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Diagnosis and treatment of autism considering features of the genetic background and metabolic status

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Title: Diagnosis and treatment of autism considering features of the genetic background and metabolic status


1
Diagnosis and treatment of autism considering
features of the genetic background and metabolic
status
Ukrainian Institute of Clinical Genetics of
KNMU Member-correspondent of NAMS of Ukraine,
M.D., professor E.Y. Grechanina
1
2
  • Genetic bases of many human diseases are
    successfully studied for last 20 years.
  • Confession of World Health Organization that the
    basis of somatic , psychic and reproductive
    health is genomic health contributed this
    success.
  • In opinion of H.Y. Zoghbi et al., Beaudet (2010)
    studying relationship between genotype and
    phenotype gives challenge for clinicists and
    researchers because some observations cant be
    explained so easily.

2
3
GENE INTERACTION
Nuclear DNA
Mitochondrial DNA
Gene 2 ACGTAGCTAG
Gene 1 ACGTAGCTAG
Substitution of gene fragment
Gene 2 ACGAG?CTAG
GENOMIC HEALTH
EPIGENETIC FACTORS
ENVIRONMENTAL FACTORS
3
4
Genomic health somatic, psychic, reproductive
health
4
5
  • The role of the epigenome (changes of genetic
    information without changes of DNA nucleotides
    sequence) in normal as well as in pathological
    physiology of the genome.

5
6
  • Many researchers proved that the causes of many
    inherent diseases are epigenetic mutations, which
    can change DNA methylation.

6
7
  • By Ellis data, relationship between human genome
    and epigenome extended type range of molecular
    events, which cause human diseases.
  • They can be de novo mutations or inherited from
    previous generations, genetic or epigenetic and
    can be a result of the influence of environmental
    factors.

7
8
  • The appearance of convincing information about
    that environmental factors (at the first place
    nutritional pattern) change the epigenome (DNA
    methylation) gave us better understanding the
    pathogenesis of human multifactorial diseases and
    at the first place neurological disorders and
    psychic diseases.

8
9
  • At the beginning of genetics creation, the well
    known psychiatrist, professor Bocherikov asked
    me, beginner genetician, to prove that psychic
    disorders are material.
  • Very long professional way led to this
    understanding.

9
10
  • We have to solve problems of thousands of
    children we have no alternative we have to
    look at these problems, try to find out all
    details, to consider the point of view of
    everybody, whom this regards and out best for
    agreement achievement.The necessity to achieve
    the success is the another cause, where we need
    to use the antagonism between different points of
    view of the problem and the sooner the better.
    Let (all) voices be heart in discussion, let they
    try to come to understanding, and dont try to
    shout down each other.

10
11
  • Autism becomes one of the global human problem.
    It influences on many sides of physical life and
    spiritual life. It requires from us emergent
    development and introduction of a new paradigm of
    medicine 4 ? ? -predictive, prognostic,
    preventive, partner.

11
12
  • Parents of children with autism and doctors
    become partners. The sooner this partnership is
    achieved, the sooner this problem will be solved.
  • Parents all day persons on duty for their
    children,thats why their information is
    invaluable, although it sometimes require medical
    correction.
  • As soon as the resonance between partners is
    established, the next autistic child will begin
    to speak.

12
13
  • A doctor, who received information from analysis
    and phenotype assessment of a patient, has to be
    at the head of the triangle child-parents-doctor
    with all responsibility in the process of
    search of the truth.
  • Considering this I allow myself to analyze our
    way to understanding autism and desire to help.
  • Everybody who will hear us, will be heard by us.

13
14
  • Autism heterogeneous syndrome, which is
    characterized by disorders in ? 3 central domains
    (fr. Domaine- area)
  • Social interaction
  • Speech
  • Interests
  • and expressed genetic and phenotypic
    heterogeneity.

14
15
Autism the most severe result of disorders of
nervous system development which is referred to
autistic spectrum disorders (ASD). The frequency
of incidence of ASD 37 in 10 000 Boys are
prevalent, especially in clinically severe
cases. The frequency of autism 13 in 10
000. Women/men ratio 41 (in severe forms
11) The frequency of Asperger syndrome 2,610
000 Women/men ratio 81
15
16
  • The main feature of modern knowledge about ASD
    its uncertainty.
  • Many parallel approaches are necessary to
    understand genetic factors which underlie ASD
  • Studies of the whole genome
  • Associative studies
  • Revealing mutation
  • Expansion of clinical genetic examination of
    probands and their relatives

16
17
  • Established genetic basis of autism
  • Increase of the number of publications confirming
    that mutation and structural changes in any of
    several genes can significantly increase the risk
    of this disease.
  • If the diagnosis of autism is established in a
    child, the risk for the family will be 25 tomes
    higher.
  • Cognitive behavior features, which are similar to
    those observed in probands, are more likely
    observed in sibs and parents of an ill child than
    in controls .
  • Independent studies of twins show concordance for
    monozygotic twins 70-90 , for dizygotic twins
    from 0 to 10.

17
18
Molecular studies of genes identified by nowadays
show that no one molecular explanation will be
enough.
18
19
  • Many studie indicate system course of disorders
    in ASD development.
  • Different influence of maternal and paternal
    15q11 in ASD is an important confirmation of
    cytogenetic disorders.
  • It is supposed that different molecular events
    are at the level of systems.

19
20
In recent years greater number of associated with
autism syndromes are found (Tab. 1).
20
21
Table 1 Syndromes associated with ASD
? Syndromes Genes which are associated with syndromes Proportions of patients with syndromes followed by ASD Proportions of patients with ASD, who have these syndromes
1 15q dup Angelman syndrome UBI3A (and other) gt40 1,2
2 16p11 del Gene is unknown high -1
3 22q del SHANK3 high -1
4 Syndrome of cortical dysplasia of focal epilepsy CNTNAP2 70 rare
5 Fragile X-chromosome FMR1 25 of men 6 of women 1-2
21
22
Table 1 (continuation) Syndromes associated
with ASD
? Syndromes Genes associated with syndromes Proportions of patients with syndromes followed by ASD Proportions of patients with ASD, who have these syndromes
6 Hobart syndrome GOUBIRT, Many loci 25 rare
7 Potocki-Lupski syndrome Chromosomes 17 ? 11 90 unknown
8 Smith-Lemli-Opitz syndrome DHSA7 50 rare
9 Rett syndrome MISP2 All individuals who have Rett syndrome 0,5
10 Timothy syndrome SASNAIS 60-80 unknown
11 Tuberous sclerosis TSC1, TSC2 20 1
22
23
  • Gene polymorphism a genetic event in which
    building of genes changes and this influence on
    protein function.
  • If only one letter changes in genetic code,
    this is called single nucleotide polymorphism.

23
24
Genetic enzymatic polymorphism of homocysteine
metabolism (G.R. Akopyan)
Name of enzyme GENE COENZYME MUTATIONS DISEASES
Methyltetra-hydrofolate reductase MTHFR Vit.B9 Vit.B2 C677T (Ala to Val) A1298C (Asp to Gly) Thromboembolia Neural tube defects Diabetes mellitus
Methionine synthase MTR Vit.B12 A2756G Thromboembolia Colorectal cancer Malignant lymphoma
Methionine synthase reductase MTRR A66G Cardiovascular
?ystathionine-ß-synthase CBS Vit.B6 Ile to Thr Gly to Ser Homocystinuria
Cystathionine-?-lyase CSE / CBL Congenital cystathionineuria
Methionine adenosyltransferase MAT I / III Hypermethioninemia
Glycine N-methyltransferase deficiency GNMT Liver pathology
S-Adenosyl-homocysteine hydrolase SAHH Psychomotor development delay, neurological abnormalities, hepatitis, myopathy
24
25
Polymorphisms of genes of folate and methionine
cycle
  • Hyperhomocysteinemia was found in every third
    from examined patients with IHD and preeclampsia
  • Genotypes with high predisposition to
    homocysteine-associated thrombophilia in the case
    of their assessment by four polymorphic loci
    MTHFR ?677T_A1298C / MTR 2756 AG / MTRR 66 AG
    CT_AA/AA/GG, CT_AC/AA/GG , C?_AA/AA/GG ,
    CT_AC/AA/AA , C?_AC/GG/GG, CC_AC/AA/AG,
    CC_AA/AA/AG were found.
  • The risk of hyperhomocysteinemia is likely
    associated with AA carrier of MTR genotype and GG
    of MTRR genotype
  • Carriers of four and more mutant alleles (MTHFR,
    MTR, MTRR) need screening for homocysteine
    content in blood plasma.
  • There is necessity of hyperhomocysteinemia
    verification using methionine loading test.

25
26
  • All biochemical processes in a cell are performed
    with the help of cycles, among them there is
    folate cycle, which achieved key positions
    folate metabolism is the basis of cellular
    metabolism (G.R. Akopyan)

26
27
  • The following events are performed in this cycle
  • Synthesis of nucleic acids
  • Synthesis of biologically active substances
    adrenaline, melatonin, creatinine, phospholipids,
    polyamines (spermicides and spermines), glutamic
    acid, dihydro-tetrahydrobiopterin, nitric oxide
  • Epigenetic changes of DNA, DNA (methylation),
    RNA, chromatin, amino acids, proteins, lipids.

27
28
  • We supposed and confirmed that if there is
    enzymatic activity of folate cycle in human body
    methylentetrahydrofolatereductase is low, this
    leads to methylation disorder (switching on and
    off gene activity) and then it causes a lot of
    inherent and multifactorial syndromes.

28
29
  • The following was underlain the basis of this
    study creation of single information database
    including all levels of prevention of inherent
    pathology at all levels of ontogenesis.

29
30
Association of families with chromosomal pathology
ONCOGENETIC CENTRE
PRENATAL CENTRE
Centre of prenatal education
Centre of studying epigenetic diseases
KHARKIV SPECIALIZED MEDICAL GENETIC
CENTRE (practical basis) UKRAINIAN INSTITUTE OF
CLINICAL GENETICS , DEPARTMENT OF MEDICAL
GENETICS OF KhNMU (scientific basis)
REGIONAL PULMONARY CENTRE
Centre of connective tissue pathology
Association of families with cystic fibrosis
Association of families with cystic fibrosis
Association of families with spinal muscle atrophy
Association of families with organic acidurias
REGIONAL METABOLIC CENTRE
Association of families with phenylketonuria
Service of urgent biochemical diagnosis
Association of families with mitochondrial
diseases
30
31
Comparative characteristics of IDD by screening
data on Kharkiv region for 2000-2008
Diseases 2000 2000 2001 2001 2002 2002 2003 2003 2004 2004 2005 2005 2006 2006 2007 2007 2008 2008
Diseases Ab. amount In. value Ab. amount In. value Ab. amount In. value Ab. amount In. value Ab. amount In. value Ab. amount In. value Ab. amount In. value Ab. amount In. value Ab. amount In. value
1.Anencephaly 2 0,99 3 1,53 3 1,45 3 1,38 1 0,44 2 0,90 1 0,41 1 0,39 1 0,36
2.Myelocele 7 3,49 5 2,55 6 2,90 9 4,16 10 4,40 11 4,75 5 2,07 12 4,72 8 2,9
3.Meningocele - - 1 0,53 1 0,48 1 0,46 - - - - - - 3 1,18 2 0,72
4.Hydrocephaly 3 1,49 9 4,59 14 6,78 10 4,63 13 5,72 7 3,56 13 5,38 12 4,72 8 2,9
5.Microcephaly 5 2,49 3 1,53 - - 4 1,85 5 2,20 5 2.97 9 3,72 5 1,96 5 1,8
6.Anotia - - - - - - 2 0,92 1 0,44 2 0,90 4 1,64 5 1,96 3 1,09
7.Anophthalmia 1 0,49 - - 1 0,48 - - - - - - - - 1 0,39 - -
8.Microphthalmia 2 0,99 1 0,53 1 0,48 - - 1 0,44 4 1,79 4 1,64 1 0,39 2 0,72
31
32
The frequency of genotypes and alleles of
polymorphic gene variants C677T MTHFR ? A66G MTRR
(n4586)
32
33
  • Since 2008 we have been conducting the stage of
    the scientific search according to the following
    hypothesis.
  • HypothesisThe influence of mtDNA polymorphisms
    on MTChD is a result of pathological
    transformation of mtDNA polymorphisms against the
    background of the changed status of methylation
    as the main genome modificator and the presence
    of triggers.

33
34
DNA methylation
Cytosine
Guanine


34
35
Methylation of biologically active
substances
35
36
Folate and methionine cycle
All reactions of methionine cycle are connected
with tanssulfuration of homocysteine
MAT I/III
(B12)
!BHMT
GNMT
SAHH
(B6)
(B2)
CBL (B6)
Betaine is a donor of methyl groups in the
reaction of remethylation of homocysteine in
participation of betaine-homocysteine-methyltransf
erase. (G.R. Akopyan )
36
37
Folate and methionine cycle
B6
B12

B6
B2
CBL (B6)
B6
The level of development of hyperhomocycteinemia
depends on the content of folic acid (B12),
pyridoxine (B6), riboflavin (B2), serine,
glycine, choline, betaine, cysteine . (G.R.
Akopyan)
37
38
Hyperhomocysteinemia and methylation
disorder(G.R. Akopyan)

38
39
Homocysteine a strong oxidant and protein
modificator
Homocysteine thiolactone
Acts in the normal level of homocysteine and in
less concentrations (10 nmol/l) !!!

Decreases the level and activity of thioredoxin,
superoxide dismutase, syntase NO Increases
NAD(P)H-oxidase activity
LDL oxidation
Endothelium damage thrombogenesis
Atheromatous plague formation
?2
Protein modification
Homocysteine thiolactonase or paraoxonase (PON 1)
can hydrolyze homocysteine thiolactone!!!
39
40
Homocystination of proteins by homocysteine
thiolactone (albumine, hemoglobine, fibrinogene,
apoliprotein B, fibriline !!!)
Binding carbamyl group of homocysteine
thiolactone with e-amino groups of lysine
residues and SH-groups of cysteine residues in
protein molecule
N-homocystination
Binding with e-amino group of lysine
Binding with SH-group of cysteine
S-homocystination
Consequences protein breakdown by
multimerization and precipitation and change of
their antigen possibilities that contributes to
disease chronization independently from
homocysteine level
40
41
  • Methylation has been admitted the main genome
    modificator, central pathway of all metabolic
    events in organism life
  • Optimization of methylation function in A.
    Yaskos opinion (2010) becomes a model for
    management of genetic polymorphism, which
    influences on many important biological events in
    the body.

41
42
METHYLATION FUNCTION
  • DNA methylation is necessary for support of
    differential expression of paternal and maternal
    gene copy susceptible to the genome imprinting .
  • 2. For stable gene silencing on inactive
    X-chromosome.

42
43
  • 3. Stable transcriptional repression of provirus
    genomes and endogen retrotransposons depends on
    DNA methylation
  • DNA methylation takes part in management and
    support tissue-specific patterns of gene
    expression in development
  • Absence of DNA methylation decreases reliability
    of support of chromosomes number that leads to
    chromosomal aberrations
  • DNA hypomethylation in consequence of influence
    of DNA-methyltransferase inhibitors leads to
    elimination of tumors
  • Formation of other types of tumors increases in
    DNA hypomethylation

43
44
  • Entirety of methylation systems determines genome
    and it means psychic, physic, reproductive
    health.
  • Studies, which explain how environmental factors
    can induce epigenetic changes and biologic
    effects, have appeared.
  • En Li, Adrian Bira (2010)

44
45
DNA methylation and chromosomal instability
  • Ehrlich, 2003 Dobge et al, 2005 established that
    DNMT3B mutations in patients with ICF syndrome or
    Dnmt 3b inactivation in mice lead to various
    chromosomal aberrations (structural and
    quantitative)
  • There is the hypothesis that DNA methylation
    contributes exact chromosomal disjunction and in
    its absence more often there is leading to
    chromosomal disorders nondisjunction
    (hypomethylation, demethylation)

45
46
  • Alternative possibility means that DNA
    methylation can inhibit expression and
    recombination of retrotransposons in animals
    genome, thus defending chromosomes from harmful
    recombinations.

46
47
Identification of folate cycle disorders include
  1. Inherent malabsorption of folic acid caused by
    mutations in the gene which encodes folic acid
    transporter.
  2. Deficiency of formiminotransferase caused by the
    mutation in FTCD gene.
  3. Deficiency of methylentetrahydrofolate reductase
    caused by the mutation in MTHFR gene.

47
48
4-5. Deficiency of functional methionine synthase
as a result of mutations in MTR gene affecting
methionine synthase (cblG) or mutations affecting
methionine synthase reductase (cblE due to the
mutation in MTR? gene). 6. Cerebral deficiency
of folic acid caused by mutations in FOLR1
gene. 7. Deficiency of thrifunctional enzyme
containing methylenetetragydrofolate
cyclohydrogenase and formyltetrahydrofolate
synthase caused by mutations in MTHFD1 gene (Mac
Gill, Rosenblatt et al.).
48
49
  • It is necessary to note that homozygotous pattern
    of the polymorphism means more expressed level of
    enzymatic activity decrease.
  • If a human is a carrier of a specific mutation,
    it not always means that function activity
    certainly will decease, SNP are indicators of
    potential problem areas which can manifest
    independently or under the influence of triggers
    or gene interaction

49
50
  • Defects in 5-methyltetrahydrofolat homocysteine
    methyltransferase can disturb detoxification
    process, meanwhile toxic substances, for example,
    mercurous can worse the effect because of
    decreased activity methionione synthase (MTR) and
    decreased detoxification effectiveness

50
51
There is summary of the genes that are included
in a complex panel of methylation analysis (Amy
Yasko, 2010)
Mutations or single nucleotide polymorphismsGene
mutations - changes affecting the sequence of a
single gene. Mutations vary in size from one
affecting base pair to large segments of
chromosomes. Single nucleotide polymorphisms are
small genetic changes or variations that may
occur in the DNA sequence. The genetic code is
denoted by 4 "letters" A, C, G and T. SNP
variation is due to the replacement of one
nucleotide for another. The presence of
mutations in genes encoding enzymes affects their
productivity. Homozygous mutations are those
mutations that affect both copies of the gene,
heterozygous mutations are those mutations that
affect only one of the copies of the gene. Each
of us has two copies of each gene obtained from
each parent. Some mutations enhance the activity
of enzymes (such as CBS) while others may
decrease the activity (such as MTHFR 677 1298
COMT)
51
52
COMT V158M, H62H, 61 The main function of this
gene is involved in the breakdown of dopamine.
Dopamine - a neurotransmitter that is involved in
the formation of behavioral reactions and
attention. Dopamine contributes to the appearance
of good feeling, because it causes a feeling of
pleasure influencing the processes of motivation
and learning. Dopamine is produced during
positive thinking. COMT exposed cleavage leads to
the formation of another neurotransmitter -
norepinephrine. The correspondence between the
level of epinephrine and dopamine levels is
involved in ADD / ADHD dopamine levels is
important in the development of diseases such as
Parkinson's disease. COMT is also involved in
transformation of the corresponding estrogen in
the body. COMT activity is often associated with
sensitivity to pain. COMT homozygotes may be
more sensitive to pain.
52
53
VDR/Taq and VDR/Fok (vitamin D receptor) The
panel contains some receptors of vitamin D, Taq
and Fok sites. While Fok change was due to the
regulation of blood sugar, modified Taq may
affect the level of dopamine. For this reason it
is important to watch the status of COMT VDR /
Taq and draw conclusions based on the totality of
the results of these two sites. Focus on changes
part of the VDR in the Fok against supplements
that support the pancreas and assist in the
maintenance of blood sugar in the normal healthy
range.
53
54
MAO A R297R (monamine oxidase A) Mao is involved
in the cleavage of serotonin in the body. Like
dopamine, serotonin - neurotransmitter. It is
associated with mood, an imbalance of serotonin
levels is associated with depression, aggression,
anxiety and OCD behavior. MAO A is localized on
chromosome X and is considered X-linked trait
that does not appear in men. Because the X
chromosome in a man can come only from the
mother, it means that Mao mutations of father (or
their absence) plays no role in the son. For
women, as one chromosome is inherited from each
parent, geneticians, tend to reflect the status
of Mao in both parents.
54
55
ACAT 102 (acetyl coenzyme A acetyltransferase) AC
AT plays a role in lipid metabolism, helps to
prevent the accumulation of excess cholesterol in
certain parts of a cell in the body. ACAT is also
involved in the production of energy in the body.
Contributes to the breakdown of proteins, fats
and carbohydrates from food, energy and then will
be used in life. Furthermore, the absence of ACAT
may also lead to depletion of B12, which is
required in methylation cycle. ACE (angiotensin
converting enzyme) Considered for all - No
longer testingVarious factors, including diet
can affect the activity of ACE gene, changes
which can lead to high blood pressure. The
connection between gene activity disorders with
increased anxiety, memory loss and learning
decrease has been revealed in animal studies.
Increased activity of ACE may also lead to the
removal of minerals in the body by decreasing
excretion of sodium in urine and increased
elimination of potassium. This reaction is also
associated with stress in a situation of chronic
stress can lead to additional sodium accumulation
and an increase excretion of potassium. This
excess of potassium is in body if the kidneys
function properly. In the case of impaired renal
function, it may result in retention of potassium
in the body.
55
56
MTHFR A1298C, C677T, 3 (methylenetetrahydrofolate
reductase) MTHFR gene product is at a critical
point in the methylation cycle. Participates in
the normalization of the level of homocysteine.
Some mutations in MTHFR were well characterized,
and are associated with the risk of
cardiovascular diseases and cancer and may play a
role in the level of neurotransmitters of
serotonin and dopamine MTR A2756G/MTRR A66G,
H595Y, K350A, R415T, S257T, 11 (methionine
synthase/ methionine synthase reductase) These
two gene product work together and are involved
in the conversion of homocysteine to methionine.
Elevated homocysteine levels are risk factors in
a number of pathologies including heart disease,
Alzheimer's disease, etc. As in the case of COMT
and VDR / Taq, MTR and MTRR should be studied
together. Mutations in the MTR can increase the
activity of the gene product in a way that leads
to greater consumability of B12 as the enzyme. On
the other hand, recent publications show that
MTRR A66G mutation reduces the activity of the
enzyme. Regardless of which theory is correct
breaking B12 cycle or methylation function
activity disorder at this point, B12 is used as
an additive in all the cases.
56
57
BHMT 1,2,4,8 (betaine homocysteine
methyltransferase) The product of this gene is
central in the short pathway of methylation,
performs remethylation of homocysteine to
methionine. This gene product activity may
influence on stress, cortisol level and may play
the role in the ADD / ADHD, affecting the levels
of norepinephrine. AHCY 1,2,19 (S
adenosylhomocysteine hydrolase) Different
mutations in the AHCY can affect the levels of
homocysteine and ammonia in the body. CBS C699T,
A360A, N212N (cystathionine-beta-synthase) CBS
enzyme basically acts as a gateway between
homocysteine and lower part of the path which
generates ammonia in the body. There are some
positive end-products that are generated by the
lower part of methylation pathway, such as
glutathione and taurine, there are also negative
side-products such as ammonia and excess sulfite.
Because of increased activity of CBS, sulfites
that are toxic for the body present an additional
upload for SUOX gene product.
57
58
SHMT C1420T (serine hydroxymethyltransferase) The
product of this gene is involved in the setting
blocks needed for synthesis of new DNA and
transformation of homocysteine to methionine.
While DNA blocks are important, mutations that
affect the ability to regulate the gene product
and thereby affecting the methylation process can
cause the accumulation of homocysteine and
imbalance in the other intermediate compounds in
the body. NOS D298E (nitric oxide synthase) NOS
enzyme plays an important role in the
detoxification of ammonia in the urea cycle.
Individuals who are homozygotous for NOS have the
enzyme with decreased activity. NOS mutations can
affect the regulation of CBS until increase of
ammonia, which is generated by CBS.
58
59
SUOX S370S (sulfite oxidase) The product of this
gene promotes detoxification of sulfites in the
body. Sulfites are generated as a natural
by-product of the methylation cycle, and enter
the body with food. Sulfites, sulfur-based
preservatives that are used to prevent or reduce
discoloration of light colored fruits and
vegetables to prevent the appearance of black
spots on the shrimps and lobsters, inhibit the
growth of microorganisms in fermented foods
(e.g., wine), and are able to maintain the
activity of certain medications. Sulfites may
also be used for bleaching edible starch, rust
and scale prevention in boilers used for steam
cooking food, and even in the production of
cellophane, for packing food products. FDA
considers that one from hundred sulfites is
sensitive, approximately 5 of individuals suffer
from asthma. A person can face the problem of
sulfite sensitivity at any time of life.
59
60
Many cases of sulfite sensitivity have been
registered, and therefore the FDA requires that
the labels have information about product content
of these substances. Scientists dont note the
smallest concentration of sulfites needed to
cause a reaction. Shortness of breath is the most
common symptom. Sulfites release sulfur dioxide
gas, which can cause irritation in the lungs and
cause severe asthma attack for those who suffer
from asthma. Sulfites can cause chest tightness,
nausea, urticaria, and in rare cases, more severe
allergic reactions. Mutations in SUOX may be a
risk factor for developing certain types of
cancer, including leukemia.
24.09.2013
61
EPIGENETICS
  • Epigenetics (ep?-over) the section of medical
    biological science studying principles of changes
    of gene expressions or cell phenotype caused by
    mechanisms not associated with DNA sequence.
  • Epigenetics characterizes the process of body and
    environment interaction in genotype formation.
  • ?. Uodington 1947

61
61
62
  • Factors which lead to switching on epigenesis
  • Nutrition
  • Infection
  • Smoking
  • Stress
  • Trauma
  • Operation
  • Alcohol.

62
63
  • Triggers (provocateurs) of switching on
    epigenesis nutrition, infection, smoking,
    stress, alcohol
  • The presence of gene predispositions (mediators)
  • Methylation is the main epigenetic mark and key
    reaction of epigenesis.

63
64
  • Cryshtof Bokk generalized scientific facts about
    epigenetic regulation occurrence and how it
    influence on human diseases.
  • T. Kouzarides thinks that such epigenetic
    mechanisms how DNA methylation and histone
    modifications (acetylation), regulate gene
    expression by DNA modulation in cellular nuclei.

64
65
  • Such environmental factors as nutrition and
    stress influence are able to cause changes of
    epigenetic status (Yeijmans B.T. et al., 2007).
  • These circumstances form opinion of many
    scientists about that human epigenome can be
    considered as the biochemical record of life
    events, accumulated changes throughout life.

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Effects of epigenetics
  • Genome imprinting (and its disorders)
  • Cellular differentiation
  • Transgenerative epigenetic effects
  • Mutation process
  • Blastemas
  • Organism ageing
  • Conservatism of genetic information

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Mechanisms of epigenetics
  • DNA methylation
  • Chromatine remodeling
  • RNA-mediated modifications
  • Protein preionization
  • X-chromosome inactivation

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  • It is established that many epigenetic changes
    may not followed by phenotypic changes, meanwhile
    some changes caused by environment factor action
    modulate gene activity (expression) (Herst M,
    Marra M.A.,2009 Feinberg A.P., 2007 Bijornson
    H.T., 2004) thats why abnormal epigenetic status
    can be associated with a number of diseases (e.g.
    rheumatoid arthritis, SLE).

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  • It is shown that neural activity in the brain is
    regulated epigenetically, and potential relevance
    of epigenetic changes in schizophrenia, biopolar
    disorders and alcoholism allow us to see the
    problem in a different way (Esteller M., 2007
    Jones P.H, Baylin S.B., 2007 Feinberg A.P. et
    al. 2006).

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EPIGENETIC DISEASES INCLUDE(HUDS Y.ZOGHBI,
ARTHUR L. BEANDET)
1.Genome imprinting disorder. 1.1. Sister
syndromes Prader-Willi syndrome. 1.2.
Beckwith-Wiedemann syndrome 1.3. Silver-Russell
syndrome 1.4. Pseudohypoparathyroidism. 2.
Disorders influencing on chromatin structure in
transconfiguration 2.1. Rubinshtein-Taybi
syndrome 2.2. Rett syndrome 2.3. X-linked
?-thalassemia followed by mental delay. The
syndrome of immunodeficiency, instability of the
centromeric region and facial anomalies 2.4.
Spondyloepiphyseal dysplasia of Schimke. 2.5.
Methylenetetrahydrofolate reductase
deficiency. 3. Disorders influencing on chromatin
structure in cis-configuration. 3.1.
?dß-dß-thalassemia 3.2. X-fragile syndrome 3.3.
Facioscapulohumeral muscular dysrtrophy
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Classification of epigenetic human diseases
(S.?. Nazarenko, 2004)
Epigenetic status disorder of separate regions of the genome (locate effect) Disorder of epigenetic status of the whole genome (global effect)
1. Diseases caused by inherited mutations disturbing monoallele gene expression diseases of genome imprinting (Beckwith-Wiedemann syndrome, Prader-Willi syndrome, Engelman syndrome) 1. Diseases caused by inherited mutations of genes, products of which are involved in the support of DNA methylation level or modification of methionine structure - ICF syndrome, Rett syndrome, ATR-X syndrome, Rubinshtein-Taybi syndrome, Coffin-Lowry syndrome
2. Diseases caused by methylation status disorder of separate genes in the result of de novo mutations in somatic cells - a)cancer areas connected with imprinting loss leading to inactive gene activation or inhibition of active gene expression b)cancer diseases caused by hypermethylation of promoters of tumor suppressor gene 2. Diseases caused by global disorders of genome methylation in the result of de novo mutations in somatic cells cancer disease connected with the global genome hypomethylation leading to activation of oncogenes, retrotransposons and chromosomal instability
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Methionine
  • Methionine an essential amino acid, is
    contained in proteins.
  • Is methyl group donor (in composition of
    S-adenosyl-methionine) in synthesis of choline,
    adrenaline and other
  • Source of sulfur in cysteine synthesis.
  • Has 52 biochemical synonyms.
  • Chemical name of methionine (2S)-2-amino-4-methy
    lsulfanyl-butanoic acid.
  • Chemical formula- C5H11NO2S.

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Unique functions of methionine
  • Takes part in trasmethylation reactions
  • Is a donor of methyl groups
  • In synthesis of biologically active substances
  • Takes part in synthesis of nucleic acids
  • Is an acceptor of methyl for 5-methylenehydrofolat
    e-homocysteine methyltransferase (methionine
    syntase).

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Metabolism
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  • Methionine cysteine precursor which gives it
    sulfur.
  • Has 52 biochemical synonyms.
  • Chemical name of methionine (2S)-2-amino-4-methy
    lsulfanyl-butanoic acid.
  • Chemical formula - C5H11NO2S.

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Biological function of methionine
  • An essential acid
  • A component of aminoacyl tRNA biosyntase
  • A component of glycine metabolism, serine and
    trianine
  • A component of histidine metabolism
  • A component of methionine metabolism
  • A component of selenium amino acid metabolism
  • A component of tyrosine metabolism

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Enzymes of methionine metabolism are presented by
  • Methionine syntase
  • Thyrosine amino transferase
  • S-adenosyl methionine synthetase isoform II type
  • Arsenit methyltransferase
  • Indomethylamine N-methyltransferase
  • S-adenosyl methionine synthetase isoform I type
  • Betaine homocysteine S-methyltransferase I.
  • Methionine-tRNA synthetase, cytoplasmic
  • Methionine adenosyltranferase II beta

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  • Disorder of processes remethylation (formation of
    methionine from homocysteine), in the result of
    deficiency of MTHFR ? MTRR enzymes leads to a
    number of pathological conditions such as
  • atherosclerosis
  • atherothrombosis
  • Neural tube closure defect
  • infarcts
  • Chromosome disjunction defect in oogenesis and
    the risk of birth of children with Down syndrome.

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Folate and methionine cycles
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Classification (N. Blau et al., 1996)
Disorder Affected component Tissue distribution Chromosome localisation ? MIM
10.1 Methionine adenosyltransferase (???) of the liver Liver 250850
10.2 Cystathionine beta-synthase (CBS) Liver, brain, lymphoblasts, cultured fibroblasts, amniocytes and choroidal fibers 21q22.3 236200
10.3 Gamma-cystatathionase(???) Liver, lymphoblasts 16 219500
10.4 Sulfitoxidase, isolated or molybdenum cofactor 10.4.1. Type ? 10.4.2 Type ? Liver, kidneys, lungs, heart, lymphoblasts, choroidal fibers, cultured fibroblasts and amniocytes 272300 252150 252160
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Classification (N. Blau et al., 1996)
Disorder Affected component Tissue distribution Chromosome localization ? MIM
10.5 5,10- Methylenetetrahydrofolate reductase (MTHFR) Liver, lymphocytes, lymphoblasts, choroidal fibers, cultured fibroblasts 1?36.3 236250
10.6 Methionine synthase (methyl cobalamin) cblE, cblG 236270 250940
10.7 Methylmalonyl-???-mutase (adenosylcobalamine) and methionine synthase methylcobalamin) Liver, cultured fibroblasts, amniocytes 277400 277410 277380
Liver, cultured fibroblasts, amniocytes
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  • Depending on the frequency, separate genotypes
    can compose bases for development of common
    pathology, other can be factors of development of
    rare (orphan) diseases.

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Spectrum of nosologies in combination of
polymorphisms ?677? MTHFR / ?66G MTRR in patient
selection (n1938)
Nosology spectrum ?677? MTHFR / ?66G MTRR ?677? MTHFR / ?66G MTRR ?677? MTHFR / ?66G MTRR ?677? MTHFR / ?66G MTRR ?677? MTHFR / ?66G MTRR ?677? MTHFR / ?66G MTRR ?677? MTHFR / ?66G MTRR ?677? MTHFR / ?66G MTRR
Nosology spectrum Hmzg/Hmzg Hmzg/Htzg Htzg/Htzg Htzg/Hmzg N/ Hmzg N/ Htzg Hmzg/N Htzg/N
Deficiency of folate cycle enzymes (16) 6 11 36 37 69 99 5 36
Deficiency of folate cycle enzymes 3 3 11 13 37 51 1 15
Homocysteine remethylation disorder 1 1 3 3
Spina bifida 1 2
HCU 1 3 7 10 8 19 2 8
HCU (in relatives) 1 1
Thromboembolias/thrombosis 1 1 4 2 3 7 6
Thromboembolias/thrombosis (in relatives ) 1 3 1 2 1
Varicose vein dilatation 1 6 6 11 11 1 5
Varicose vein dilatation (in relatives ) 1 2 4 3 4 4 1 2
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Spectrum of nosologies in combination of
polymorphisms ?677? MTHFR / ?66G MTRR in patient
selection (n1938)
Nosology spectrum ?677? MTHFR / ?66G MTRR ?677? MTHFR / ?66G MTRR ?677? MTHFR / ?66G MTRR ?677? MTHFR / ?66G MTRR ?677? MTHFR / ?66G MTRR ?677? MTHFR / ?66G MTRR ?677? MTHFR / ?66G MTRR ?677? MTHFR / ?66G MTRR
Nosology spectrum Hmzg/Hmzg Hmzg/Htzg Htzg/Htzg Htzg/Hmzg N/ Hmzg N/ Htzg Hmzg/N Htzg/N
IMD (7.8) 9 10 71 64 71 124 10 44
IMD 2 10 11 13 23 4 13
IMD (in relatives) 2 2 2 1
IMD of amino acids 1 1 2 1 2 2 3
IMD of sulfur-containing amino acids 4 8 5 9 17 1 3
IMD of sulfur-containing amino acids (in relatives) 2 1 1
IMD of fatty acids 3 1 2 4
IMD of methionine 2 7 8 8 3 1
CTD 1 3 21 19 13 33 2 11
CTD (in relatives)
DMD 1 1 3 1
Disorder of tryptophan metabolism 1
Disaccharidose deficiency 1
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Spectrum of nosologies in combination of
polymorphisms ?677? MTHFR / ?66G MTRR in patient
selection (n1938)
Nosology spectrum ?677? MTHFR / ?66G MTRR ?677? MTHFR / ?66G MTRR ?677? MTHFR / ?66G MTRR ?677? MTHFR / ?66G MTRR ?677? MTHFR / ?66G MTRR ?677? MTHFR / ?66G MTRR ?677? MTHFR / ?66G MTRR ?677? MTHFR / ?66G MTRR
Nosology spectrum Hmzg/Hmzg Hmzg/Htzg Htzg/Htzg Htzg/Hmzg N/ Hmzg N/ Htzg Hmzg/N Htzg/N
Sulfite oxidase deficiency 2 1 3
Metabolism disorder in urea cycle 1
Maple syrup disease 1
Hyperprolinemia 2 1 1
Aminoacidemia 1
Aciduria 2 2 4 1
Hypothyrodism 1
Autism 2
Mitochondrial diseases 1 1 8 9 10 19 1 7
Mitochondrial diseases (in relatives) 1
Kearns-Sayre syndrome 1
Epilepsy 1 1 3 1 5 10 1 2
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Spectrum of nosologies in combination of
polymorphisms ?677? MTHFR / ?66G MTRR in patient
selection (n1938)
Nosology spectrum ?677? MTHFR / ?66G MTRR ?677? MTHFR / ?66G MTRR ?677? MTHFR / ?66G MTRR ?677? MTHFR / ?66G MTRR ?677? MTHFR / ?66G MTRR ?677? MTHFR / ?66G MTRR ?677? MTHFR / ?66G MTRR ?677? MTHFR / ?66G MTRR
Nosology spectrum Hmzg/Hmzg Hmzg/Htzg Htzg/Htzg Htzg/Hmzg N/ Hmzg N/ Htzg Hmzg/N Htzg/N
Vascular pathology(8) 2 5 13 13 46 43 2 22
Inborn heart defect 2 1 5 1
Inborn heart defect (in relatives) 1 3
Cardiopathy 1 1 2
Myocardial infarction 1 1 1
Myocardial infarction (in relatives) 1 1 2 2 3
Ischemic heart disease 1 1
Ischemic heart disease (in relatives) 1 1 1 1
Vascular pathology 1 11 8 8
Vascular pathology (in relatives) 1 9 6 2
Insults 2 1 3
Insults (in relatives) 2 3 4 13 7 4




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Spectrum of nosologies in combination of
polymorphisms ?677? MTHFR / ?66G MTRR in patient
selection (n1938)
Nosology spectrum ?677? MTHFR / ?66G MTRR ?677? MTHFR / ?66G MTRR ?677? MTHFR / ?66G MTRR ?677? MTHFR / ?66G MTRR ?677? MTHFR / ?66G MTRR ?677? MTHFR / ?66G MTRR ?677? MTHFR / ?66G MTRR ?677? MTHFR / ?66G MTRR
Nosology spectrum Hmzg/Hmzg Hmzg/Htzg Htzg/Htzg Htzg/Hmzg N/ Hmzg N/ Htzg Hmzg/N Htzg/N
Monogene pathology (5) 2 4 11 11 20 21 4 8
Ehlers-Danlos syndrome 1 2 1 4 5 6 2
Prader-Willy syndrome 1 1 1 1
Louis-Bar syndrome 1 1
Klippel-Trenaunay syndrome 1 1
Tuberous sclerosis 2 2 1
Rendu-Osler syndrome 1 1
Silver-Russell syndrome 1
Rubinstein-Taybi syndrome 1
Hyperirritability syndrome 1 2 1
Arnold-Kiari syndrome 1
IDD syndrome 1
AGS 1
Anonichia-ectodactyly syndrome 1
McCune-Albright syndrome 1
Lesch-Nyhan syndrome 1
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Spectrum of nosologies in combination of
polymorphisms ?677? MTHFR / ?66G MTRR in patient
selection (n1938)
Nosology spectrum ?677? MTHFR / ?66G MTRR ?677? MTHFR / ?66G MTRR ?677? MTHFR / ?66G MTRR ?677? MTHFR / ?66G MTRR ?677? MTHFR / ?66G MTRR ?677? MTHFR / ?66G MTRR ?677? MTHFR / ?66G MTRR ?677? MTHFR / ?66G MTRR
Nosology spectrum Hmzg/Hmzg Hmzg/Htzg Htzg/Htzg Htzg/Hmzg N/ Hmzg N/ Htzg Hmzg/N Htzg/N
Hemorrhagic syndrome 1
Erb-Rott myopathy 1
Myopathy syndrome 1 1
Duchenne muscular dystrophy 2
PKU 1 1 1
Cystic fibrosis 3 2 1 2
Reiter syndrome 1
Marfan syndrome 1 1 2
Dandy-Walker syndrome 1
Fridreichs ataxia 1
Polyneuropathy 1 1
Pertas disease 1
Gilberts syndrome 1 2
DHD syndrome 1
Hypophyseal nanism 1
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Spectrum of nosologies in combination of
polymorphisms ?677? MTHFR / ?66G MTRR in
patient selection (n1938)
Nosology spectrum ?677? MTHFR / ?66G MTRR ?677? MTHFR / ?66G MTRR ?677? MTHFR / ?66G MTRR ?677? MTHFR / ?66G MTRR ?677? MTHFR / ?66G MTRR ?677? MTHFR / ?66G MTRR ?677? MTHFR / ?66G MTRR ?677? MTHFR / ?66G MTRR
Nosology spectrum Hmzg/Hmzg Hmzg/Htzg Htzg/Htzg Htzg/Hmzg N/ Hmzg N/ Htzg Hmzg/N Htzg/N
Chromosomal pathology(6)   2 16 10 29 27 2 14
Down syndrome 1 5 1 5 14 1 2
Down syndrome (in relatives) 6 3 14 6 1 6
Shereshevsky-Turner syndrome 2 5 4 4
Various chromosomal pathologies/polymorphisms 1 3 6 5 3 2
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Epigenetic disease (hypomethylation, chromosomal
polymorphism (46,??, 9 phqh ) and polymorphic
gene variants of folate cycle (677 ?-?, ?222 V
mutation in heterozygotous state). Mild
homocystinuria. Syndromal epilepsy.
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Rendu-Osler disease. Polymorphic variant of 677
C/T MTHFR gene in homozygotous state
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Epigenetic disease? Mosaic form of
Shereshevsky-Turner syndrome. Disorders of
active enzymes of folate cycle. Polymorphic
variant of 677 ?/? MTHFR gene was found in
heterozygotous state, gene of endothelial
NO-synthase 4a/4b ?in homozygotous state).
Energy metabolism disorder (MNGIE?).
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Familial case of epigenetic disease ? DNA
hypomethylation, folate cycle deficiency ,
methionine metabolism disorder (mosaic form of
trisomy 21, chromosomal polymorphism of
chromosome 1 ). Polymorphic variants of MTHFR
677 C/T gene in heterozygotous state, MTRR 66 G
gene in homozygotous state
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Epigenetic disease? glycoprotein metabolism
disorder (defect of posttranslation of lysosomal
enzymes). Disorder of folate cycle metabolism
(66A?G (122?) polymorphism in MTRR gene in
heterozygotous state). Chromosomal polymorphism
46, ?Y, 14 ?s.
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Saethre-Chotzen syndrome, secondary
mitochondriopathy, folate cycle deficiency
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McCune-Albright syndrome in mother.
Polymorphic variants of 677?? MTHFR/66A/G MTRR
genes. Healthy children
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Robinow syndrome. Multiple harmatose growth in
the liver Polymorphic variants of 677??
MTHFR/66GG MTRR genes
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THANKS FOR YOUR ATTENTION
Ukrainian Institute of Clinical
Genetics KhNMU Kharkiv-22, Pravdu avenue,
13 ?-mail mgc_at_ukr.net
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