EPIDEMIOLOGY OF GENETIC DISEASES AND ITS CONTROL MEASURES

1. EPIDEMIOLOGY OF GENETIC DISEASES AND ITS CONTROL MEASURES Pravin Pisudde Moderator: Dr Subodh Gupta

2. Framework • Introduction • Categories of genetic diseases • Epidemiology of genetic diseases • Control measures • Genetic counseling • Newer advances • DNA technology • The human genome project • Human genome diversity project • Gene therapy • Genetic engineering • Organization of genetic services in health system

3. Introduction • 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

4. 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.

5. 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

6. 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

7. Multifactorial disorders • With the genetic etiology other factors also plays important role Genetic Enviromental By breast feeding prematurity Inherited disorder of Bi metab Neonatal jaundice infection Congenital hypothyroidism Rh incompatibility G6PD deficiency

8. 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

9. Contribution of genetic and congenital disorders of infant and child mortality in atypical developed country

10. Importance of the genetic component in chronically disabling congenital disorders in a typical developed country The birth incidence of the infants with conginitaldisoreder include those that are trival or relatively easily corrected, is about 25-60 per 1000

12. 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

13. Burden of genetic disease at birth in India

14. Role of genetic predisposition in some common disorder

15. 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.

16. 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.

17. Approaches for prevention • 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

18. Basic public health measures

19. Detection of genetic risk

20. Objectives of different types of genetic population-screening programmes

21. 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.

22. 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 • 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

23. 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

24. Preconception screening and counseling • When to go • The significance of a family history if • With increase in maternal age • Parents must know • 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 • 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

25. Antenatal screening and Perinatal diagnosis

26. 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.

27. 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.

28. 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 USG-guided 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.

29. 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

30. Screening of neonates

31. 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.

32. 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.

33. 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 • Cloning, • PCR, • Recombinant DNA technology, • DNA fingerprinting, • Gene therapy, • DNA microarray technology

34. The human genome project • 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 • 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.

35. 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.

36. 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

37. 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.

38. 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.

39. 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