SELECTED STUDIES

 

Preventive Genetics (Part II)

Primary Health Care and Preventive Genetics

 By Prof. Wagida A. Anwar, M.D.
 

 

 

Introduction:

The spectrum of diseases affecting human kinds is ranging from those, which are purely acquired (environmental) to those, which are purely genetic. Purely acquired disorders are those resulting from infections caused by a wide variety of microorganisms, environmental pollution and those due to nutritional deficiencies. However, over the past few decades, advances in public health have lead to a significant shift where the overall prevalence of acquired diseases has decreased considerably in most population of the world. This has lead to the surfacing of genetic disorders as a major cause of morbidity and mortality (Weatheral, 1991 and Gelehrter et al, 1998). Consequently, infant mortality decreases with an increasing proportion of infants with potentially disabling conditions.

Over the last two generations, there was increasing proportion of death, morbidity, chronic handicap and disability due to Genetically-determined disorders in industrialized countries (Emery and Rimoin, 1999). Recently, they become apparent in a number of developing countries. In the absence of prevention and successful management they may have unforeseen cost implications. Instead of dying in childhood, affected people survive into adult life. As new patients continue to be born, the number of cases requiring treatment, and the costs of treatment, rise cumulatively.

Genetic diseases could affect not only the human physical status but also the mental and psychological built which has the same importance as well. Genetic diseases are chronic in nature and they often require life long care and management strategies. Also, they lead to psychological burden for the patient, the family, the health care system and the community as a whole. 

Genetic diagnosis usually starts with the family history. Clustering of a disorder within families suggests a genetic cause, though infectious diseases, for example, may also cluster within families for environmental reasons. Disorders that are due to mutation in a single specific gene (e.g. family cancer syndromes, haemophilia, or haemoglobin disorders) often follow classical (Mendelian) inheritance patterns, and this permits a diagnosis of inherited disease, even when no appropriate laboratory tests are available. Health care begins even before childbirth through proper antenatal care for pregnant women regarding detection and management of high-risk pregnancies and fetal monitoring.

There are several available initiatives such as implementation of basic reproductive health approaches, including accessible family planning, a diet adequate in folate, iodine, and iron, prevention and management of maternal infections, avoidance of excess alcohol and smoking, which can reduce the birth prevalence of infants with serious congenital disorders to a baseline level. Further reduction depends on population screening programmes, which aim at identifying individuals at increased risk of having children with specific disorders. Approaches include ultrasound scanning for congenital malformations, offering chromosome studies to older mothers, and carrier and neonatal screening using clinical and biochemical methods. However, despite some encouraging recent initiatives, the control of genetic disorders and congenital abnormalities is generally not given the importance it deserves in developing countries (Hamamy, and Alwan, 1997) and no comprehensive model for such interventions is available. Therefore, there is growing recognition of the need for integrated actions towards genetic diseases, including prevention, services for diagnosis and best possible patient care. Worldwide, primary health care services need strengthening in this important area. In each country, this calls for identification of an appropriate infrastructure, reinforcement of laboratory diagnostic services, development of educational programmes, integrating interventions into reproductive health programmes and ensuring feasibility of strategies, as well as on the increasingly important issues related to cost effectiveness of proposed interventions.

Positive contribution is needed in motivating action to control congenital and genetic disorders among developing countries. If health authorities are committed, the agenda for action should include measuring the health burden of congenital and genetic disorders through collection of reliable data, identification of national or local priorities, selection of appropriate strategies and interventions, promotion of the training of health care professionals, increasing the efficiency of existing services and fostering greater involvement of the community in prevention and care through education at the primary health care level. This will result in further planning with all concerned parties towards the implementation of the proposed national or regional or district plan within the primary health care structure(s) available, which will contribute in strengthening of genetic health system delivery and to develop appropriate structures for prevention and control.

 

 

Overview Genetic Disorders:

Genetic disorders and congenital abnormalities occur in about 2%-5% of all live births, account for up to 30% of paediatric hospital admissions and cause about 50% of childhood deaths in industrialized countries (Emery and Rimion, 1999). The magnitude of the problem of such disorders can be attributed to several factors including:

·        the high rate of traditional consanguineous marriages, which increases the frequency of autosomal recessive disorders;

·        a relatively high birth rate of infants with chromosomal disorders related to advanced maternal age such as Down syndrome and other trisomies;

·        a relatively high birth rate of infants with malformations due to new dominant mutations related to advanced paternal age;

·        the high frequency of haemoglobinopathies and glucose-6-phosphate dehydrogenase deficiency in many countries, possibly related to selective advantage against falciparum malaria and other as yet unknown factors;

·        large family sizes, which may increase the number of affected children in families with autosomal recessive conditions;

·        the lack of public health measures directed at the prevention of congenital and genetically determined disorders, the dearth of genetic services and inadequate health care prior to and during pregnancy.

Congenital malformations arise during intrauterine life and are thus present at birth, whether they are recognized at that time or not. Causative factors include chromosomal anomalies, multifactorial etiology, single gene disorders and environmental factors; can be found in many cases. There are considerable ethnic and geographical variations in the birth prevalence of specific congenital malformations, (WHO, 1997).

Studies in the Eastern Mediterranean Region showed that congenital malformations are as important a cause of perinatal mortality as in industrialized countries, a higher frequency of congenital malformations due to autosomal recessive inheritance, related to traditional consanguineous marriage in the Region, a relatively high birth rate of infants with chromosomal disorders related to advanced maternal age: a proportion of these have severe malformations that lead to perinatal or infant death; and a relatively high birth rate of infants with malformations due to new dominant mutations, related to advanced paternal age (WHO, 1997).

Inadequate health care prior to and during pregnancy leading to increased frequency of congenital infections including rubella and toxoplasmosis, poorly controlled maternal diabetes mellitus, unsupervised intake of drugs or folk remedies during pregnancy, inadequate dietary intake of folate, other vitamins, iron, and iodine before and during pregnancy.

The wide variation in the rates of congenital malformations in different countries may be ascribed to a multitude of factors including:

·        local variations in experience and expertise

·        local variations in the demographic factors

·        age at which diagnoses were made and registered

·        design of the study (e.g. prospective or retrospective)

·        inclusion or exclusion of stillbirths and neonatal deaths

·        the extent of physical examination and investigations performed

·        differentiation between major and minor anomalies, how the latter are defined, and the extent of exclusion

·        lack of postmortem examination.

 

Some preventable causes of genetic diseases and congenital malformations:

It is estimated however that over 75% of severe congenital disorders can be treated or prevented, though a wide range of approaches and an appropriate health infrastructure are required (Czeizel  et al, 1993). Some disorders can be prevented from arising in the first place by correcting their cause (primary prevention). Others can be avoided by early detection and appropriate management, or by identifying individuals and couples at risk and providing genetic counselling. Increased understanding of the role of genetic predisposition in common diseases is also opening the door for prevention based on identifying susceptible individuals or groups. These may then be advised to modify their lifestyle so as to avoid exacerbating environmental factors, or may be offered regular surveillance. The role of genetic diagnosis in general medical practice is developing rapidly.

Examples of preventable congenital malformations.

1- Phenylketonuria (PKU) is a disease of significant importance with an inborn error of metabolism. It leads to mental retardation and other developmental disabilities if untreated in infancy. With an inborn error of metabolism, the body is unable to produce proteins or enzymes needed to convert certain toxic chemicals into nontoxic products, or to transport substances from one place to another (Glanze, 1996). The body's inability to carry out these vital internal functions may result in neurological damage. In the case of PKU, the amino acid called phenylalanine accumulates. As phenylalanine builds up in the bloodstream, it causes brain damage. Infants with untreated PKU appear to develop typically for the first few months of life, but by twelve months of age most babies will have a significant developmental delay and will be diagnosed with mental retardation before school entry.

In a recessive condition, an individual must have two defective genes in order to have the disorder. Individuals with only one copy of a defective gene are called "carriers," show no symptoms of having the disease, and usually remain unaware of their status until they have an affected child. In order for a child to inherit PKU, both parents must be PKU carriers. When this occurs, there is a one in four chance of their producing an affected child with each pregnancy. Boys and girls are equally at risk of inheriting this disorder.

Genetic screening is a search in the population for persons that possess genotypes which are associated with diseases or predispose to diseases. The principle of newborn screening is to detect disorders in which symptoms would not be clinically present until irreversible damage occurred (Galvis, 1998). Selective screening program is important in order to detect individuals who are likely to have the disorder and their high risk relatives for prevention and therapy.

The food program used to treat those with PKU is quite expensive. Although government may pay for the formula, most insurance companies do not cover the cost of treatment for children/adults with PKU because it is considered nutritional rather than medical therapy. While phenylalanine restricted diets have proven to be highly effective in preventing mental retardation, it is now recognized that there may still be subtle cognitive deficits. Usually the individual has a normal IQ, but the incidence of attention deficit hyperactivity disorder (ADHD) and learning disabilities is higher compared to those children who do not have PKU (Yanicelli, et al, 1986). Therefore there is an immediate need for the development of an accurate, sensitive and reliable method for the early detection system of the PKU.

Experts recommend that testing for PKU should be done when the infant is at least twenty-four hours of age but less than seven days old. If an infant is tested too soon after birth, there is a chance that some cases of PKU will be missed, as the phenylalanine level will not have risen yet. Now that many hospitals are discharging mothers and infants twenty-four hours after birth, there is a greater likelihood of this happening. It is recommended that infants receiving the test during the first twenty-four hours of life be re-tested at two to three weeks of age during their first postnatal pediatric visit (March of Dimes, 1994).

2- Thalassaemia are a group of heritable anaemias of varying degrees of severity, occurring early in life. They are caused by a decreased rate of synthesis of one or more globin chains, resultant in chronic haemolysis (Honig, 1990). It was originally widespread in the Mediterranean Basin, South-East Asia and various countries in equatorial Africa. However, following its persistent migration over planet it is today verifiable in almost all regions of the globe.

National screening and prenatal diagnosis programmes can be provided once the spectrum of beta-thalassaemia mutations has been identified within a population. From a molecular genetic standpoint a beta-thalassemia prevention program based on carrier screening and prenatal diagnosis can be implemented.

3- Women should be informed of there is a risk of miscarriage after the age of 40. Between the ages of 40 and 50 the risk in each pregnancy of a live born child with a serious chromosomal anomaly rises from 1.5% to 8% and estimated data indicate that in some countries of the Eastern Mediterranean Region, almost 50% of Down syndrome children are born to mothers over 40 years of age. The incidence of chromosomal disorders and spontaneous abortion rises rapidly with maternal age after the age of 35 (Hook, 1992). Provision of appropriate family planning services leads to a selective fall in births to older parents and a reduction of genetic risk.

4- Iodine deficiency is well established as the commonest single cause of preventable mental subnormality of all degrees, particularly in mountainous areas and where there is a subsistence economy. A concerted effort to eliminate the problem through iodization of salt and provision of iodized oil (World Health Organization 1993).

5- Iron deficiency is also extremely common among pregnant women and children. Haemoglobin level is directly related to physical energy, and iron deficiency causes a measurable reduction of IQ levels in children (Cook et al, 1994). Iron supplementation of basic foodstuffs might therefore be considered.

6- Consideration may be given to monitoring seronegative pregnant women, as fetal abnormality may be avoided if Toxoplasmosis is diagnosed and treated (Desmonts et al-1985).

7- Women with insulin-dependent diabetes mellitus have about a 6% risk of a seriously malformed child in each pregnancy. They can greatly reduce their risk by meticulous control of the blood sugar, which must be started before pregnoncy begins because major malformations arise very early in embryonic development (Ylinen et al, 1984). Appropriate advice for women and assistance in achieving the necessary standard of blood sugar control should be a routine part of diabetes care throughout the Region.

Prevention of genetic diseases and congenital malformations:

The experience available shows that over half of congenital and genetic diseases can be prevented, but this requires a variety of approaches. There is an urgent need for systematic national and international initiatives aimed at reducing the health burden of congenital disorders and disabilities. It is necessary to  integrate health planning for prevention and rehabilitation of disabled with the establishment of a control program through the available Primary Health Care system. Primary health care has a major role in all activities related to prevention and health promotion supported by an effective referral system.  The medical, paramedical and community workers should be the resource persons for community genetics services.

Responsibilities in implementing planned activities should be defined according to the level of health professionals in each country. Major issues to be addressed should include correct information on genetic risks that are common locally and ways to reduce them.  In developing countries, there is a lack of knowledge about national pattern, the magnitude and the determinants of the genetic diseases. This gap of knowledge may affect the judgment of decision makers and practitioners in prevention and control of genetic diseases.   The priority is to develop a system depending on the available information of different centers and to ensure sustainability of data collection and analysis.

Assessment of the existing resources available for the introduction of genetic services in primary health care, include the following

1-      Information about the local/national health budget and proportion of spending/expenditure on genetic services.

2-      Evidence based description of the organization of primary health care and reproductive health services, including a description of referral pathways for patients and families thought to be at risk. Description of existing infrastructure and mechanisms for monitoring quality assurance in genetic services especially laboratories. Assessment of the acceptability of prenatal diagnosis and genetic abortion at different stages of pregnancy. Description of procedures for obtaining informed consent from patients and families, if any.

3-      Screening and early detection of genetic diseases, whether routine schedules or national campaigns, are the cornerstones for prevention of these diseases in childhood. Integrated network can play an important role in saving thousands of lives every year in developing countries. Benefiting from local and international technical experiences and available human resources to improve provided health programs and develop new methods for diagnosis and provision of health services. Attain the complete integration of health service package for these target groups with continuous monitoring and evaluation to improve quality of services achieving herewith-main goals and objectives.

 

In the planning process it is important to assure the following:

1-     Proper distribution of health services provided by these programs covering deprived unreached and slum areas, high risk areas and the poor categories through outreached programs and health insurance services including all school children and births. It is mandatory to implement national campaigns and establishing more intensive care units for neonates, treatment centers and child care units in all governorates.

2-     It is extremely important to coordinate at the planning phase with other health protection and promotion programmes like maternal and child health, and family health and reproductive health. Close coordination with the Expanded Programme on Immunization (e.g. on rubella vaccination), the nutrition programme (on correction of micronutrient deficiencies), and laboratory and blood transfusion services should also be ensured. Such collaboration and coordination should continue throughout the implementation and evaluation phases.

3-     Consider educational institutions for health professionals, e.g. medical and nursing schools, should be at the forefront of the national programme and should be actively involved in preparing the national plan. They have two major roles, first in revising teaching curricula and methods to respond to current and future needs of the programmes, and secondly, to provide leadership in promoting preventive and clinical services, and human resources development.

4-     Involving the community is of paramount importance. The public and the parents should be represented on the national committee and be involved in major initiatives during the planning, implementation and evaluation phases of the programme. Nongovernmental organizations should be actively involved in fund-raising, and in public and professional education.

 

Strengthening Primary health care services: This calls for identification of an appropriate infrastructure, reinforcement of laboratory diagnostic services, development of educational materials for women and primary care workers, and training in basic genetic counselling for primary care workers. Incorporation of services into the maternal and child health programme can represent a great opportunity for the prevention of congenital and genetic disorders. 

Accessibility to modem genetic diagnostic services: The health care system should be developed to make genetic counselling available to all families who need it. The role of family doctor and the paediatrician in identifying families at risk and providing genetic counselling is crucial. There is a need for training of experts in medical genetics, of non-medical genetic counsellors to work with them in primary health care. Facilities for cytogenetic deoxyribonucleic acid (DNA) and biochemical studies are needed in order to improve diagnosis capabilities which are very limited in developing countries. A molecular revolution is increasing the power of medical diagnostic techniques, and expanding the possibilities for identifying genetic disease and predispositions.

Human Resources Development: Despite having a large number of scientists specialized in Clinical Genetics or related specialties, there is no unified approach to teaching these disciplines to family doctors providing primary health care.

Primary health care workers need the following training and information:

a.       Training in taking and recording a basic genetic family history, including for large families with multiple consanguineous marriages.

b.      Guidelines on detecting possible genetic risk, e.g. suspicion of diabetes, single gene disorders or a familial cancer, and on lines of referral.

c.       Training in methods for examining newborn children for congenital malformations, for timely specialist referral.

d.      Training in the basic ethical principles and techniques of genetic counselling.

e.       When genetic screening is available, e.g. for haemoglobin disorders, training in how to detect and counsel carriers and appropriately refer couples at risk.

f.        Access to appropriate information materials for patients and families and the general public.

g.       Information on specialist services available and on any family support associations that exist, and their role.

 

Medical geneticists have an important role in training primary health care workers in genetic aspects of disease and should have a long-term role in the education programme.

 

Appropriate infrastructure for pre-conception counselling will differ in different communities. It may be integrated into a comprehensive primary health care network where one exists. Implementation of WHO's mother- baby package for safe motherhood could have a considerable potential for the prevention of hereditary disorders and congenital abnormalities, if the above-mentioned public health approaches are integrated into it. When resources permit, newborn screening demonstration and research programmes should be established. Research protocols, methods and training should be standardized.

 Premarital counseling, especially in the presence of parental consanguinity and family history of a congenitally malformed child is a necessity. It is recommend to perform the following:

Prevention of congenital and genetic disorders at the population level depends on a combination of the following approaches:

1- Basic public health approaches. Some simple public health approaches (rubella immunization, prevention of rhesus haemolytic disease, correcting iodine deficiency, and family spacing) are effective and are already being implemented in some countries of the Region.

Family planning is particularly used by older couples, and can reduce the prevalence of genetic problems related to parental age. Ensuring that all women will have access to appropriate health care, all through their lives, that will enable them to go safely through pregnancy and childbirth, and provide married couples with the best chance of having a healthy baby. General availability of information and family planning would lead to a significant reduction in the frequency of miscarriage, and the frequency of new cases of Down syndrome could fall by up to 50%.

2- Maternal nutrition. Women need a balanced diet that is adequate in iron, vitamins including folate, and iodine where appropriate, throughout the reproductive years, and particularly pre-conception. There is strong evidence that an optimal diet reduces the frequency of unsuccessful pregnancy outcomes and severe congenital malformations.

3- Special control programmes for the haemoglobin disorders. These, including population screening, are being adopted by many.

4- Availability of genetics services. Genetic diagnosis and counselling should be available to all families where there is the possibility of congenital or genetic disorders. The benefits of genetic counselling are substantial. It permits diagnosis, prognosis and guidance on management of affected people. It replaces misinformation and misconceptions with correct information, often provides reassurance for family members, and allows reproductive and other relevant decisions to be made on an informed basis. Genetic counselling is most effective when it is available to the whole population at risk, and when it is delivered prospectively (i.e. before a couple has started to have children).

A nucleus of specialist genetic counselling services exists in some countries, but in general genetic counselling is currently limited to some families with an affected child. Its impact is also limited by lack of awareness among health workers. Key laboratory services exist in some centers, but prenatal diagnosis is available on a very limited scale.

5- Newborn screening. This is an effective means of preventing morbidity due to some disorders, such as phenylketonuria, congenital hypothyroidism, and sickle cell disease and G6PD deficiency when relevant. Each country needs to decide which disorders to screen for, on the basis of local epidemiological studies.

Genetic approaches appropriate at the primary care level include pre-conception information, screening, counselling, identification and referral of individuals and families at increased genetic risk. Since the structure of primary health care and level of service provision differ widely between the countries, these approaches will need to be developed and implemented according to local circumstances and available resources: the situation in many countries allows immediate implementation, but in others prior planning is needed.

When the relatively simple and effective measures are incorporated into primary health care, many serious disorders will be prevented from arising in the first place.

Pre-conception information and counselling:

Primary prevention of genetic and congenital disorders depends largely on pre-conception information, screening, and counselling. Basic information that should be available to women prior to pregnancy is as follows:

  1. The risk of miscarriage and newborn chromosomal abnormality rises with maternal age. These risks can be reduced by family planning.
  2. Diet should be adequate in iodine, vitamins and iron, before, as well as during pregnancy.
  3. It is desirable to know your rhesus blood group.
  4. It is desirable to be tested for immunity to rubella.
  5. Risk of infection with toxoplasma or listeria can be avoided.
  6. Smoking, alcohol, and medications for specific disorders can increase the risk of miscarriage, congenital abnormality and fetal growth retardation.
  7. Genetic counselling is available for families with a history of repeated abortions, stillbirth, perinatal and infant death, congenital malformations, disability and unexplained childhood death.
  8. Availability and implications of carrier testing for specific common genetic risks (e.g. haemoglobin disorders, G6PD deficiency).

 

 

Role of primary care workers in basic community genetics

At the primary health care facilities, identification of patients and families for referral to specialist genetic counselling is required. When specialist services exist, their usefulness to the community depends on appropriate awareness and referral by primary health care workers. In general, very little genetics was included in the training of existing health workers. The adjustments needed in the medical and nursing curricula and the requirements for updating current primary care workers.

The role of primary health care workers in community genetics are summarized as follows:

  1. Provide correct information on genetic risks that are common locally and ways to reduce risks.
  2. Be aware of common genetic disorders and their management.
  3. Be aware of local specialist centres, and refer affected children and couples at risk appropriately.
  4. Be able to take a basic genetic family history, in order to identify people in need of specialist referral.
  5. When services are available, arrange screening and counselling for carriers of common single gene disorders (e.g. haemoglobin disorders). Inform relatives of known carriers of their high chance of also being carriers and offer testing.
  6. Give advice on reducing the risk of common disorders with genetic predisposition.
  7. Understand the basic ethical; principles and techniques of non-directive genetic counselling.

 

Priority areas and actions need to be achieved for management of congenital disorders:

These can help to control congenital disorders.

·        Establishment of a system for screening of genetic diseases (such as Beta-thalassemias and Phenylketonuria (PKU) in cooperation with other well recognized centers. Developing such model of national network can be applied to different diseases in order to evaluate the problem on scientific basis.

·        Establishment of a National Program for Genetic Counseling.  The main goal of the program is to limit the occurrence of genetic diseases that lead to handicapping and mental retardation. In order to achieve such goal, several strategies were considered including the following:

·        Constitution of Higher Committee to supervise the program. The committee headed by the Minister of Health and includes members from different universities and Clinical Genetics Centers in Egypt.

·        Establishment of Genetics Counseling Clinics to act as a linkage between the Primary Health Care (Family Doctors) in rural and urban areas and the Specialized Centers.

·        Cooperation between MOHP, universities and the specialized Genetics Counseling Centers in preparation of well trained technical staff who can work effectively in the program.

·        Establishment of an effective referral system between different levels of services. At the primary health care units in rural and urban areas, physicians can identify suspected cases and refer them to the genetic counseling clinics. At the clinics, provisional diagnosis is made depending on examination of the referred cases, to be referred to the higher level (Specialized Centers) if needed.

 

While these advances have the potential to dramatically impact medicine and research, clearly there is a great deal of work to be done to address these issues and they also raise a number of concerns and critical questions to be answered…….?

·        What should people know before genetic testing? 

·        How do you inform family members of genetic results?

·        Who should have access to genetic information?

·        Should insurances companies have access to genetic information?

·        Can developing countries devote their limited resources to these issues, or should they remain indifferent and ignore these issues?

References:

Further Readings

Ahmed S. Teebi & Talaat I. Farag (1997, Eds). Genetic Disorders Among Arab Populations. New York: Oxford University Press.

Sadika, A. Al-Awadi & Talaat I. Farag (2006). Community Genetics in Kuwait: A 25 Year Experience. Ambassadors Online Magazine. Vol 9. Issue 2: http://ambassadors.net/archives/issue20/selectedstudy12.htm

 

Prof. Wagida Anwar, MD is a Professor of Community, Environmental and Occupational Medicine and Director of Ain Shams Center for Genetic Engineering and Biotechnology (ACGEB) at Ain Shams University, Cairo, Egypt. She is the first recipient of the EMS-Hollaender International Fellow Award, 2000. She was a fellow at Collegium Ramazini (Italy); adjunct associate professor in the Department of Preventive Medicine and Community Health, University of Texas; adjunct professor at the Medical School of the University of Northumbria (UK); chairperson of the Regional Advisory Panel (RAP) for Reproductive Health Research, WHO (Switzerland); and Secretary-General of the International Association of Environmental Mutagen Societies (IAEMS). In Egypt, she has served as the former president of the Pan African Environmental Mutagen Society (PAEMS); the Secretary-General of the Egyptian Environmental Mutagen Society; a member of the National Environmental Research Council; National Academy of Scientific Research and Technology; National Committee of Genetics; National Academy of Scientific Research and Technology;  Member of the National Committee of Toxicology; National Academy of Scientific Research and Technology; member of the Environment Committee; National Women Council; and member of the Board of the General Federation of  Non-Governmental Organizations. Her email is wagidaanwar@yahoo.com


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