Down syndrome, vaccinations

and genetic susceptibility

to injury
What does the research show?

Laurette Janak
Autism One
May 2009

Email: laurette.janak@verizon.net
 Overview
Description of Down syndrome
Down syndrome autism prevalence
Down syndrome and mercury sensitivity
Down syndrome & mitochondrial dysfunction
Cancer and vaccines; is there a connection?
Down syndrome and aluminum sensitivity
One-size-fits-all philosophy
Vaccines and immune overload
Scenario for DS injury from vaccines
Future directions of study
 Common knowledge about DS

• Characteristic facial features

• Learning challenges
• Immune system deficiencies
• Mitochondrial dysfunction
• Adverse reaction to some pharmaceuticals
• High occurrence of celiac disease
• Diabetes
• Advanced aging with early development of
Alzheimer’s disease or dementia
• A 15-20 fold increased risk of leukemia
Genetics of Down syndrome

Extra chromosome 21
Why shed light on DS at an
autism conference?
• Medical literature shows autism
within the DS population to be
in the range of 5-11% (1)

• Much is known about the

genetics, biochemistry and
neurology of DS.
Why shed light on DS at an
autism conference?
• Can we learn anything about why
the unique genetics of DS
increase the risk for the
occurrence of autism?

• Can this knowledge then be applied

toward understanding an autism
risk within the general
population?
 Subjectivity verses
Objectivity

It’s down
syndrome
It’s just down
syndrome. and
autism.
 Neuroanatomic correlates of autism
and stereotypy in children with
Down Syndrome (Neuroreport. 2008 Apr 16;19(6):653-6)

Included MRIs of 15 children with

DS, 15 children with DS-ASD and
22 controls.
DSM-IV criteria was used for ASD
diagnosis.
Aberrant Behavior Checklist (ABC)
Irritability
Lethargy
Stereotypy (repetitive movements)
Hyperactivity
Inappropriate speech
 Mean ABC scores
All DS DS only DS-ASD
Irritabili
ty 7.1 2.3 11.9
Lethargy 9.3 2.5 16.1
Stereotypy 6.9 0.7 13.1
Hyperactiv
ity 11.7 4.7 18.7
Inappropri
ate 1.5 0.1 2.9
speech
Total
score 36.4 10.2 62.7
 MRI findings
Brain volumes were significantly
decreased in DS versus controls.

A distinguishing feature of
significantly more white matter in
the brainstem and cerebellum of DS-
ASD children compared to DS alone.
This pattern resembles that seen in children
with autism alone.
Increased white matter correlated with the
ABC stereotypy subscale score.
 Subjectivity verses
Objectivity

It’s down
syndrome
It’s just down
syndrome. and
autism.
Chicken or the Egg

Autism Oxidative
stress
 Early oxidative stress in amniotic fluid of
pregnancies with Down syndrome
Clin Biochem. 2007 Feb;40(3-4):177-80

Tested the hypothesis that oxidative stress

occurs early in DS pregnancies
Measured Isoprostanes (IPs) in the amniotic fluid
of DS pregnancies as a marker of free radical
damage to lipids
A 9-fold increase in IPs was found in the
amniotic fluid of pregnancies with DS fetuses
Early oxidative stress in amniotic fluid of
pregnancies with Down syndrome.
Clin Biochem. 2007 Feb;40(3-4):177-80

• Oxidative stress
occurs early in a DS
pregnancy and
appears to
“predispose patients
to oxidative injury
that begins in utero,
as a result of gene
loading.”
• Oxidative stress begins in-utero in DS. Oxidative
stress is implicated in neurodegenerative disorders.

• What happens if an infant with DS is exposed to

things that worsens their oxidative stress?

• What types of exposures could do this?

 Glutathione Utilization
Over expressed in Down syndrome
Cysteine (glycine, glutamate)

GST Detoxification of
SOD L drugs and
H2O2 GSH chemicals

GPx GR

H2O GSSG
Up-regulated by metal
exposure

GSH: glutathione
GST: glutathione transferase
GSSG: oxidized glutathione
SOD: superoxide dismutase
GR: glutathione reductase
H2O2: hydrogen peroxide
GPx: glutathione peroxidase
 Notes on
 A major
glutathione
antioxidant made in the body

 Has antiviral properties

 Removes heavy metals from the body

 Is needed for detoxification of many

chemicals and pharmaceutical drugs

 Protects against DNA & mitochondrial

damage

 Found to be low in children with DS

 IOM 2004
With respect to the hypothesis that there
may be a subgroup of children who are
genetically more sensitive to the toxic
effects of thimerosal (a mercury
preservative found in vaccines), the IOM
had this to say:
“This hypothesis cannot be excluded by
epidemiological data from large population
groups that do not show an association
between a vaccine and an adverse
outcome. Depending upon the frequency of
the genetic defect, a rare event caused by
genetic susceptibility could be missed even
in large study samples.”
 Before After
Studies showed that the
overexpression of SOD and
increased oxidative stress
occurs in Down syndrome

Heavy metals (including

mercury) increase oxidative
stress and upregulates SOD

2004 IOM
declaration
 Before After

Studies showed decreased

levels of GSH in DS
•J Pediatr. 2003 May;142(5):583-5.
•Am J Hum Genet. 2001 Jul;69(1):88-95.

Mercury and other metals

deplete GSH in a dose-
dependent manner
•Immunopharmacol Immunotoxicol. 1993
Mar-Jun;15(2-3):273-90.

2004 IOM
declaration
 Before After
An animal model of DS which showed
decreased GSH in hippocampal neurons
stated:

–“Additional lowering of GSH levels

led to enhanced cell death…..Based
on these results we suggest that a
GSH level which is decreased under a
specific threshold by increased
consumption, reduced synthesis or
lack in precursor contributes to cell
loss and neurodegeneration in Down
syndrome.”
–Brain Res 1997 Aug 15;765(2):313-8

2004 IOM
declaration
 Before After
Animal models and human
studies have found cholinergic
dysfunction in DS
•Eur J Neurosci. 2000 Sep;12(9):3259-64.
•Brain Res. 1994 Sep 26;658(1-2):27-32.
•Neurosci Lett. 1997 Feb 7;222(3):183-6.

Exposure to mercury can induce

cholinergic dysfunction
•J toxicol Sci 1979 Nov;4(4):351-62
•Res Commun Chem Pathol Pharm 1980
Nov;30(2):381-4
•Brain Res Dev Brain Res 1995 Mar
16;85(1):96-109

2004 IOM
declaration
 Before After

Other abnormalities that

are noted in DS and may
be impacted by mercury
exposure include:
•Calcium dysregulation
•Alterations in glutamate
metabolism
•Autoimmune disorders
•Leukemia

2004 IOM
declaration
 Before After

Despite all that was known about

both DS and the mechanisms by
which mercury induces toxicity…

I have been unable to find any study

that has investigated the toxic effects
of thimerosal in individuals with DS.

2004 IOM
declaration
Before After
A 2004 in-vitro animal study
investigated thimerosal’s effect
on cells suffering from
oxidative stress induced by
hydrogen peroxide (H2O2); a
situation similar to that found
in DS:
–The toxicity of thimerosal was,
“greatly augmented when the
cells suffered oxidative stress
induced by (H2O2).” Toxicol In Vitro
2004 Oct;18(5):563-9.

2004 IOM
declaration
The BIG Question
• Does this mean
mercury exposure
in DS individuals
causes autism?

– not necessarily

BUT…
 Another BIG Question
• Should such a
damaging agent be
given to a DS
population, all of
whom are at high
risk for
neurodegeneration
and Alzheimer’s ?
 November 9, 2007

U.S. Government
conceded a vaccine-
autism case in the
Court of Federal
Claims
Vaccinations
aggravated an
underlying
mitochondrial
disorder
resulting in
features of
Media
Puppets
Mitochondrial
disorders are
rare!
 Mitochondria in DS
✏ It is extremely well documented that Down
syndrome individuals have mitochondrial dysfunction.
✏ The nature of this dysfunction is multi-factorial &
includes:
✏ Impaired mitochondrial enzyme activities
✏ Cytochrome oxidase (complex IV)
✏ Isocitrate dehydrogenase (Krebs cycle enzyme)
✏ Decreased protein levels of complex I
✏ Decreased gene expression of ATPase6 (effects functioning of complex
V)
 Mitochondria in DS
✏ Accumulation of toxic free radicals
begins in-utero.
✏ Clin Biochem. 2007 Feb;40(3-4):177-80

✏ Studies on fetal DS brain and in fetal DS

amniocytes demonstrate mitochondrial
dysfunction occurs prior to birth.
✏ J Neural Transm Suppl. 2001;(61):109-16.
✏ Mol Cells. 2003 Apr 30;15(2):181-5.
More Questions
• Are vaccines also
aggravating the
underlying
mitochondrial
dysfunction in
children with DS?

• Could this explain

the vastly higher
incidence of
autism among
children with DS?
 Mitochondria in DS/ASD
• DS mitochondria have a
lower mitochondrial
membrane potential
which, is “underlying the
presence of an increasing
susceptibility of these
organelles to damaging
agents”.
– FEBS Lett. 2007 Feb 6;581(3):521-5.

CAN THIMEROSAL BE
ONE OF THESE
Cristae - the site of the electron transport chain “DAMAGING AGENTS”?
Matrix- the site of the citric acid cycle
Mitochondria and Thimerosal
• Thimerosal induces programmed cell
death via the mitochondrial pathway by
inducing oxidative stress and depletion of
glutathione (GSH).
– Genes Immun 2002 Aug;3(5):270-8
thimerosal Does dose
make the
poison
 GSH
GSH

GSH

GSH
H
GS

thimerosal H
GS

GSH GSH

Glutathione (GSH) protects against

thimerosal induced apoptosis (cell death)
Genes Immun 2002 Aug;3(5):270-8
 GSH

Cell Death
GSH

thimerosal

GSH

SAME DOSE of
thimerosal as
in previous Lower GSH in DS
slide! leaving cells more
vulnerable to
toxins
 GSH

QuickTimeª and a
decompressor
are needed to see this picture.

Low glutathione levels can make people

more sensitive to DNA damage from a
variety of mutagenic environmental
exposures.
 Illuminating Cancer in DS and Autism
• Cancer in DS and ASD
– Children with DS have a 15-20 fold increased
occurrence of leukemia.

– Individuals with autism have an increased

mortality from cancer.
• J Autism Dev Disord 2001 Dec;31(6)569-76
» (this was a small study)

– “We have seen the co-occurrence in families of

autism and leukemia”
– NIH Autism Research Network
http://www.autismresearchnetwork.org/AN/IACC/wfAim.aspx?Aim=4
 Illuminating Mercury as a Mutagen

• It has been clearly demonstrated that mercury at low

levels is a mutagen.

• The mutagenic property of mercury has been shown to

be causally related to its ability to induce H2O2.
• Environ Mol Mutagen 1998;31(4):352-61

• Therefore: children with low glutathione may be at

higher risk for cancer from exposure to heavy metals
and other environmental toxins.
 Illuminating Metal DNA Damage in DS

“The mechanism of carcinogenesis in Down

syndrome could be explained by our findings:
SODs enhance metal-mediated DNA damage
induced by H2O2. We conclude that SODs may
increase the frequency of mutations due to
oxidative DNA damage in cells, increasing
carcinogenic potential.”
» FEBS Lett. 2001 Apr 27;495(3):187-90.
 Illuminating Mercury and Leukemia

• Biological mechanisms are consistent with

epidemiology studies showing an increased mortality
from leukemia with exposure to mercury.

– Age standardized cancer mortality ratios in areas heavily exposed to

• N.Int Arch Occup Environ Health. 2007 Aug;80(8):679-88.

– Cancer mortality in Minamata disease patients exposed to

methylmercury through fish diet.
• J Epidemiol. 1996 Sep;6(3):134-8.
 Poster Presentation April 9, 2002
American Association for Cancer Research Annual Meeting (2)

Epidemiologica
l association
of Hep B
vaccine and
risk of acute
lymphocytic
leukemia.
Suggested mechanism
Thimerosal
 Thimerosa
l

Hep B Leukemi
vaccine a
?
• 167 matched case-control pairs from the Northern California
Childhood Leukemia study diagnosed 1995-1999 (3)

• OR = 2.6 for 3 or more doses of Hep B vaccines

• OR = 5.0 for 3 or more doses of Hep B vaccine during infancy

• Thimerosal free Hep B vaccines became available in Fall 1999

– MMWR July 21, 2000 / 49(28); 642,651
Safety of immunization and adverse events
following vaccination against hepatitis B.
J Hepatol. 2003;39 Suppl 1:S83-8.

• “…the safety of hepatitis

B vaccine has repeatedly
been under attack.”

• By claims of being
associated with: RA,
diabetes, MS, “and more
recently lymphoblastic
leukemia.”
 Following the thread of science

Int J Epidemiol. 2005 Oct;34(5)

• “Receiving three or more doses of hepatitis B vaccines

during infancy appears to be associated with an increased
risk of overall leukemia and ALL among children who were
born in or before 1995, but the associations were only of
borderline significance.” OR = 1.8

• Thimerosal vs thimerosal free Hep B not considered

 Following the thread of science

Int J Epidemiol. 2007 Feb;36(1):110-6

• Childhood leukemia diagnosed 2003-2004 in France

• 53.8 % of the cases were 4 years old or less at time of diagnosis

• Likely that many received thirmerosal free Hep B

• No association found
1999 thimerosal free Hep B introduced in U.S.

2002 OR = 5.0 for 3 or more in infancy

OR = 2.6 for 3 or more
case cohort (1995-1999)

2005 OR = 1.8 on or before 1995

OR = 1.08 (after 1995 )
Case cohort (1995-2002)

2007
No association
 Glutathione and Mild Infections

Common childhood illness such as ear

infections (otitis media) and tonsillitis:
serum antioxidant
vitamins
levels of glutathione (GSH)
malondialdehyde - a marker of oxidative stress
Cemek et al. 2005
Vaccination during Mild Illness
• In 1996, JAMA reported it is safe to give
MMR to children who presented with mild
illnesses such as upper respiratory
infection, otitis media and diarrhea.
• (King GE et al., 1996)

– Position supported by the American Academy of

Pediatrics (AAP).
 Glutathione and Measles
• Viral infections such as measles can decrease
GSH and other antioxidants.
• Cemek et al. 2007

• CAN THE MEASLES VACCINE DO THE SAME?

Measles Vaccine and Glutathione
• I could not find a study
with respect to measles
vaccination and
glutathione.

• Then how do we know

measles vaccine is not
causing damage
especially when given
during a course of mild
illness in susceptible
children such as
children with DS who
already have low GSH?
 DNA Repair in DS

• Individuals with DS
QuickTimeª and a have poor DNA
decompressor repair mechanisms.
are needed to see this picture.
• So viral DNA
damage can be
more problematic in
persons with DS.
 Measles Viral Damage in DS
• “…to gain insight into the relation between
Down’s syndrome and leukemia, we have
compared the incidence of chromosomal
QuickTimeª
breakage in lymphocytes and a
from children
with Down’s syndrome and those from
decompressor
normal children before and after measles
areinfection.”
needed to see this picture.
• “Patients with Down’s syndrome show
more chromosomal breaks after virus
infection than do normal control
subjects.”
• Pediat Res 7: 582-587 (1973) Higurashi
 What We Knew Then…
Chromosomal breaks have been documented
in patients receiving attenuated measles vaccines.

– “Breakage here was of the same type as seen with

the clinical disease.”
• Am J Hum Genet. 1966 Jan;18(1):81-92

Reconfirmed vaccine
breakage in both DS and QuickTimeª and a
decompressor
are needed to see this picture.
typical children.
Ilyinskikh NN 1981
 Vaccines and Chromosomal Damage
“…study on the effects of the vaccines on the
hereditary material of the inoculated organisms is
very meager, although it is directly concerned with
human health.”

“…the chromosomes of male mice are

comparatively more susceptible to aberration on
exposure to measles vaccine than that of the
female mice.”
Int J hum Genet, 3(1): 51-58 2003
 Of Mice and Men

QuickTimeª and a
decompressor
are needed to see this picture.

• Clastogenicity of “rubella vaccine in mouse bone

marrow, recorded here, is in agreement with the
earlier reports on the induction of chromosomal
breaks in human embryonic cell cultures.”
• Int J hum Genet, 3(1): 51-58 2003
 More Study Needed

• “Further study is essential to unveil the

exact mechanism of the clastogenic action
of different vaccines on the hereditary
materials of the inoculated organisms.” Int J
Genet, 3(1): 51-58 (2003)

• DO UPCOMING VACCINES UNDERGO

TESTING ON THE CLASTOGENIC
PROPERTIES OF THE VACCINE PRIOR TO
PUBLIC RELEASE?
• sanofi pasteur Influenza Virus Vaccine, H5N1
HIGHLIGHTS OF PRESCRIBING INFORMATION
http://www.fda.gov/cber/label/h5n1san041707LB.pdf

Safety and effectiveness have NOT been established in

pregnant or lactating women, and in pediatric and geriatric
populations.

Each dose contains 50 ug mercury; you get 2 doses over a 28

day time frame.

The clinical trials used an “investigational” vaccine that did

NOT contain any mercury.
• “There are no data to assess the concomitant
administration of Influenza Virus Vaccine, H5N1,
with other vaccines.”

• “Influenza Virus Vaccine, H5N1, has NOT been

evaluated for carcinogenic or mutagenic potential,
or for impairment of fertility.”
 Think on this

• A child with DS who has

constitutionally low GSH arrives at the
doctors office for her MMR
 Think on this

• The child is cleared for vaccination

despite having an ear infection
– Ear infections can lower GSH
 Think on this

• Measles vaccine can damage DNA

– Remember: DS individuals have poor DNA
repair mechanisms

QuickTimeª and a
decompressor
are needed to see this picture.
 Think on this

• Instructed to give acetaminophen (Tylenol)

to help with pain and/or fever
– Can reduce GSH
– Can cause transitory decreases in DNA repair
ability

QuickTimeª and a QuickTimeª and a

decompressor decompressor
are needed to see this picture.
are needed to see this picture.
 Think on this

• Because this child has DS it is

recommended that she have a flu shot.
– Flu shots still contain thimerosal
• Can decrease glutathione further

QuickTimeª and a
decompressor
are needed to see this picture.
 Think on this

• Depletion of GSH below a certain

threshold has been implicated in the
process of neurodegeneration in DS
– Stabel-Burrow et al., 1997
 Think on this

• Low GSH is a risk factor for leukemia

– Increased prevalence of leukemia in DS
Bacterial infections, immune overload,
and MMR vaccine
Inclusion criteria; hospitalization for:
meningococcal infection
septicaemia
bacterial meningitis
pyogenic arthritis
acute osteomyelitis
lobar (pneumococcal) pneumonia

“Cases in children with additional diagnostic

codes indicating an underlying disorder
predisposing to bacterial infection, such as
immunosuppression, malignancy, cystic fibrosis,
congenital heart, defect, or a cerebrospinal fluid
shunt were excluded.”
Full text available at: http://adc.bmj.com/cgi/reprint/88/3/222
 Vaccinated vs. Unvaccinated

• “For the majority of the vaccines in the study, the

unvaccinated group was primarily composed of
children vaccinated with other vaccines.”

• “…using only hospitalization, presumably

representing the more severe cases of infectious
disease, as our study outcome is a limitation.”
– Childhood Vaccination and Nontargeted Infectious Disease
Hospitalization JAMA 2005;294(6):699-705
 QuickTimeª and a
decompressor
are needed to see this picture.

Aluminum containing
vaccines
and
Down syndrome
 Facts about aluminum
• In typical healthy people,
the gastrointestinal tract
excludes greater than 95%
of dietary Al.

• Even with normal renal

QuickTimeª and a
excretion, tissue
decompressor
accumulation of Al
are needed to see this picture.

occurs.
 Facts about aluminum

• “…infants may be at risk from aluminum toxicity

when consuming formula containing > 300
micrograms/L”

• Mean aluminum concentrations in milks:

– Breast milk 9.2 ug/L
– Soy 534 ug/L
– Casein hydrolysate 773ug/L
– J Pediatr Gastroenterol Nutr 1994 Nov; 19(4):377-81
 Side note

Breast-feeding reduces risk of:

Acute otitis media
Non-specific gastroenteritis
Lower respiratory tract infections
Atopic dermatitis
Asthma (young children)
Obesity
Type 1 and 2 diabetes
Childhood leukemia
Sudden infant death syndrome
Evid Rep Technol Assess . 2006
Necrotizing enterocolitis
Apr;(134):1-161.
 Facts about Aluminum

• The mean
aluminum
absorption in
Alzheimer’s
disease (AD)
exceeds controls
by a factor of 1.64
– Moore PB et al,, 2000
 Facts about Aluminum

• The mean aluminum

absorption in DS
exceeds that of
controls by a factor of
6.

– Moore PB et al., 1997

 Facts about Aluminum
• “Our findings suggest that it may be prudent to
minimize the uptake of Al from the diet of patients
who are at high risk of developing Alzheimer-type
pathology, in particular DS patients, subjects with
a strong family history of AD, and patients who
are showing early signs of cognitive decline.”
• Moore PB et al., 1997
 Facts about Aluminum

Are DS and AD patients warned about the

amount of aluminum used in vaccines?

Where are the safety studies on injected

aluminum in these populations?
One-size-fits-all?
• Celiac Disease
– Varying prevalence depending
on country
– 0.3-1% general population
– 4.6%-13% in DS
• Hep B Vaccine
– 53.9% of children with
untreated celiac are non-
QuickTimeª and a
decompressor
are needed to see this picture. responders to the Hep B
vaccine. Park et al 2007
– Response rate of 95% with
gluten free diet. Nemes et al 2008
• Testing for Celiac in DS
 IOM 2004
Epidemiology vs Biological Studies
IOM is correct; you cannot determine subgroups of
sensitive persons from large epi studies

The biology of DS is consistent with

what the medical literature indicates for
increased damage from exposure to
mercury, aluminum & viruses.

One group of genetically

sensitive individuals means it is
likely that there are others.
 Future directions
» Studies should be conducted by
independent researchers with no
conflict of interest.

» Emphasis should be on biological

mechanisms not epidemiology.

» DS/autism studies should receive

the same level of vigor as those of
DS/Alzheimer’s and DS/leukemia.
How confident do I feel that sufficient
biological studies have been done on
mandatory vaccines?
 Thank you for
touching my life!
 References
• Carter et al., 2008; Lowenthal et al., 2007;
Zafeiriou et al., 2007; Kentet al., 1999
• Ma X, Does M, Buffler PA, Wiencke JK.
Immunization and risk for childhood leukemia --
preliminary results from the Northern California
Childhood Leukemia Study, a poster presented
at American Association for Cancer Research
Annual Meeting, San Francisco, April 9, 2002
• Vaccination history and risk of childhood
leukaemia.Ma X, Does MB, Metayer C, Russo C,
Wong A, Buffler PA.Int J Epidemiol. 2005
Oct;34(5):1100-9
• Ramesh C. Choudhury and Pramod K. Sahu
Clastogenic Potential of Certain Vaccines on
Bone Marrow Cells of Swiss Mice
Int J Hum Genet, 3(1): 51-58 (2003)
 Down syndrome, vaccinations
and genetic susceptibility
to injury
What
the
research
showed

Laurette Janak
Autism One
May 2009

laurette.janak@verizon.net