Haemoglobinopathies haemoglobin variants. Thalassemia is an inherited

Haemoglobinopathies
are the most common recessive monogenic disorders around the globe and they are
broadly divided into two groups: i) thalassemia syndromes and ii) the
structural haemoglobin variants. The thalassemia syndromes include the abnormal
haemoglobins ?, ?, ? etc whereas the HbS, HbE, HbC and HbD constitute the
structural haemoglobin variants. Thalassemia is an inherited form of anemia
caused by faulty synthesis of hemoglobin. 
It is a heterogeneous group of single gene disorders caused mainly due
the underproduction of the normal beta globin chains or normal alpha globin
chains or both. Beta Thalassaemia is caused
due to mutations in the Hb B (Hemoglobin B) gene on chromosome 11.  The first description of severe thalassemia
is credited to Cooley et al., in year 1925 and thus it is also referred to as
Cooley’s anemia. Three main forms of beta- thalassemia have been known as viz.,
thalassemia minor, thalassemia intermedia and thalassemia major. (Barua S.
2007) Thalassemia minor is the most common form of thalassemia which is also
referred to as ‘thalassemia trait’.  The
individuals affected by thalassemia minor are asymptomatic because they are
heterozygous and carry one normal HbB allele and one thalassemia allele (Thein
S. L. 2004).  During clinical diagnosis,
sometimes, it shows mild anemia and increased level of HbA2 (Hemoglobin A2)
level. In this case if both the parents carry the gene for thalassemia minor
then they are at a potential risk of having affected children with more serious
thalassemia. In case of Thalassemia intermedia the patients carrying mutations
show symptoms ranging from thalassemia major and thalassemia minor. They have
mild to moderate anemia and do not require blood transfusions so often (Taher
et al 2006). However, thalassemia major is the most severe form of beta
thalassemia. In this case of thalassemia both the beta globin producing genes
are absent. The individuals carrying the mutated gene for the thalassemia major
are diagnosed and show symptoms during the early stages of development usually
within two years of their life. 

 

They
suffer with severe anemia and other clinical manifestations include fatigue,
dyspnea (difficulty in breathing), hepatosplenomegaly (enlargement of liver and
spleen), heart failure and delayed puberty (Bunn H. F. 1984, Rund et al. 2005,
Wonk B. 2001). Patients suffering from thalassemia major require regular blood
transfusions and if the blood is not provided at the appropriate time it can
also lead to death of the patient. Almost all the ?- thalassemia variants are
inherited in a Mendelian recessive manner, except for a small subgroup of
alleles that behave in a dominant fashion.

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Prevalence of Beta thalassemia:

 Around the globe it is estimated that there
are 270 million carriers with thalassemia and abnormal haemoglobins. Out of the
270 million 80 million are carriers of ?- thalassemia. The recent studies
reveal that each year between 300,000-400,000 babies are born with serious
haemoglobin disorder with 23,000 accounting alone for ?- thalassemia and about
90% of these births occur in middle or low income countries (Sanctis De et al;
2017). The carrier frequencies of ?-thalassemia vary in different parts of the
world from 1-20% or may be higher. On the other hand the frequencies for milder
forms are greater in some population ranging from 10-20% in parts of Sub-
Saharan Africa, more than 40% in some Middle Eastern and Indian populations and
as high as 80% in some isolated groups of Northeast India and Northern Papua
New Guinea (Williams T.N. et al; 2012). In India alone the numbers of beta
thalassemia patients are approximately 30 million. At about ten percent of the
total world thalassemic individuals are born in India every year (Bashyam M.D.
et al., 2004). Certain communities in India, like Sindhis (Colah .R. et al.
2010) Gujratis (Bhukhanvala et al. 2013), Punjabis (Grow K. et al. 2014), and
Bengalis (De M.et al. 1997) are more commonly affected with beta thalassemia
and the incidence varies from 1 to 17% (Gupta et al. 2003).

As far as the
studies conducted in different parts of the world more than 150-200 mutations
causing beta thalassemia have been reported (Cao A. 2010). Studies conducted in
India have identified about 28 mutations in Indian population (Old J.M. et al.
2001). Out of these five to six

 

mutations are
found to be common. These include IVS 1-5, 619 bp del, IVS 1-1, frameshift 8-9,
41-42, and codon 15 (Bandyopadhay A. et al. 2004). The type of mutation varies
in different ethnic groups with a particular type of mutation being more common
in a specific ethnic group (Bashyam et al. 2004). The frequency of mutations in
carriers originated in different states of India and it varies from region to
region with the predominant mutation being IVS 1-5 (Agarwal S .et al.
2000).  However, in migrants from West
Pakistan the predominant mutation is 619 bp del.  In India it is reported that the overall
common mutations for beta thalassemia account for 90- 93.6 % (Mehta S.D. 2011)

The difference in
prevalence of DNA mutations in beta thalassemia from different regions of India
reflects the ethnic and genetic diversity of populations. The heterogeneous
populations belonging to the Indian subcontinent has been studied (Grow. K. et
al 2014).  These studies has been
conducted in Pakistan (Usman et al 2009), Sindh (Jawahirani et al. 2005),
Punjab (Garewal et al. 2003), Gujarat (Bhukhanvala et al. 2013), Tamil Nadu
(Colah et al. 2009), Maharashtra (Ambedkar et al. 2001), and Kerala (Edison et
al. 2008).

The clinical and
hematological features mainly show the symptoms of growth retardation in
infancy and child stage whereas the adult individuals having beta thalassemia
are susceptible to thrombosis (Ataga et al 2007). The further complications
include symptoms like jaundice, osteoporosis, hypothyroidism etc. Since, the
disorder is caused due to mutations in gene there are various molecular
diagnostic techniques available for the detection of mutated gene (Grow K. et
al 2014). The cost of the blood transfusions for beta thalassemia major has
been projected at approximately 3200 U.S. dollars per child per year (Agarwal
et al 2003, Weatheral D.J. 2003).  The
disorder can be controlled and prevented by proper counseling at individual
& mass level and through prenatal diagnosis.  At the same time mutations can be detected by
microarray and PCR technology.  The
treatment of beta thalassemia mainly includes regular blood transfusion, iron
chelation therapy and management of secondary complications due to

 

 

iron
overload.  In some cases splenectomy has
also been performed. However, bone marrow transplant is the only definitive
cure for beta thalassemia (Galanello R. et al., 2010). 

Uttarakhand is
the 27th state of India and was carved out of Uttar Pradesh and the
adjoining states in the year 2000. It is broadly divided into two regions viz;
Garhwal and Kumaon. Garhwal region is a part of the Uttarakhand state and is bounded on four sides by Tibet in the North,
Uttar Pradesh in South, Kumaun region in the East and Himachal Pradesh towards
West. It lies 28o 43′ to 31o 27′ N and 77o
34′ to 81o 02′ E and has a total geographical area of 53,483 sq kms
(Sing. R.L 2008). It comprises of seven districts and the main language spoken
by the people is Garhwali. The tribals of Garhwal are of Mongoloid origin and
mostly reside in the upper tracts of Garhwal Himalaya whereas few reside near
Dehradun and Uttarkashi districts. Base line data on thalassemia was completely unavailable in the
populations of Garhwal region. Considering the severity and importance of the
disorder it was necessary to carry out such studies in the population of this
area.  Hence, the study was being
proposed to be conducted on prevalence of beta thalassemia from the population
of Garhwal with the following aim & objectives:-

Aim:
Generate base line data on Beta thalassemia through mass screening of
cross-sectional population of Garhwal.

Objectives:  

1.   
Screening
of Beta thalassemia for Garhwal population on the basis of NESTROFT and   HPLC.

2.   
Characterization
of Molecular variants of Beta thalassemia and comparison with other
populations.