Download epidemiology of genetic diseases and its control measures

EPIDEMIOLOGY OF
GENETIC DISEASES AND
ITS CONTROL MEASURES
Pravin Pisudde
Moderator: Dr Subodh Gupta
Framework
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Introduction
Categories of genetic diseases
Epidemiology of genetic diseases
Control measures
Genetic counseling
Newer advances
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DNA technology
The human genome project
Human genome diversity project
Gene therapy
Genetic engineering
• Organization of genetic services in health system
Introduction
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Determinants of health
Majority of determinants are being controlled
Standard of living and healthcare is improving.
Genetic makeup is becoming a progressively more
important determinant of health of the individual
• In developed countries, genetic disorders are
responsible for a large proportion of infant mortality
and childhood disability
• Basic principles of genetics were laid down by Mendel
and Galton towards the close of the 19th century
Categories of Genetic Diseases
• Chromosomal abnormalities
– Chromosome 21(down syndrome), 18(Edward
syndrome) or 13(Patau syndrome) or an additional or
missing sex chromosome, survive to birth.
• 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
transmembrane conductance regulator gene.
Categories of Genetic Diseases
• Single gene disorder
– Dominant inheritance
• Early-onset: eg osteogenesis imperfecta , brittle bone
disease
• Late onset: e.g. Huntington disease, adult polycystic
disease of the kidney, familial cancer syndrome,
tuberculous sclerosis, neurofibromatosis
– Recessive inheritance
• Carriers are healthy themselves but have reproductive
risk
• Eg-haemoglobin disorders, cystic fibrosis,
phenylketonuria and werdnig-hoffman disease
• X-linked inheritance
– Unaffected carrier females(with two X
chromosomes) and affect mainly, but not
exclusively male.
– E.g. duchnee 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
Multifactorial disorders
• With the genetic etiology other factors also plays
important role
By breast
feeding
Genetic
Enviromental
prematurity
Inherited
disorder of
Bi metab
Congenital
hypothyroidism
Neonatal
jaundice
infection
Rh
incompatibility
G6PD
deficiency
EPIDEMIOLOGY OF DISEASES
• Congenital anomaly
– Structural, functional, or biochemical abnormality
present at birth regardless of whether or not it is
detected at that time
• Accurate data is difficult to collect
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
Importance of the genetic component in chronically disabling
congenital disorders in a typical developed country
Type of disorder
Mental handicap:
 Severe
 Moderate/mild
Cerebral palsy
Blindness
Deafness(severe)
Congenital anomalies
Incidence per 1000
births
Genetic component
3.5
25.0
2.5
0.6
Approx 1.0
>50
most
Up to 30%
Very small
50%
>50%
Approx 50%
The birth incidence of the infants with conginital disoreder include those that
are trival or relatively easily corrected, is about 25-60 per 1000
Category
Estimated
birth
/1000
Commonest diagnosis
Dominant
7.0
X-linked
1.33
Recessive
1.66
Familial hypercholesterolemia, Adult polycystic disease of the kidney,
Huntington disease, Neurofibromatosis, Chondrodystropy
Muscular dystrophy, Haemophilia and Christmas disease, Colour vision
disorders, X-linked mental retardation., Glutathione deficiency
Cystic fibrosis, Phenylketonuria, Amino-acid disorder, Werdnig-Hoffman
disease, Thalassaaemias
Chromosomal
3.49
Autosomes
Sex chromosome
Congenital
abnormalities
1.69
1.8
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
Other multifactorial
Genetic, unknown
type
Total genetic
26.2
-
10.06
1.2
Strabismus, Inguinal hernia, Epilepsy, Diabetes, Mild mental retardation
-
Total genetic + nongenetic congenital
anomalies
77.54
Single-gene disorders
51.34
• Incidence of genetic disorders and congenital anomalies up to
the age of 30 years in a typical developed country
• If multifactorial conditions of late onset are added to this
figure, it is estimated that 60-65% of population will suffer
from the genetic diseases in lifetime
• If major environmental causes of death avoided, people must
die of their constitutional, often genetically determined
limitation
• Demographic factors
– Advanced materal age
• Chromosomal disorder & down
• syndromeHaemoglobin disorder and G6PD deficiency
– Consangious marriage
• Still birth, neonatal & childhood death and Congenital malformation
Burden of genetic disease at birth in India
Disorder
Congenital
malformations
G-6-PD deficiency
Down Syndrome
Congenital
hypothyroidism
Beta thalassemia
Sickle cell disease
Amino-acid disorder
Other metabolic
disorders
Duchenne muscular
dystrophy
Spinal muscular atrophy
Incidence
1 in 50
Number per year
595,096
1 in 10-30(M)
1:1139
1:2500
390,000
21,412
10,400
1:2347
1:2500
9,000
5,200
9,760
9,000
1:5000(M)
2,250
1:10,000
2,250
Role of genetic predisposition in some common disorder
Disease
Remarks
Coronart heart
disease
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Cancer
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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
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strong familial tendency with increase prevalence with advancing age
Asthma & allergy
Diabetes
Control Measures
Eugenics
– The study of, or belief in, the possibility of improving the
qualities of the human species or a human population
Negative eugenics:
– To reduce the frequency of hereditary disease and disability in
the community to be as low as possible.
– Done by debarring the people who are suffering from serious
hereditary disease from producing children.
Positive eugenics:
– To improve the genetic composition of the population by
encouraging the carriers of desirable genotypes to assume
parenthood.
Control Measures(cont…)
• Euthenics:
– Euthenics deals with human improvement through
altering external factors such as education and the
controllable environment, including the prevention
and removal of contagious disease and parasites,
environmentalism, education regarding home
economics, sanitation, and housing.
Approaches for prevention
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Basic public health measures
Detection of genetic risk
Genetic family studies
Genetic population screening
– Preconception counseling and screening
– Antenatal screening and Perinatal diagnosis
– Screening of neonate
Basic public health measures
Diseases
Preventive measures
Rhesus haemolytic disease Screening for rhesus blood group
Congenital rubella
Immunizing children and non pregnant women
Testing pregnant women for antibody
Congenital toxoplasmosis Pregnant women to eat only well cooked meat
Neural tube defects
Supplementation of folic acid around the time of
conception
Severly malformed babies Control of blood sugar before pregnancy begins
of IDDM mother
G6PD deficiency
Screening of neonates
Detection of genetic risk
Type of programme
Primary objective
Preconception screening Reducing risks to the
health of the fetus
Antenatal screening
Identification of at-risk
couples and affected
fetuses in time for
possible abortion
Neonatal screening
Case detection for early
treatment
General population
Identification of high risk
screening
factors
Secondary objective
Informed reproductive
choice
Diagnosis of affected
fetus, and prenatal or
neonatal treatment
Data on disease
incidence
Prevention, early
diagnosis and treatment
Objectives of different types of genetic population-screening programmes
Type of service
Condition
Preventive or screening action
Primary
prevention
Rhesus haemolytic disease
Postpartum use of anti-D globulin
Congenital rubella
Immunization of girls
Congenital malformation
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Antenatal
screening
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
Genetic Family Study
• Genetic diagnosis has implications for whole
families as well as the individuals
• Correct diagnosis not only benefits the
individual patient but is also valuable for the
others
• Detailed family history has to be taken for all
diagnosed genetic diseased patient.
Genetic population screening
• A genetic population-screening programme
• A simple “primary screening test” is usually offered to
the whole population
• A screening programme is a public health policy. The
classical requirements are
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A common and potentially serious condition
A clear diagnosis in each case
Sound knowledge of the natural history of the condition
An effective and acceptable method of treatment or
prevention
– Affordable test
Flow chart of genetic screening and Perinatal diagnosis for carriers of a recessive gene,
indicating the non financial benefits and cost of each step in the sequence
Preconception screening and counseling
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When to go
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Parents must know
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The significance of a family history if
With increase in maternal age
Importance of balanced nutrition
Effect of folic acid and multivitamin supplementation
Importance of immunity to rubella
Indication for testing for specific genetic task
eg: rhesus blood group, haemolglobin disorder, Tay-Sachs disease, cystic fibrosis
Effects of smoking, alcohol consumption and medication having risk of miscarriage, congenital,
abnormality and fetal growth retardation
Importance of avoiding certain maternal infection that can harm the fetus
Preconception screening and counseling requires
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The establishment of suitable infrastructure
Improved medical and community education on genetic matter
Freely available educational materials for women and health worker
Basic training in genetic counseling for health workers
Strengthening of laboratory facilities
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
Fetal Anomaly Scaning
• Grossest morphological abnormalities can be detected
• Mostly offered for confirming intrauterine gestation,
gestational age, and fetal viability and number
• Congenital abnormalities scaning, 19 weeks.
• 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.
• Trained ultrasonographers can detect over 70% of all
major malformation. 15-30% of the fetuses in which
abnormalities are detected are chromosomally
abnormal.
Amniocentesis
• Medical procedure, in which a small amount of amniotic fluid,
which contains fetal tissues, is extracted from the amnion or
amniotic sac surrounding a developing fetus, and the fetal DNA is
examined for genetic abnormalities.
• 14th-16th week of pregnancy
• The fetal cells are separated from it. The cells are 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.
• Choriononic villus sampling
– Prenatal diagnosis to determine chromosomal or genetic
disorders in the fetus.
– 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
• Fetal blood sampling(cordocentesis)
– Fetal blood is obtained after 18 weeks safely by USGguided trans-abdominal needle puncture of fetal cord
insertion.
– Fetal loss is 1-2%.
– Used 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.
• Fetal tissue biopsy
– Its best done at 19-20 weeks.
– Sample like fetal skin, muscle liver are taken to diagnose
the disease.
• FISH(fluorescent in situ hybridization)
– New method for detecting numerical chromosome
abnormalities in non dividing cells, it uses fluorescent DNA
probes for specific sequences
• 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,
• PCR in diagnosis of diseases
– early diagnosis of malignant diseases such as leukemia and lymphomas
Screening of neonates
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
Genetic Counseling
• Complex process by which patients or relatives, at risk 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 family planning in order to
prevent, avoid or ameliorate it.
• Basic principles of genetic counseling, the feasibility of
incorporating counseling into primary health care, and the relief of
anxiety of the parents.
• Counseling is important in genetics because of
– The predictive nature of much genetic information
– The physiological impact of knowledge of genetic risk for the
individual and family
– Correct information on risk, on particular disorders and on the
availability of management and prenatal diagnosis.
• The main components are
– A correct diagnosis
– The estimation of genetic risk; this often requires a pedigree and may
call for investigations involving other family members
– The provision of information on existence of risk and on any option for
avoiding it;
– Accessibility for long-term contact; people at genetic risk may need
counseling and support at several times in their lives.
• Types of genetic counseling
– Prospective genetic counseling
• Identifying heterozygous individuals for any particular defect by screening
procedures and explaining to them the risk of having affected children if they marry
another heterozygote for the same gene.
– Retrospective genetic counseling
• Most genetic counseling at present are retrospective, i.e. the hereditary disorder has
already occurred within the family. The couples and family members seek genetic
counseling in connection with congenital abnormalities; mental retardation, etc. and
only a few seek premarital advice.
DNA technology
• Deoxyribonucleic acid (DNA), or an organism's genetic
material—inherited from one generation to the next—
holds many clues that have unlocked some of the
mysteries behind human behavior, disease, evolution,
and aging.
• Recent advances in DNA technology including
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Cloning,
PCR,
Recombinant DNA technology,
DNA fingerprinting,
Gene therapy,
DNA microarray technology
The human genome project
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International scientific research project with a primary goal to determine the
sequence of chemical base pairs which make up DNA and to identify and map the
approximately 20,000-25,000 genes of the human genome from both a physical and
functional standpoint.
The project began in 1990 initially headed by James D. Watson at the U.S. National
Institutes of Health
It remains one of the largest single investigational projects in modern science
While the objective of the Human Genome Project is 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.
Goals
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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.
• Key findings of Genome Project
– will provide clues to how diseases are caused.
– All human races are 99.99 % alike, so racial differences are genetically insignificant. This
could mean all humans are descended from a single original mother.
– Most genetic mutation occurs in the male of the species and as such are agents of
change. They are also more likely to be responsible for genetic disorders.
– Genomics has led to advances in genetic archaeology and has improved our
understanding of how we evolved as humans and diverged from apes 25 million years
ago. It also tells how our body works, including the mystery behind how the sense of
taste works.
• Benefits
– new avenues for advances in medicine and biotechnology.
– easy ways to administer genetic tests that can show predisposition to a variety of
illnesses, including breast cancer, disorders of hemostasis, cystic fibrosis, liver diseases
and many others.
– The etiologies for cancers, Alzheimer's disease and other areas of clinical interest are
benefited
– A researcher investigating a certain form of cancer may have narrowed down his/her
search to a particular gene.
Human genome diversity project
• Started by Stanford University's Morrison Institute and a
collaboration of scientists around the world.
• 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.
– The success of a multi-center trial for treating children with
SCID (severe combined immune deficiency or "bubble
boy" disease) held from 2000 and 2002. (Which was
questioned when two of the ten children treated at the trial's
Paris center developed a leukemia-like condition).
– 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 through the use of modified
bacteria, erythropoietin in hamster ovary cells
– the production of new types of experimental mice such as the oncomouse
– Manufacture of human growth hormone, vaccine for humans, for hepatitis B.
– Creation of GMOs for food use (genetically modified foods