecularly characterized to date. SOD1, or CuZn-SOD (EC 1.15.1.1), was the
first enzyme to be characterized and is a copper and zinc-containing homodimer
that is found almost exclusively in intracellular cytoplasmic spaces. SOD2, or MnSOD (EC 1.15.1.1), exists as a tetramer and is initially synthesized containing a
leader peptide, which targets this manganese-containing enzyme exclusively to the
mitochondrial spaces. SOD3, or EC-SOD (EC 1.15.1.1), is the most recently
characterized SOD, exists as a copper and zinc-containing tetramer, and is
synthesized containing a signal peptide that directs this enzyme exclusively to
extracellular spaces. What role(s) these SODs play in both normal and disease
states is only slowly beginning to be understood. A molecular understanding of
each of these genes has proven useful toward the deciphering of their biological
roles.
Free Radic Biol Med. 2002 Aug 1;33(3):337-49.
Zelko IN, Mariani TJ, Folz RJ.
Superoxide dismutase multigene family: a comparison of the CuZn-SOD (SOD1), Mn-SOD (SOD2), and
EC-SOD (SOD3) gene structures, evolution, and expression.
SOD Reaction
http://cropsoil.psu.edu/Courses/AGRO518/IMG00024.GIF
SOD
•
•
•
•
•
Free oxygen radicals are extremely reactive and can cause damage
to the body. The oxygen free radical is also known as super oxide
radical.
Super oxide can be converted to even more damaging radicals by a
chain reaction.
Radicals are highly reactive and unstable, and will attack any
molecule in the body.
SOD enzymes scavenge and destroy free radicals in the body,
including super oxide radicals. Organ or tissue damage can occur
whenever production of free radicals exceeds that of free radical
scavenger enzymes such as SOD.
There are several types of SOD:
SOD1 or CuZnSOD = Intracellular (cytosolic) SOD
SOD2 or MnSOD = Mitochondrial SOD
SOD3 or EcSOD = Extracellular SOD
•
Complicating mutation : CBS C699T + +
AMMONIA
Fragile X
•
•
•
•
DNA methylation
FMRP is an RNA binding protein
Excessive glutamate
Decreased pruning
Glucose 6 Phopshate
Dehydrogenase (G6PD)
Labcorp
Number001917
CPT82955; 85041
Synonyms G6PDH; G6PD, Quant, Blood and RBC;
G6PD, Quantitative,
Blood Test Includes Quantitative G6PD; red blood
cell count (RBC)
The Hexose Monophosphate Shunt
G6PDH and Blood Sugar
• Hexokinase converts glucose into a form
that is trapped in the cells.
• Hexokinases are inhibited by Glucose 6
phosphate dehydrogenase accumulation
Inhibitory effects of various sulfur compounds on the activity of
bovine erythrocyte enzymes.
Khan AA, Schuler MM, Coppock RW.
J Toxicol Environ Health. 1987;22(4):481-90
Studies were conducted to assess the in vitro effects of selected
sulfur compounds on the activities of superoxide dismutase
(SOD), catalase, glutathione peroxidase (GSHPX), and glucose6-phosphate dehydrogenase (G6PDH) in hemolyzates of
bovine erythrocytes. All sulfur compounds produced
concentration-dependent inhibition in the activities of these
enzymes, but their effects on each enzyme were different. SOD
and catalase activities were most sensitive to sulfide (S2-),
followed by sulfite (SO3(2-)) and sulfate (SO4(2-)). GSHPX
activity was most sensitive to SO3(2-), followed by S2-, cysteine
and SO4(2-). The activity of G6PDH, however, was maximally
inhibited by reduced glutathione (GSH), followed by SO3(2-) and
SO4(2-); S2- was inhibitory only at high concentrations. Dialysis
of the S2- and SO3(2-)-inhibited enzymes resulted in complete or
partial reversal of inhibitory effects. The biochemical significance
of these effects in relation to erythrocyte physiology is discussed.
The effect of N,N'-p-phenylenedimaleimide (PMD) on deoxygenation-induced
K loss in sickle erythrocytes.
Wall SN, Berkowitz LR.
J Toxicol Environ Health. 1987;22(4):481-90
Am J Med Sci. 1987 Aug;294(2):105-9
A variety of thiol reactive agents have been found to have antisickling
properties thought to be due to the ability of these drugs to bind to
hemoglobin, resulting in increased hemoglobin-oxygen affinity. Because thiol
reactive agents also influence K movements in red cells and deoxygenation
leads to K loss and Na gain in sickle erythrocytes, the authors investigated
the possibility that deoxygenation-induced K loss could be influenced by thiol
agents, independent of an effect on hemoglobin-oxygen affinity. Experiments
were performed with the thiol crosslinking agent N,N'-pphenylenedimaleimide (PMD). The authors found that PMD inhibited
deoxygenation-induced K loss in sickle erythrocytes. This effect was not due
to sickling inhibition as PMD-treated cells gained Na with deoxygenation, nor
could the effect be explained by monofunctional PMD binding to membrane
sulfhydryl groups, as a monofunctional analogue of PMD was not able to
retard deoxygenation-induced K loss. These findings support a role for
membrane sulfhydryl groups in deoxygenation-induced K movements in
sickle red cells and suggest that this K loss may be prevented by
crosslinking of certain membrane sulfhydryl groups.
G6PD deficiency is caused by one copy of a defective G6PD gene in males
or two copies of a defective G6PD gene in females. Hemolytic anemic
attacks can be caused by oxidants, infection, and or by eating fava beans.
Sudden attacks of G6PD deficiency can be caused by
any serious illness and certain medicines such as:
Medicines for the treatment of malaria: Chloroquine, Primaquine,
Pamaquine, Pentaquine, Plasmoquine, Quinine, Quinocide
Medicines for fever and pain: Acetanilid, Acetylsalicylic acid, Aminopyrine,
Antipyrine
Sulphonamides: Sulphanilamide, Sulphacetamide, Sulphapyridine,
Sulphamethoxypyradizine
Sulphones: Sulphoxone, Thiazolsulfone, Diaminodiphenyl Sulphone
Nitrofurans: Nitrofurantonin, Furazolidone, Nitrofurazone
Others: Phenylhydrazine, Acetylphenylhydrazine, Probenecid,
Dimercaprol(DMSA), Methylene blue, Naphthalene, Vitamin K,
Aminosalicylic acid, Chloramphenicol, Vitamin C (only in very high doses),
Neosalvarsan
Glucose-6-phosphate dehydrogenase deficiency
promotes endothelial oxidant stress and decreases
endothelial nitric oxide bioavailability
JANE A. LEOPOLD2, ANDRE CAP, ANNE W. SCRIBNER, ROBERT C. STANTON* and JOSEPH LOSCALZO
Deficient G6PD activity is
associated with a reduction
in NADPH stores, which in
turn may influence levels of
BH4.
Impact of G6PDH Deficiency
•
•
•
•
•
•
•
•
Decreased CO2
Glucose imbalances
Increased AGE (advanced glucosyl end products)
Decreased NADPH
decreased BH4
Decreased reduced glutathione
Decreased sugars for ATP,CoA,NAD,FAD, DNA, RNA
Decreased Nitric Oxide availability
Increased pyruvate
Factors Affecting G6PDH Levels
•
•
•
•
•
•
•
•
•
•
•
•
•
Thyroid hormones increase the level
High carbohydrate diets increase the level
Insulin increases the level (relationship to vitamin D)
Adrenal support increases the level
EGF increases the level
Estrogen increases the level
PDGF increases the level
Fatty acids decrease the level
Cortisol decreases the level
Copper decreases the level
High vitamin C may be an issue
High dose of vitamin K3 (synthetic menadione) may be an issue
DHEA inhibits G6PDH activity
Additional Resources
•
Glutamate and Gaba
– Neurological Inflammation
•
Virus, Metals, Methylation
– Austin Conference, November 2004
– Phoenix Conference, April 2005
•
Factors Contributing to Autism
– Putting It All Together Parents Weekend
– Boston Conference, August 2004
•
Genetics of Autism
– Personalized Medicine DVD/ Implications of Genetic Testing Book
•
RNA
– Boston Conference, August 2004
www.holistichealth.com
www.holisticheal.com
www.autismanswer.com Parents chatroom
www.longevityplus-rna.com

Personalized Medicine

Transcription

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