Transcript EPIMEDIOLOGY OF HERIDITARY DISEASES IN INDIA

EPIMEDIOLOGY OF
GENETIC DISEASES
Framework

Introduction

Types of genetic diseases

Epidemiology of genetic diseases

Preventive and social measures


Promotional measures

Specific protection

Early diagnosis and treatment
Advances in genetics

DNA technology

The human genome project

Human genome diversity project

Gene therapy

Genetic engineering
INTRODUCTION
 Genetic epidemiology is a relatively new discipline that seeks to
elucidate the role of genetic factors and their interaction with
environmental factors in the occurrence of disease in populations
(Khoury et al., 1993).
 Basic principles of genetics -Mendel and Galton by end of the 19th
century
 Genetic makeup is one of the determinants of health and is
responsible for a large proportion of infant mortality and childhood
disability in developed countries
Types of genetic diseases Single gene inheritance
 Chromosome abnormalities
 Point mutations
 Multifactorial inheritance
Single gene inheritance
 also called Mendelian or monogenetic inheritance.
 caused by changes or mutations that occur in the DNA sequence of a single
gene.

There are more than 6,000 known single-gene disorders, which occur in about 1
out of every 200 births.

inherited in recognizable patterns:
1.
autosomal dominant,
2.
autosomal recessive,
3.
X-linked.
autosomal dominant
Early onset- eg: brittle bone disease, osteogenesis
imperfect
Late onset- eg: . Huntington disease, adult
polycystic disease of the kidney, familial cancer
syndrome, tuberculous sclerosis, neurofibromatosis
Autosomal recessive
Carriers are healthy themselves but have
reproductive risk
Eghemoglobin disorders,
cystic fibrosis,
phenylketonuria and
Werdnig - hoffman disease
X-linked inheritance
X-linked inheritance
 Unaffected
carrier females(with two X chromosomes) and affect
mainly, but not exclusively male.
 E.g.
duchenes muscular dystrophy, fragile X mental retardation
and G6PD deficiency
 About
60% of carriers of X linked disorders might be detected by
family studies.
 Family
carriers are high genetic risk; in each pregnancy there is
25% risk of affected son and 25% risk of carrier daughter
Chromosome abnormalities

abnormalities in chromosome number or structure can result in disease.

Abnormalities in chromosomes typically occur due to a problem with cell division.
 eg:
Down syndrome or trisomy 21, turner syndrome (45,x), klinefelters syndrome
(47,XXY)
Point mutations
 Sickle-cell hemoglobin
is the result of a specific, single-base change in the β-
globin gene.
β
–thalassemia can be due to any one of more than 100 different mutation in
and around the β-globin gene.
 Cystic
fibrosis is caused by any of more than 400 different changes in and
around the cystic fibrosis trans-membrane conductance regulator gene.
Multifactorial inheritance
 When in combination of small variation of genes, in combination with
environmental factors, predispose to or produce the condition.
 Tend to recur in families but DONOT show mendelian pattern of
inheritance.

cancer is an eg of very common multifactorial disorder
Multifactorial inheritance-
Contribution of genetic and congenital disorders of infant and
child mortality in atypical developed country
Main causes of the death at <1 %
year
Perinatal factors
38
Congenital & genetic disorders 25
Sudden infant death syndrome
Infections
other
22
9
6
Main causes of the death at
1 to 4 years
Accidents
Congenital & genetic
disorders
neoplasms
Infections
other
%
31
23
16
11
9
Role of genetic predisposition in some common disorder
Disease
Remarks
Coronart heart
disease
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
Cancer
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
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Familial hypercholesterolaemia
Serum cholesterol
Blood pressure
Familial hyperlipidemias
High levels of fibrinogen, homocystine, Lp(a) lipoprotein &
apolipoprotein E4
Retinoblastoma
Familial polyposis coli
Breast: chromosome 17,
Colon cancer
Neurofibromatosis
Specific genes that affects plasma IgE level
Mental disorder
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IDDM- chromosome 6
NIDDM:
schizophrenia
Alzheimer disease

strong familial tendency with increase prevalence with advancing age
Asthma & allergy
Diabetes
Category
Estimated
birth /1000
Commonest diagnosis
Dominant
7.0
Familial hypercholesterolemia, Adult polycystic disease of the kidney, Huntington
disease, Neurofibromatosis, Chondrodystropy
X-linked
1.33
Muscular dystrophy, Haemophilia and Christmas disease, Colour vision disorders, Xlinked mental retardation., Glutathione deficiency
Recessive
1.66
Cystic fibrosis, Phenylketonuria, Amino-acid disorder, Werdnig-Hoffman disease,
Thalassaaemias
Chromosomal
3.49
Single-gene disorders
Autosomes
1.69
Sex chromosome
1.8
Congenital abnormalities 52.8
> 70% Down Syndrome
Mostly Klinefelter and turner syndromes
26.6
Congenital heart disease, Club foot, CDH, pyloric stenosis, cleft palate/lip
No genetic component
26.2
-
Other multifactorial
10.06
Strabismus, Inguinal hernia, Epilepsy, Diabetes, Mild mental retardation
Genetic, unknown type
1.2
-
Total genetic
51.34
Total genetic + nongenetic congenital
anomalies
77.54
DISEASE
PREVALENCE IN COUNTRY
Cleft Lip +CP
Cleft lip ± Cleft palate 0.93 /1000 live
births. Cleft palate alone 0.17 / 1000
Talipes (club foot)
1-2 in every 1000 live birth
Developmental dysplasia of the hip
One in 1,000 children is born with a
dislocated hip, and 10 in 1,000 may have
hip subluxation. (No Indian data)
Congenital heart diseases
Incidence is 8-10 per 1000 live births
Congenital Deafness
5.6 to 10 per 1000 live birth
Congenital cataract
1-15/10,000 children
Retinopathy of maturity
20 TO 22 % IN neonatal ICU
Sickle cell anemia
5 TO 34 %
Beta Thalassemia
3 TO 4 %
Promotional Measures
1) Eugenics
Science which aim to improve genetic endowment of human
population
Negative eugenics:
 To
reduce the frequency of hereditary disease and disability in
the community to be as low as possible.
 debarring
those with hereditary disease from producing
children.
 Eg;
 Can
Hitler
eliminate genetic defects? (fresh mutation, marital
alliance)
Positive eugenics:
 encouraging
carriers of desirable genotypes to assume burden of
parenthood.
 Limitations Valuable traits have
 No

multifactorial determination
control over transmission
2) Euthenics:
 Euthenics deals
with human improvement through improving
mutual interaction btw hereditary and environment.
mental retarded –exposure to +ve environment stimulation -improved IQ
 Eg
3) Genetic Counseling
at risks of an inherited disorder, are advised of the consequences and nature of the disorder,
 the probability of developing or transmitting it and
 the options open to them in management and FP to prevent/avoid or
ameliorate

importance of genetic Counseling is because of The predictive nature genetic information
 Impact of knowledge of genetic risk for the individual and family
 Correct information on risk,
 Availability of management and prenatal diagnosis.

The main components are
 A correct diagnosis
 Estimation
 The
of genetic risk (pedigree, investigations involving other family members)
provision of information on existence of risk and on any option for avoiding it;
 Accessibility for

long-term contact
Types of genetic counseling
Prospective
Retrospective
True prevention
Identify the heterozygous and explain risk on marrying
another heterozygous
Eg sickle cell anaemia, thalassemia
More common
Disorder already occurred
Methods suggested- contraception, MTP, sterilization
Consanguineous marriage
Degree of consanguinity
Genetic make-up
1st degree- between brother and sister
(rare in India)
50% genetic material common
Max P of expression of autosomal recessive traits
2nd degree- with fathers own sister OR mothers
own brother
25% genetic material common
3rd degree- with fathers sisters son/daughter OR
mothers brothers son/daughter
(common in India)
12.5% genetic material common
4th degree- btw distant relatives
Minimal risk of auto recessive
Early diagnosis and treatment1.
Detection of genetic carriers
2.
Perinatal diagnosis
3.
Screening of new born infant
4.
Recognising pre clinical cases
1) Detection of genetic carriers
Genetic population screening-

A “screening test” is applied to the whole population

A screening programme is a public health policy. The classical requirements are
 A common
and potentially serious condition
 A clear diagnosis
 Sound
 An
in each case
knowledge of the natural history of the condition
effective and acceptable method of treatment or prevention
 Affordable
test
Flow chart of genetic screening and Perinatal diagnosis for carriers of a recessive gene
Antenatal screening and Perinatal diagnosis
Test
Scan
Blood test
Carrier screening
Maternal serum AFP or
triple screen
Routine fetal anomaly scan
Reason
Fetal viablilty
Number
Gestational age
Haemoglobin
ABO and rhesus blood groups
Hepatitis B virus
HIV
Haemoglobin disorder
Tay-Sach disease
Cystic fibrosis
Neural tube defects
Down syndrome
RBSK
6 to 7 per 100 born with birth defect ( 17 lac annually , 9.6 % of all newborn deaths)

Aim - early identification and early intervention for children from birth to 18 years
to cover 4 ‘D’s viz. Defects at birth, Deficiencies, Diseases, Development delays
including disability.

0-6 years age group -(DEIC) level while for 6-18 yrs-through existing public health
facilities

First level of screening -delivery points (mo, ANM)

48 HRS to 6 wks-ASHA

6wks to 6yrs- outreach screening …mobile health team at anganwadi
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6yrs to 18 yrs- school
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Treatment and intervention at zero cost to family

Mobile health team- MO (AYUSH) 2, ANM, Pharmacist

Defects at Birth

1. Neural tube defect

2. Down's Syndrome

3. Cleft Lip & Palate / Cleft palate

4. Tallipes (club foot)
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5. Developmental dysplasia of the hip

6. Congenital cataract

7. Congenital deafness

8. Congenital heart diseases

9. Retinopathy of Prematurity
2) Perinatal diagnosis
1.
Fetal Anomaly Scan
2.
Amniocentesis
3.
Chorionic villus sampling
4.
Foetal blood sampling(cordocentesis)
5.
Foetal tissue biopsy
6.
FISH(fluorescent in situ hybridization)
7.
Polymerase chain reaction
1) Fetal Anomaly Scan

To confirm intrauterine gestation, gestational age, and fetal viability and number

Congenital abnormalities scan at >19 weeks.


Gross morphological abnormalities can be detected
Scanning is generally offered to women belonging to recognized risk groups
 e.g.
those with DM, raised serum AFP level, twins or H/O fetal abnormality or
possible exposure of teratogen.
2) Amniocentesis

fetal DNA from amniotic fluid is examined for genetic abnormalities.

14th-16th week of pregnancy

The fetal cells are separated, grown in a culture medium, then fixed and stained.
Under a microscope the chromosomes are examined for abnormalities.

Used in prenatal diagnosis of chromosomal abnormalities and fetal infection

The most common abnormalities detected are Down syndrome, Edward
syndrome[Trisomy 18] and Turner syndrome[Monosomy X].

Usually genetic counseling is offered prior to amniocentesis.
3) Chorionic villus sampling

Prenatal diagnosis

Done by catheter passed through uterine cervix or by inserting needle in abdominal cavity

It entails getting a sample of the chorionic villus (placental tissue) and testing it.

Carried out 10-13 weeks after the last period
4) Fetal blood sampling ( cordocentesis )
 Fetal
blood is obtained after 18 weeks safely by USG-guided trans-abdominal needle
puncture of fetal cord insertion.
 Fetal
 Used
loss is 1-2%.
for Perinatal diagnosis of blood disorder, but now commonly used for the rapid
karyotyping of fetal lymphocytes when a major malformation has been detected by
USG.
5) Fetal tissue biopsy

At 19-20 weeks.

Sample like fetal skin, muscle liver are taken to diagnose the disease.
6) FISH (fluorescent in situ hybridization)
 New
method for detecting numerical chromosome abnormalities in non dividing
cells, it uses fluorescent DNA probes for specific sequences
7)
Polymerase chain reaction
 Technique
to amplify a single or few copies of a piece of DNA across several
orders of magnitude, generating millions or more copies of a particular DNA
sequence.
 Application of PCR
 Isolation of genomic DNA,
 Amplification and quantitation of DNA
 early diagnosis of malignant diseases such as leukemia and lymphomas
3) Screening of new born infants
Disorder
Phenylketonuria
Congenital hypothyroidism
Sickle cell disease
Cystic fibrosis
Duchenne muscular
dystrophy
Congenital adrenal
hyperplasia
Congenital dislocation of hip
Neonatal assay
Phenylalanine
Thyroid stimulating harmone
Haemoglobin electrophoresis
Immunoreactive trypsin
Creatine phosphokinase
17-hydroxy-progesterone
Ortolani and barlow manoeuvres
4) Recognising pre clinical cases - Objectives of different types of genetic population-screening
Preventive or screening action
programmes Type of service Condition
Primary
prevention
Antenatal
screening
Rhesus haemolytic disease
Postpartum use of anti-D globulin
Congenital rubella
Immunization of girls
Congenital malformation



Congenital malformation
Chromosomal abnormalites
Inherited disease
Neonatal
screening
Congenital malformation
Phenylketonuria, congenital
hypothyroidism, sickle cell disease
Addition of folic acid to maternal diet
Control of maternal diabetes
Avoidance of mutagens and teratogens
such as alcohol, certain drugs and possibly
tobacco
Ultrasound fetal anomaly scan, maternal serum
alfa protein estimation
Noting maternal age and maternal serum
factors
 Checking family history
 Carrier screening for haemoglobinopathies,
tay-Sachs disease
Examination of the newborn for early
treatment e.g. congenital dislocation of hip
Biochemical tests for early treatment
Advances in genetics
1.
The human genome project
2.
Human genome diversity project
3.
Gene therapy
4.
Genetic engineering
The human genome project
to understand the genetic makeup of the human species.

the project also has focused on several other nonhuman organisms such as E. coli, the fruit fly, and
the laboratory mouse.

The project began in 1990 headed by James D. Watson at the U.S. National Institutes of Health

Objectives
identify all the approximately 20,000-25,000 genes in human DNA,

determine the sequences of the 3 billion chemical base pairs that make up human DNA,

store this information in databases,

improve tools for data analysis,

transfer related technologies to the private sector, and

address the ethical, legal, and social issues (ELSI) that may arise from the project.
The human genome project
Agencies involved-
UNESCO , Genome data base , HUGO , National institute of health / dept of
energy (USA) , Medical research council (UK) , European union , genetion france

Some of the findings Causation of disease
 All human races are 99.99 % alike, so racial differences are genetically insignificant.
 Most mutation are in the male and are agents of change. They are also more likely to
be responsible for genetic disorders.

understanding of how we evolved as humans and diverged from apes 25 million
years ago.
Human genome diversity project

Started by Stanford University's Morrison Institute and a collaboration of scientists around the
world.

Aim- increase understanding of human evolution

HGDP has attempted to map the DNA that varies between humans, which is less than 1%
different.

Benefit

Yield new data on various fields of study ranging from disease surveillance to anthropology.
The Morrison Institute has maintained that diversity research could create definitive proof of
the origin of individual racial groups.

Potential gain lies in research on human traits.

Disease research.

Diversity research could help explain why certain racial groups are vulnerable to certain
diseases and how populations have adapted to these vulnerabilities
Gene therapy


Gene therapy is the insertion of genes into an individual's cells
and tissues to treat a disease, such as a hereditary disease in
which a deleterious mutant allele is replaced with a functional
one.
Gene therapy may be classified into the following types:
Germ line gene therapy
germ cells, i.e., sperm or eggs, are modified by the introduction of
functional genes, which are ordinarily integrated into their genomes.
Therefore, the change due to therapy would be heritable and would be
passed on to later generations.
Somatic gene therapy
Therapeutic genes are transferred into the somatic cells of a patient.
Any modifications and effects will be restricted to the individual patient
only, and will not be inherited by the patient's offspring.

Advantages/developments in gene therapy

Potential to treat the blood disorder thalassaemia, cystic fibrosis, and
some cancers.

Sickle cell disease is successfully treated in mice.

Treatment for Parkinson's disease, Huntington’s disease

gene therapy can be effective in treating cancer. Eg successfully treated
metastatic melanoma, disease affecting myeloid cells.

developed a way to prevent the immune system from rejecting a newly
delivered gene.

the world's first gene therapy trial for inherited retinal disease.
Genetic engineering

Genetic engineering, recombinant DNA technology, genetic
modification/manipulation (GM) and gene splicing are terms
that apply to the direct manipulation of an organism's genes.
Genetic engineering uses the techniques of molecular cloning
and transformation to alter the structure and characteristics of
genes directly.

Genetic engineering techniques have found some successes in
numerous applications.

Improving crop technology,

The manufacture of synthetic human insulin

the production of new types of experimental mice such as the oncomouse

Manufacture of human growth hormone, vaccine for humans, for hepatitis B.
References
Muin j. khoury, terri h. beaty, berrnice h, cohen /fundamentals of
genetic epidemiology, 1993

The human genome project, national human genome research
institute, http://www.genome.gov/10001772

K.park, textbook of preventive and social medicine, 22 edition 2013

http://nrhm.gov.in/images/pdf/programmes/RBSK/For_more_inform
ation.pdf

http://www.who.int/genomics/public/geneticdiseases/en/index2.ht
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