Current Status of Beta Thalassemia in India

225

Current Status of Beta Thalassemia in India

15
Current Status of Beta Thalassemia in India
Challenges and Road Map Ahead
Roumi Deb and Ratika Samtani

Introduction

Thalassemia are hemoglobinopathies which are a result of inherited

genetic conditions that originate from a lack or malfunction of the adult
haemoglobin protein. Hereditary haemoglobin disorders, particularly
Beta Thalassemia and Sickle cell disease are the most common single
gene disorders globally and are also one of the important causes of
genetic mortality and morbidity. They represent one of the most common
monogenic disorders in India rendering a heavy economic burden on the
families and nation. In their severe forms, they are associated with chronic,
life impairing and life threatening diseases that can lead to disability or
death. Considering Beta Thalassemia, unfortunately many children in
and across the globe continue to be born and suffer from it mainly due to
lack of awareness and lack of comprehensive programmes and strategies
to prevent them.
The term thalassemia comes from the Greek word “Thalassa,” which
according to the Greek mythology represents the “spirit of the sea”. Even
though Thalassemias are prevalent across diverse geographies, the name
thalassemia was coined so as a very high frequency of thalassemia was
first observed in the Mediterranean Basin with many families passing the
mutations through generations. Thalassemia’s basically involves changes
or alterations in the globin chains (alpha or beta chains) that make up the
haemoglobin molecule. The disease is classified as either alpha or beta
thalassemia depending on whether the alpha or beta haemoglobin gene
harbours a mutation. Four genes (two from each parent) are needed to make
enough alpha or beta globin protein chains of the haemoglobin molecule.
226 Anthropology of Health and Wellbeing

The severity of thalassemia is determined by how many of these genes are

affected—higher the number, more severe the symptoms.
Beta Thalassemia, caused by mutations in the Human Beta-Globin
gene, is more diverse as compared to Alpha Thalassemia (which is
caused by the reduction of alpha globin chains) and is characterised
by a quantitative reduction of Beta globin chains. Different types of
Beta-thalassemia include Beta-Thalassemia minor/Beta-thalassemia
carrier/Beta-thalassemia trait, Beta-thalassemia intermediate and Beta
Thalassemia major. The HBB gene directs the production of a protein
known as beta-globin. As mentioned earlier, haemoglobin contains
beta-globin as a component (subunit) and is made up of four protein
subunits, two of which are beta-globin subunits and two of which are
alpha-globin subunits. The generation of Beta-globin chains is decreased
or absent when the Beta-globin gene is mutated. Point mutations which
account for the vast majority of mutations in the Beta globin gene causing
Beta Thalassemia are unique to geographic populations. These genetic
mutations cause a range of reduction and severity in the expression of Beta
globin gene—from a minor reduction (mild β+ thalassemia alleles) to a
total loss (β0 thalassemia). In other words, some mutations in the HBB
gene block beta-globin development entirely. Beta-zero (0) thalassemia
is characterised by the lack of beta-globin. Other HBB gene mutations
enable some beta-globin production but at a lower level.
Of all the types of Beta Thalassemia, Beta thalassemia major is the
most severe and Beta thalassemia intermedia is milder than thalassemia
major. Beta Thalassemia major occurs when two mutated copies of the
Human Beta Globin gene are inherited resulting in absence of beta-
globin thereby leading to reduced amount of functional hemoglobin.
Red blood cells do not grow normally without enough haemoglobin,
resulting in a lack of mature red blood cells. The signs and symptoms
of the disease appear in the first two years of life. This condition causes
severe anaemia which can make one feel exhausted and frail. Additionally,
beta thalassemia major slows development in infants and young children.
This condition requires regular blood transfusions for the management of
severe anaemia. Furthermore, too much iron may build up in one’s body
as a result of frequent transfusions, causing damage to liver, heart, and
endocrine system of the affected. Due to an accumulation of damaged red
blood cells, the spleen and liver can develop to an abnormally large size
from childhood to adulthood. Since the disease causes the bone marrow
(i.e. the spongy part of the bones) to expand, the bones can also become
brittle and thin.
Current Status of Beta Thalassemia in India 227

The symptoms of beta thalassemia intermedia are milder than those

of beta thalassemia major, due to which frequent blood transfusions
may not be required if at all they are needed. Thalassemia intermedia
symptoms may occur in early childhood or later in life. People who are
affected have mild to severe anaemia as well as sluggish growth and
bone defects. Patients with TI who do not receive care have a higher
rate of morbidity and a lower health-related quality of life. Patients
with TI can develop severe symptoms that affect almost every organ
system. Some of the complications seen in TI patients include pulmonary
hypertension, osteoporosis, 25-hydroxy vitamin D deficiency, gallstones,
and thromboembolic disease.
Individuals who have Beta Thalassemia minor (also referred to as Beta
Thalassemia trait) are phenotypically normal, with very fewer symptoms
and mild anaemia. They carry one copy of the mutated gene which is
recessive in nature and therefore, not expressed in the heterozygous state.
They have both normal hemoglobin A and the abnormal beta thalassemia
(β) hemoglobin in their red blood cells. In other words, people with beta
thalassemia trait do not have beta thalassemia disease and also cannot
develop the diseases later in life. However, they can pass beta thalassemia
trait to their children.
Thalassemia major and intermedia are autosomal recessive diseases,
meaning both copies of the HBB (Human Beta globin) in each cell are
mutated. The parents of a person with Beta Thalassemia have one copy of
the mutated gene but they usually do not display any signs or symptoms
of the disease.

Epidemiology of β-thalassemia

World Scenario

According to the WHO report published in 2008, more than 40,000

infants each year are born with β-thalassemia, of whom about 25,500 are
transfusion-dependent β-thalassemia (Modell et al, 2008). Worldwide,
Beta Thalassemia has been observed to be in the highest frequency in the
Mediterranean region, the Middle East, and Southeast Asia and lowest in
Northern Europe and North America (Colah et al., 2010). It is estimated
that 1.5 per cent of the individuals are β-thalassemia carriers (Colah et al.,
2010). The prevalence of carrier rates of β-thalassemia is relatively high in
Southeast Asia, with the reported prevalence ranges from 1.25 per cent to
1.66 per cent in India (Mondal, 2016) and is 2.21 per cent in China (Huan,
228 Anthropology of Health and Wellbeing

2016). It is very high in the middle east region of the world; one of the
reasons for this is increase in the cultural preference for consanguineous
mating (De Sanctis, 2017). In the recent past, Northern, Western, and
Southern Europe has witnessed a heavy increase in the frequency of
hemoglobinopathies. Many people have also migrated from regions where
β-thalassemia is endemic, such as Syria, Afghanistan, and Myanmar
to countries such as Italy, Turkey, U.S. etc. where the incidence and
prevalence of β-thalassemia has increased significantly in the recent years.
There exist multiple factors for the changing epidemiology of Beta
Thalassemia in the world today. Furthermore, with the rise in knowledge
and general awareness, comprehensive prevention programmes which
include public education, genetic counselling and population screening
accompanied by prenatal diagnostics have been extremely fruitful.
Public awareness and education is the backbone for all the prevention
programmes. Massive Screening programmes have been effectively
developed in multiple countries and have been tailored to local needs
and customs (Colah et al., 2010). In many European countries where
β-thalassemia has been historically endemic, for example Greece, Italy,
and Cyprus, screening programmes have been well established and that
they receive an enormous number of immigrants from endemic countries,
such as the United Kingdom and France. Italy’s prevention programme
has been a major success due to an increase in awareness among the
general population which has lead to acceptance of screening in the
population. Since 1970s, in Italy, there has been policies and planning for
prevention of Haemoglobinopathies in place. Cyprus is one success story,
where a thalassemia preventive initiative began in the year 1973 and has
resulted in a substantial reduction in the incidence of Beta Thalassemia.
Similarly, the Greek National Prevention Programme for Thalassemia and
Other Hemoglobinopathies, which began in the year 1974 and involved
education and prenatal diagnosis, has resulted in a substantial reduction
in the number of affected new-borns, from 150 to 200 cases per year
prior to the screening programme to less than 5 cases per year by 2010
(Voskaridou et al, 2010). The national programme for the prevention and
control of thalassemia major and thalassemia/Hb E in Thailand, which
was developed in the year 1994 has proven to be very beneficial because
it provides complete reimbursement for carrier screening in pregnant
women and their partners. Since the Thai government requires women
who have a molecularly confirmed compromised foetus with extreme
thalassemia syndromes, including thalassemia major and thalassemia/Hb
E to terminate their pregnancy before 24 weeks of pregnancy, this policy
Current Status of Beta Thalassemia in India 229

has largely resulted in a substantial decline in Beta Thalassemia major

(Wanapirak, 2004).
However, there is a great deal of variation in how these preventive
programmes are accepted and used around the world. Acceptance rates
in European countries, such as the United Kingdom, were over 90 per
cent in couples of Mediterranean descent, but just 20 per cent in couples
of Asian (mostly Pakistani) origin (Modell et al., 2001). Consanguineous
relationships, religious values, and low socio-economic status are all
barriers to the effectiveness of these screening systems. Consanguineous
marriages, which are widespread in many areas where thalassemia is
prevalent, such as North Africa and the Middle East, have played a role in
raising the risk of autosomal recessive diseases, such as Beta Thalassemia.
A prospective study in Turkey observed that 48 per cent of beta thalassemia
major or intermedia babies were born to consanguineous parents (Aydınok
et al., 2018). Similarly, a study from Egypt consisting of 44 patients with
β-thalassemia reported that 60.6 per cent had consanguineous parents
(Hussein et al., 2007). It is important to define the disease’s prevalence
in each country in order to better coordinate health-care services.

Indian Scenario

With a population of 1.21 billion people, India is home to 4,693

communities, including 427 tribal groups, according to the 2011 Census.
While all states have Beta-thalassemia and other haemoglobinopathies, the
incidence varies greatly from region to region. Thalassemia and structural
haemoglobin variants are extremely common in India, but only a small
percentage of patients are properly treated, and prolonged care is out of
reach for most families. In our multi-ethnic, culturally and linguistically
diverse population of 1.21 billion people, the estimated prevalence of
Beta thalassemia carriers is 3-4 per cent, which corresponds to 35 to 45
million carriers (Madan et al., 2010). Every year, 10,000-12,000 children
are born with thalassemia major in India (Aggarwal et al., 2014). It is the
commonest single gene disorder in India accounting for highest incidence
of offspring mortality. The average prevalence of Beta-thalassemia trait
was 2.78 per cent, ranging from 1.48 to 3.64 per cent in different nations,
while Beta-thalassemia trait prevalence in 59 ethnic groups ranged from 0
to 9.3 per cent (Mohanty et al., 2013). Very limited information is available
on the prevalence of β-thalassemias and other haemoglobinopathies among
various ethnic communities/groups across India. Previous research has
shown that some populations in Western and Northern India, such as the
230 Anthropology of Health and Wellbeing

Sindhis, Kutchhi Bhanushalis, and Punjabis, have a high prevalence of

Beta-thalassemia (Sukumaran, 1975; Mehta et al., 1972; Balgir, 2005).
The prevalence of the Beta-thalassemia trait was 16.81 per cent among
Sindhis in Nagpur, Maharashtra, according to a survey (Mulchandani et
al., 2008). The highest prevalence of the Beta-thalassemia phenotype
was observed in Jains from Bangalore (9.6%) followed by Buddhists
from Mumbai (5.9%) and Sikhs from Ludhiana (3.7%) (Mohanty et al.,
2013). According to Patel et al., the Bhanushalis (8.1%), Bhaktas (7.9%)
and Lohanas (6.5%) have a high prevalence of Beta-thalassemia trait
(Patel et al., 2012). Thalassemia has also been found to be prevalent in
tribal communities. Rao and Gorakshakar (1990) found a prevalence
of Beta-thalassemia trait of 1.6 to 5.6 per cent among tribal groups in
Maharashtra, while the prevalence of Beta-thalassemia trait was also
high (6.3 to 8.5%) among tribal groups in Orissa (Balgir, 2005, 2006) and
non-tribal populations in Madhya Pradesh in Central India (Chatterjee
et al., 2010). According to Colah et al., 2017; overall, the communities
with a high frequency of Beta Thalassemias are: “Sindhis, Lohanas,
Bhanushalis, Vellalas (8–17%); Vasava, Chaudhry, Gamit, Kokana tribes
from Surat, south Gujarat (12–15%); Aroras, Khatris, Jaths, (6–10%);
Prajapatis, Banias, Jains, Patels, Mayavanshis (6–8%); Bhuyan, Pik,
Dudh Kharia tribes from Sundargarh, Odisha and Rohit tribe from Surat,
south Gujarat (6–8%); Kayastha, Mandols (5–9%); Menons, Shiyas,
Fakirs (5–7%); Neo Buddhists, Mahars (4-6%)”.
Various government and non-government organisations have worked
hard in the past three to four decades to achieve the goal of Thalassemia
free society, but community regulation in such a large and diverse country
is extremely difficult. Beta-Thalassemia condition is life threatening
causing immense suffering to the patient as well as the family. In the
Indian context, the treatment of a thalassemia major child necessitates
daily blood transfusions and iron chelation therapy, both of which are
costly and time-consuming, putting a significant and growing demand on
the family as well as already limited health services available. India has
numerous population groups which are stratified based on socio-cultural
mileu. Anthropological research will help to explain and analyse the socio-
cultural barriers that exist in genetic diseases such as thalassemia. As a
result, the need of the hour is to place a greater emphasis on preventing
the birth of such children in the future. Therefore, preventing thalassemia
is the only practical way to achieve rapid reduction in the frequency of
the disorder. Countries like Cyprus, Greece and Sardinia could achieve
Current Status of Beta Thalassemia in India 231

a 90 per cent reduction in thalassemia by creating prevention strategies

rather than looking into treatment alternatives.
Various projects, such as the Indian Council of Medical Research’s
Multicentre Jai Vigyan programme, the West Bengal State Thalassemia
Control Programme, the Gujarat State Thalassemia Control Programme,
and Punjab’s “Project Rainbow have all aided in developing screening
programmes and determining the prevalence of Beta-thalassemia and
other hemoglobinopathies. These programmes have had a significant
impact and thalassemia control programmes have now been developed
in many states, with screening being conducted in various target groups.
However, these programmes must be implemented at regular intervals,
and a strict follow-up should be made a practice. Promoting community
education and understanding, intensifying screening in all states with
micro-mapping to determine the true burden and developing appropriate
facilities for genetic counselling and prenatal diagnosis in public sector
institutions are all worthwhile options for thalassemia control.

Molecular Characterization of Beta Thalassemia in Indian Population

Molecular Characterization of Beta thalassemia of either the patients

with Beta thalassemia major and their families or individuals from
different geographic regions is very much needed in order to devise
better management and diagnostic strategies. The beta-globin chain of
Haemoglobin molecule is encoded by the HBB gene, which spans 1.6
kb on the short-arm of chromosome 11 (Bunn et al, 1986). The genomic
sequence of HBB contains three exons, two intervening sequences (IVS1
and IVS2) and the 5’ and 3’ untranslated regions (UTRs). The beta-globin
locus harbours, in addition to the HBB gene, the -globin (HBE) gene, the
two -globin (HBG) genes (HBG-G and HBG-A), and the -globin (HBD)
gene. Most genes at this locus are expressed at specific time points in
development (Bunn et al., 1986).
As defined by various population studies, there exist more than
200 HBB gene mutations with a sub-set of ~40 mutations responsible
for the majority of beta-thalassemia cases globally (Flint et al., 1998).
The various classes of mutations which cause beta-thalassemia include
missense/nonsense, splicing, regulatory, deletions, insertions. Out of over
200 causal β-globin gene mutations, 11 have been shown to be common in
India, which are mainly community specific and this can be instrumental
in identification, diagnosis and curtailing the propagation of the disease.
Among these 11, six account for about 94 per cent of all positive cases
232 Anthropology of Health and Wellbeing

in India (Kazazian et al., 1984) which includes— “619 bp deletion at 3’

end of beta-globin gene, IVS-1 nt 5 (G-C), IVS-1 nt 1 (G-T), frame shift
mutations FS 8/9 (+G), codon 41/42 (-CTTT) and nonsense codon 15”.
The spectrum of mutations varies and are different in different population
groups of India.
Molecular characterization of Beta Thalassemia in patients with
Beta thalassemia major and their families as well as individuals from
various geographic regions was previously studied in Indian populations
by various scholars (Verawalla et al., 1991, 1992; Garewal et al., 1994;
Verma et al., 1997; Madan et al.,1998; Vaz et al., 2000; Chakrabarti et al.,
2005; Nadkarni et al., 2009; Tamhankar et al., 2009; Munshi et al., 2009).
Such research has been extremely beneficial in terms of gaining a better
understanding of the disease’s prevalence and subsequent management.
According to these authors, of the 6 most prevalent mutations of Beta
thalassemia in India, IVS 1-5 G-C is the most common Indian mutation
in most states of India whereas among the migrants from Pakistan, 619 bp
del is found to be most frequent. There exists vast regional differences or
disparities in the prevalence of the mutation across north, east and south
India, which has also been demonstrated by various scholars. Mutations
which are less frequent and observed in the Indian populace, which are:
“codon 15 (G-A), codon 16 (-C), codon 30 (G-C), IVS-1-110 (G-A), -88
(C-T), CAP+1 (A-C), codon 5 (-CT), FS 41/42 (-CTTT), codon 88 (+T),
25 bp deletion, IVS-2nt1 (G-A) and IVS-1 minus 1 (G-A)”.
The frequency of different mutations varies significantly in different
regions of India. The IVS-1-5 mutation, which is the most common
in India and ranges from 22.8 to 81.4 per cent in different parts of the
country, with Tamil Nadu in south-eastern India having the highest rate.
The 619 bp deletion mutation has been identified as the most common
beta-thalassemia mutation in patients from the north-western part of India
(including the states of Punjab, Haryana, Uttar Pradesh, and Rajasthan,
adjoining Delhi), Sindh, and Gujarat. Study by Shah in 2017 revealed IVS
1-5 G-C mutation exhibited higher incidence followed by 619 bp deletion
in Rajasthan, Gujarat, and Maharashtra (Western India) populations as
compared to West Bengal and Assam populations of Eastern India (Shah
et al., 2017).
There exists an ethnic and genetic variation in prevalence of DNA
mutations in beta-thalassemia among individuals from different parts of
India. Documenting community specific mutations for beta thalassemia
in various communities of India can be extremely beneficial in diagnosis,
prevention and management of the disorder. Thus, it becomes a matter of
Current Status of Beta Thalassemia in India 233

grave concern to screen more populations groups for the disease as there
are about 25-30 million people carrying the beta-thalassemia trait in India
and about 8000 children homozygous for this trait are born every year.
Molecular characterization among high risk communities and screening for
more communities for Beta Thalassemia in India can ensure a cost effective
diagnosis programme for that population. For example, 619 bp del which is
prevalent among the Sindhi community can be used as a diagnostic marker
for carrier detection of Beta thalassemia among Sindhi community (India)
followed by codon 41/42 (-TCTT) and codon 8/9 especially in northern
India. The most commonly used methods for molecular diagnosis are
reverse dot blot analysis or primer-specific amplification, ARMS PCR,
real-time PCR or microarray technology. Sequencing of the HBB coding
region can also detect and analyse mutations in the HBB coding region
and associated flanking regions.

Challenges and Way Forward: Road Map for India

The enormous burden of Beta Thalassemia in India emphasizes on

creating strategies for reducing the burden of the disease among the vast
and varied population. Over the past decades, management of the disease
has been possible to an extent with regular blood transfusions and iron
chelation therapy, however the complications associated with the disease
are always on a rise. Emerging developments in micro array technology,
newer methods in mutation detection are leading to genetic identification
and control of the disorder specifically at the population level, but these
methods are still at its early stage and largely unreachable by the majority
of the Indian population. Research into gene therapy is still ongoing and
may emerge as one of the treatment options available for Beta Thalassemia.
The prospect of curing Beta Thalassemia holds a great potential for the
future for alleviating human suffering in India.
In spite of the steps taken by the Government, control of Thalassemia
has been difficult in India due to lack of awareness of the disease among
people and adequate planning and management for prevention of disease
and due to social and cultural taboos. As India is a vast country with
about 4635 ethnic communities, it becomes extremely necessary to
know the spectrum of mutations of Beta Thalassemia gene in different
regions among different ethnic groups for prenatal diagnosis and Genetic
counselling. Thus, the first step in the prevention of Beta Thalassemia is
the identification of the carrier. To reach the goal of “Thalassemia free
society”, a control programme is needed involving Community Specific
234 Anthropology of Health and Wellbeing

Screening, Awareness and Counselling Programme for Beta-Thalassemia

Prevention and a detailed comprehensive strategy must be adopted to
know the exact magnitude of genetic health load.
The road map for reducing the burden of Beta Thalassemia needs
a systematic effort which includes education and awareness generation
among the diverse communities of India as well as both urban and rural
populations; micro mapping of various ethnic groups across diverse
geographies as well as creating state-wise registries will give an indication
of the true burden of the disease since most studies available today are
reports from hospital records; extensive screening centres need to be
established that will be instrumental in screening and providing genetic
counselling services. Since majority of Indian population lives in rural
areas, a robust concentrated effort is required specially aimed at populations
residing in these areas for awareness generation and sensitization. Other
steps include educating health professionals, schools and colleges students,
pregnant mothers and the general public as well as developing prenatal
diagnosis centres in various parts of the country along with developing
cost-effective treatment facilities across the country. A concerted effort
with the involvement of universities, hospitals and institutions along with
the medical fraternity, non-government organizations working in the area
of thalassemia reduction can aid in successfully reducing thalassemias.
In conclusion, need of the hour is that the emphasis must shift from
treatment to the prevention of birth of such children in future. Therefore,
preventing thalassemia is the only practical way to achieve rapid reduction
in the frequency of the disorder. Countries like Cyprus, Greece and
Sardinia could achieve a 90 per cent reduction in Thalassemia by creating
prevention strategies rather than looking into treatment alternatives. There
is a pressing need to raise public knowledge about Beta Thalassemia, which
necessitates awareness generation and mobilisation programmes, as well
as proper health education and sensitization of individuals, families, and
communities to embrace these preventive remedial steps. Carrier screening
and antenatal screening with inductive programme can be very fruitful
strategy in containing the disease. High cost of Bone Marrow transplant,
regular blood transfusions and iron chelation therapies, all point out to
a single fact that prevention of this disorder is better than cure in every
aspect.
Current Status of Beta Thalassemia in India 235

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