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Indian Journal of Human Genetics, Vol. 13, No. 1, January-April, 2007, pp. 21-25 Original Article A monozygotic twin pair with β-thalassemia carrier status in a Dudh Kharia tribal family of Orissa Balgir RS Division of Human Genetics, Regional Medical Research Centre (ICMR) Chandrasekharpur, Bhubaneswar - 751 023, Orissa Code Number: hg07004 Abstract Background: The β -thalassemia syndrome is a genetically inherited commonly encountered hematological disorder in the state of Orissa. It causes high degree of morbidity, mortality and fetal wastage in the poor vulnerable people.Aims and Objectives: There is an equal probability (50% chance) in every singleton pregnancy that a carrier parent of β -thalassemia major would either bear normal or carrier offspring, but not two offspring with carrier of β -thalassemia major genotype together. For the first time, a carrier parent of β -thalassemia major gene has born progeny (three daughters and a twin male offspring) with a carrier status of β -thalassemia major in Dudh Kharia tribal family studied from Sundargarh district of Orissa. Materials and Methods: We screened randomly selected population of Dudh Kharia tribe from Sundargarh district of Orissa for hemoglobinopathies to assess the extent of the problem, design possible interventions and provide genetic counseling to them. A family with twin children was identified during screening in Lata Gaon in Bargaon block of Sundargarh district of Orissa for the above-mentioned study. Background information for this family such as name, age, sex, tribe, native place, reproductive history, family pedigree and clinical signs and symptoms were also recorded. Standardized genetic and hematological procedures and techniques were followed for analysis. Results: Laboratory investigations for alkaline electrophoresis of blood lysate on cellulose acetate membrane showed raised hemoglobin A 2 level in mother (Hb A 2 = 5.3%), in three daughters (Hb A 2 =6.5, 5.9, 5.5% in chronological and birth order), in two twin sons (Hb A 2 =5.9% and 6.0%) and normal (Hb A 2 = 3.3%) for father. Hence, all the children i.e., three daughters and two twin sons, including the mother were β -thalassemia carriers. Since all the hematological parameters i.e., red cell indices, G-6-PD enzyme activity, ABO and Rhesus blood groups and identical β -thalassemia (trait) genotypes with identical clinical manifestations and hematological profile of the twin sons under similar environmental conditions, hence they were labeled as identical monozygotic twins. Conclusions: It is a rare occasion when a single pregnancy carries either one or two abnormal genotypes at a time in a womb in human beings. Monozygotic twins are genetically alike and provide appraisal of the expression of identical genotype under the different environmental conditions. Keywords: β-thalassemia syndrome, carrier parents, environment, hematogenetical disorder, monozygotic twins, Orissa Introduction The β -thalassemia syndrome is an inherited hemoglobin disorder characterized by reduced production of β -globin chain. β -thalassemias are among the commonest genetic disorders in the world and more than 200 mutations have been described to date. The severe forms of β -thalassemia produce marked anemia starting a few months after birth and survival relies on regular blood transfusion and the lifelong use of drugs to prevent iron accumulation. The victims include the growing children, adolescent girls, pregnant women and a large chunk of ignorant people. [1] Inherited disorders of hemoglobin cause high degree of hemolytic anemia, frequent vulnerability to jaundice, painful crisis and highly susceptible to various infections and are responsible for high infant morbidity, mortality and fetal wastage. [2],[3],[4] These disorders have become a life long social, psychological and financial burden on the society. [1],[5],[6] There is no permanent cure of β -thalassemia. Most of the cases remain undetected, undiagnosed and untreated in Orissa. Due to nonavailability of basic diagnostic facilities and absence of optimal treatment, many of these affected individuals die in infancy, childhood or with a limited span of life. [2] The β -thalassemia syndrome, which has an autosomal recessive inheritance, is not uncommon in Central-Eastern India. The homozygous β -thalassemia is a major cause of high infant morbidity, mortality and fetal wastage in Orissa. [4],[7] The frequency of β -thalassemia is high in general castes, [8] scheduled castes [9] and in some scheduled tribes [10],[11],[12] in the state of Orissa. Since the time of Sir Francis Galton who studied intelligence in twins in the later part of the nineteenth century to reveal the contribution of heredity and have provided research inputs for the appraisal of nature-nurture controversy for determining the relative effects of genetics and environment. Human twins provide the simplest and most powerful method for disentangling the influence of environmental and genetic factors on human characteristics. As the identical, monovular or monozygotic (MZ) twins are more similar with respect to same genotype or the same genes than the fraternal, binovular or dizygotic (DZ) twins, therefore, this is taken as evidence of a genetic influence on particular characteristics. Identical twins are genetic duplicates. Both types of twins share common life experiences. Identical twins differ from fraternal twins in the number of genes they have in common. By studying identical and fraternal twins and their families, we can estimate how genes and environment interact to influence characters, strengths, vulnerabilities and values. In other words, the information collected about how alike or different members of a twin pair allow us to determine the influence of genes and environment. If a pair of identical twins are separated at birth and raised apart, then the similarities and differences between them can be very interesting. The similarities are more likely to be due to heredity and the differences are more likely to be due to environment. The MZ and DZ twins who are separated early in life and reared apart are a fascinating experiment of nature. The comparison of MZ with DZ twins yields information on the percentage of phenotype variance ascribable to heredity (H). If under a given environment, both members of a twin pair develop the same phenotype, the twins are said to be concordant. The comparison of MZ twins who have been reared apart gives an opportunity of nature-nurture interaction to the appraisal of the effects of two different environments on the same genotype. Thus, twin studies provide information on the relative contribution of heredity and environment in the manifestation of a trait, but the mode of inheritance could not be known by multiple births. To the best of our knowledge, no study has ever reported the occurrence of monozygotic twins in β -thalassemia carrier parent(s). This study reports one family of scheduled tribe community (Dudh Kharia) with a rare monozygotic twin pair with β -thalassemia trait (carrier) born to one β -thalassemia carrier parent in Orissa. Materials and Methods Traditionally, the Kharia tribe is a hunting and food gathering community, practicing shifting cultivation and follows tribal endogamy; and mostly confined to Sundargarh and adjacent districts of Orissa. Kharia tribe has three distinct subgroups, Dudh (Pure) Kharia, Delki (Late comer) Kharia and Hill (Dwellers of hills) Kharia based on the religion and socio-cultural practices, although originally they belonged to one ethnic stock. Dudh Kharias are now converted Christians, whereas, the Delki Kharias are Hinduised tribe. Hill Kharias who reside in Simlipal forest reserve in Mayurbhanj district are the most primitive out of them. The marriage between these three sects is now unheard. Reproductively and genetically, they are completely isolated from each other. We screened randomly selected population of Dudh Kharia tribe for hemoglobinopathies to assess the extent of the problem and design possible interventions and provide genetic counseling to them. A family with twin children was identified during screening in Lata Gaon in Bargaon block of Sundargarh district of Orissa for the above-mentioned study. Background information for this family such as name, age, sex, tribe, native place, reproductive history, family pedigree and clinical signs and symptoms were also recorded. The index case and other available family members such as parents, brother/sister after taking informed/written consent were also subjected to clinical examination and laboratory investigations for confirmation of the diagnosis. They were also imparted genetic/marriage counseling accordingly as a measure to prevent further spread of the disease in the community. 2-3 ml intravenous blood samples were collected using sodium salt of ethylene diamine tetra acetic acid (EDTA) as anticoagulant by disposable syringes and needles from each individual under aseptic conditions after obtaining the informed consent. Laboratory investigations were carried out following the standard procedures. Hematological parameters were studied by using an automated Blood Cell Counter (Model- MS4, Melet Schloesing Laboratories, France). The routine hemoglobin lysate electrophoresis was carried out on cellulose acetate membrane (CAM) in Tris-EDTA-Borate buffer at pH 8.9 and quantification of A 2 fraction of hemoglobin was done by elution method; [13],[14] the value more than 3.5% of A 2 fraction of adult hemoglobin was taken as cut off point for determining the β -thalassemia trait. Estimation of fetal hemoglobin was done as described by Weatherall. [14] All the blood samples were further subjected to confirmation by doing the hemoglobin variant analysis (made for Bio-Rad Diagnostics Group, Hercules, California, USA). Results Both parents (father and mother) were clinically examined by a medical doctor for signs and symptoms of β -thalassemia, irrespective of laboratory findings. They did not complain of any health problem. They were healthy (husband aged 48 years and wife 39 years) couple having non-consanguineous love marriage within the same village (Lata Gaon) in Bargarh block of Sundargarh district in Orissa. They had neither taken any blood transfusion nor suffered from jaundice or respiratory problems. They had in all five children (3 elder daughters and 2 younger twin sons), without any abortion, stillbirth or neonatal death. Both parents as well as children had abnormal hematological (red cell) indices as well as red cell morphology indicating iron deficiency/hematological disorder [Table - 1]. The red cell indices like hemoglobin level, RBC count, HCT, MCH and MCHC were quite low in both parents as well as in the children [Table - 1]. The sickling test was negative for all, whereas, the NESTROFT was positive for all except the father, suggesting either iron deficiency or β -thalassemia. Laboratory investigations for alkaline (pH 8.9) electrophoresis of blood lysate on cellulose acetate membrane (CAM) showed raised hemoglobin A 2 level in mother (Hb A 2 = 5.3%), in three daughters (Hb A 2 =6.5, 5.9, 5.5% in chronological and birth order), in two twin sons (Hb A 2 =5.9% and 6.0%) and normal (Hb A 2 = 3.3%) for father [Table - 1]. Hence, all the children i.e., three daughters and two twin sons, including the mother were β -thalassemia carriers. However, fetal hemoglobin levels for all family members were in the normal range (Hb F= 0.6-0.9%). The G-6-PD enzyme activity was normal in all. The Rhesus (D) blood group was also positive in all family members. The father had O phenotype, whereas, the mother had B phenotype. Since all the hematological parameters i.e., red cell indices, G-6-PD enzyme activity, ABO and Rhesus blood groups and identical β -thalassemia (trait) genotypes with identical clinical manifestations and hematological profile of the twin sons under similar environmental conditions, hence they were labeled as identical monozygotic twins. Discussion The most striking and rare finding in the present study is that one of the parents with carrier of β-thalassemia major gene has born progeny (three daughters and a twin male offspring) with a carrier status of β -thalassemia major in Dudh Kharia tribal family from Sundargarh district of Orissa [Table - 1]. There is an equal probability (50% chance) in every singleton pregnancy that a carrier parent of β -thalassemia major would either bear normal or carrier offspring, but not two offspring with carrier of β -thalassemia major genotype together in a singleton pregnancy. It is a rare occasion when a single pregnancy carries either one or two abnormal genotypes at a time in a womb in human beings. The present study reports for the first time the occurrence of monozygotic twins in a singleton pregnancy in the β -thalassemia carrier parent from Sundargarh district of Orissa. The nature-nurture debate may overlook the most important forces that shape human life. It is well established that identical twins-who develop from a single egg that splits after fertilization and, therefore, have the same genes-to learn how genes influence traits or predispose people to disease. Identical twins who grew up in the same household (and presumably ate the same foods, went to the same schools and so forth) share a particular trait more strongly than do fraternal twins, who come from two, separately fertilized eggs and whose genes are no more alike than those of any other siblings, it would be interesting that the similarity is due to genes rather than environment. It is the Nature rather than the nurture. In other words, monozygotic twins are genetically alike and, thus, provide means of appraisal of the expression of identical genotype under the different environmental conditions. Identical or monozygotic twins share cent percent (100%) of their genes. The present study points to the above ideological and conceptual debate. Tests for prenatal diagnosis such as amniocentesis, cord blood or chorionic villi sampling, fetal biopsy, non-invasive technology, etc. already exist to check a fetus for β -thalassemia during pregnancy. But some couples have strong personal objections to abortion when a pregnancy is already established. Pre-implantation genetic diagnosis (PGD) could provide couples with another way to avoid passing on β -thalassemia syndrome or sickle cell disease. A couple who was carrier of sickle cell disease had twin babies who were completely free of the sickle cell gene with the application of a technique called pre-implantation genetic diagnosis (PGD), in which fertilized embryos are tested for the disorder before implantation in the woman′s uterus. [15] Further refinement in this technology will become a powerful diagnostic tool in the assistive reproductive technology (ART) in the near future. Individuals with the β-thalassemia syndrome or sickle cell disease have recurring episodes of intense pain; an increased susceptibility to infections, strokes and organ failure; and a lowered life expectancy. It is very imperative that predictive or preventive genetics and novel technologies can play a significant role in mitigating the sufferings of the affected persons. Further molecular studies are called for in such type of monozygotic twins that may provide new insight into this common genetic and health problem in India. Conclusions Both identical and fraternal twins allow us to determine the influence of genes and environment. Dizygotic twins with different β-thalassemia syndrome or sickle cell genotypes under similar environmental conditions manifest different clinical and hematological picture. It is a rare occasion when a single pregnancy carries either one or two abnormal genotypes at a time in a womb in human beings. Monozygotic twins are genetically identical and, thus, provide means of appraisal of the expression of identical genotype under the different environmental conditions. The present study reports for the first time the occurrence of monozygotic twins (β-thalassemia offspring) in a singleton pregnancy in a β-thalassemia carrier parent from Sundargarh district of Orissa.Acknowledgements Author is grateful to Prof. N. K. Ganguly, Director General, ICMR, New Delhi and Dr. S. K. Kar, Director, RMRC (ICMR), Bhubaneswar for providing the necessary facilities. Thanks are also due to Mr. R. K. Mishra, Laboratory Technician for his field and laboratory support.References
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