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INTRODUCTION
The prevalence of diseases is becoming higher nowadays. Some of these
diseases can be transmitted genetically from one population to another or
passed from parents to their offspring. There are different types of genetic
inheritance: 1) Autosomal recessive, 2) Autosomal dominant, in which are
carried by the chromosomes other than sex chromosomes. 3) X-linked recessive,
4) X-linked dominant, where the mutant gene is carried by female sex determined
chromosomes (X-chromosome). 5) Y-linked diseases, where the disease is only
carried by Y-chromosome (the male sex determined chromosome) [1].
The incidence of the carriers due to autosomal recessive hemoglobin
mutation (e.g. sickle cell disease and thalassemia disorder) is about 5% of the
global population and >2/1000 in Middle Eastern ethnic groups [2]. This was
highlighted by Yesilipek [3], when he addressed that sickle cell disease is
probably increasing all over the world. According to Al-Gazali et al. [4], the
recent data shows that genetic diseases, such as hemoglobinopathies and
Glucose-6-phosphate dehydrogenase (G-6-PD), are common in Arab countries. The
consanguinity marriages (first cousin) and large family production are the
important factors that enhance hemoglobinopathies in the “Arabian Peninsula”.
Saudi Arabia, the core country of this review, is a big part of that Peninsula,
so, the extent of sickle cell and thalassemia diseases are highly evident [4].
Hence that the consanguinity marriages is about 50% of the total marriages as
the Saudi population is mostly dependent upon tribes, making this a main
contributory factor for boosting up the number of affected newborns with sickle
cell disease [5].
In an effort to reduce the prevalence of the above genetic
diseases, certain procedures were carried out. One of these procedures is
screening tests to detect the carrier status of the individuals, to offer them
early genetic counselling or even early treatment [6]. The screening programme
can be applied either as prenatal screening tests, neonatal screening tests or
adult screening tests such as in Cyprus in 1973 [7,8]. Moreover, adult
screening tests can be applied as pre-marital screening tests. Such programmes introduced
in Iran in 1996, in Ashkenazi Jewish and then in Saudi Arabia in 2003 [2,4,9].
This essay will discuss the National Pre-marital Screening
programme in Saudi Arabia, its procedure and the possibility of its success.
Advantages and disadvantages of the programme and the effectiveness of the
genetic counseling will be stated. Finally, the recommendations will be
applied.
SICKLE CELL DISEASE
OVERVIEW
Sickle cell disease
epidemiology
Molecular pathology of sickle
cell
Globin chain synthesis occurs on RBC-specific ribosomes, which are
generated from particular structural genes, known as the beta (β), delta (δ),
epsilon (ε) and gamma (γ) which are located on the short arm of chromosome 11
at 11p15.5 and alpha (α) and zeta (ζ) which are located on the short arm of
chromosome 16 at 16p3.3. These genes can produce α, β, δ, γ, ε and ζ globin
chains. During human development different hemoglobin are manufactured
depending upon his stage of life (Table
1).
Sickle cell
disease (MIM 603903) is one of the hemoglobinopathy disorders. This disease was
first defined in 1910. This illness is inherited in an autosomal recessive
mode, where the patient is homozygous for the mutant genes and both parents are
carriers of the mutation. This disease is prevalent in many parts of the world
[11].
The missense point mutation of the β-globin gene considered to be the
major causative for SCD. Caused by the transversion substitution of the
nucleotide A of the 6th codon to the T, leading to a substitution of glutamic
acid by valine [1]. This mutation leads to the production of undesired
hemoglobin known as hemoglobin S (HbS) [12]. Hemoglobin S shows less stability
at the condition of lower O2 concentration e.g. <85%, at this
level the blood pH will be diminished as well as body dehydration. This causes
the RBCs to change their normal round biconcave shape to sickle shape or
crescent shape. These cells wouldn’t be able to move through thinner blood
vessels, due to their abnormal and inflexible shape, leading to blood flow blockage
and reducing O2 that reaches the tissues all over the body, leading
to severe crises of Table 2.
Moreover, chronic hemolytic anemia would be induced due to the RBCs becoming
highly fragile, then short-lived [13].
Recently, a study conducted by Steinberg and
Sebastiani [14], where several candidate genes (38 single nucleotide
polymorphism; SNPs) that have shown a previous association to the stroke with
SCD patients, have been genotyped in 2 subsets of children with well-defined
stroke phenotypes (130 stroke and 103 non-stroke). Distinctly, 3 polymorphisms
(ANXA2, TGFBR3 and TEK) were identified to have linked to increased stroke risk
(Table 2).
Interestingly, the ontology analysis of those defined polymorphisms
were linked to some critical biological functions such as neuronal signaling
mediators, hematopoietic stem cells proliferation, effecting the
hypercoagulable status of SCD and cerebrovascular disease associations.
Clinical manifestation
The serious problems of SCD are compiled mainly in the medical
complications that arise from this illness. Serious microbial infections can
lead to frequent mortalities of the child, repeated vaso-occlusive crisis,
splenic sequestration, pulmonary hypertension. Cerebral infarction is prevalent
in about 30% of SCD patients. Acute chest syndrome, the main causative factor
leading to death in adulthood affected with SCD. Renal failure, sickle
retinopathy are also related to this disease. In some cases psychosocial
dysfunction and chronic disability can be seen with the patient suffered with
SCD. Significantly shortened life span of about 25-30 years lower than normal
individuals and about 3% mortality rate in children making the situation
seriously horrific [15,16].
SICKLE CELL DISEASE IN SAUDI
ARABIA
Historically, the first description for SCD in the kingdom of Saudi
Arabia was in in the Eastern state in early 1960s [17].
Much effort has been carried out to estimate the prevalence of sickle
cell disease in Saudi Arabia [18]. At the same time a researcher reported the
prevalence of SCD in the South-Western area of Saudi Arabia [19]. Latterly, in
1994 SDC was reported in about 0.029 of Makkah region population [20]. Whereas,
a study has shown that the frequency of SCD in Madinah region in the north-western
area was higher than the other in Saudi Arabia [21]. Therefore, a national
screening programme to determine the incidence of HbS and identify affected
individuals would be extremely beneficial.
Screening programme would be
the right choice
The pre-marital screening programme was started by the Ministry of
Health (MOH) in Saudi Arabia in 21st February 2004 by royal decree.
Based on recent research, it was recommended that a national screening
programme be established as a means of tackling the high prevalence of
inherited hematological diseases [22].
A network of 123 counseling centers send screening samples to 40
laboratories throughout Saudi Arabia. The negative results are given directly
to the couple. Positive results are communicated via the genetic counselor so
that advice on the possibility of marriage can be provided.
Whereas, in 2016 A network of around 1800 primary health care centers,
200 hospitals and a subset of related national and private health bodies were
engaged in the screening. The well oriented laboratory staff at these centers
records all important demographic information for each, then blood samples in the
EDTA coated tubes is collected. At the laboratory, several hematological
investigations will be carried out on the sample including; complete blood
count (hemoglobin, red cell count, hematocrit, mean corpuscular volume, red
cell distribution width), peripheral blood film for red blood cell morphology,
reticulocyte count and sickling test does not seem necessary. Main
hemoglobinopathy diagnosis was depended on hemoglobin electrophoresis, and
results were interpreted in accordance with standard laboratory diagnostic
protocols [11].
A marital certificate would not be submitted to a couple whose results
categorize them to be at high risk (positive for sickle cell trait or disease)
until they had received the proper genetic counseling from the candidate
clinic. However, couples had the right to complete their marital project
regardless of the results. Follow ups of all the high-risk couples were
provided with genetic counseling physicians working in the different clinics
have been conducted with several difficulties.
National pre-marital screening
program outcomes
Although, large numbers of relevant research has yet to be conducted in
this field in Saudi Arabia, there is a recent study that deal with this issue a
precise scientific procedure was published in 2011 [23]. In this study, the
total number of 242000 and 296000 men and women were investigated for sickle
cell genotyping in 2004 and 2009, respectively. The prevalence of sickle cell
disease has been stated as 4.5% in which still the highest among the other genetic
disorders especially hematologically related disorders was stated by authors.
Moreover, ~60% of at-high-risk couples were able to be followed up and
~26% of them have cancelled their marital project. Likely, the frequency of
cancellation was higher by the continuity of the programme as it was ~9.2% in
2004 and 51.9% in 2009. In regards to the rates of SCD prevalence within Saudi
Arabian different provinces, the Eastern province has recorded ~58% of at-risk
couples compared to the others, making it the highest. Also the study reported
that the SCD carrier incidence was about 93%. Unfortunately, about >50% of
at-risk couples decided to stop their marital project in 2009 compared to ~26%
in 2004. The estimation was reported in a previous research where ~52% of
at-risk couples decided to terminate their marital project [24]. These results
show relatively desired outcomes.
Factors affecting the above
success
The above results have shown relatively desired numbers although the
number of SC disease and carriers in some provinces in Saudi Arabia. The
Eastern and Southern provinces for instance, remains the highest incidence of
the disease. This might be referred to the malarial parasitic disease is
persistently endemic. Hence, Carriers for hemoglobinopathies are believed to be
more resistant to malaria parasite infection and their increased biological
strength results in an expansion in the number of carriers within the
population.
On the other hands, the consanguinity marriages was
and still is the initiative core of an autosomal recessive diseases and
hemoglobinopathies are not excluded [25]. In Saudi Arabia consanguineous
marriage is proudly one of the traditional behaviors in most of the tribes.
This is refers to the characterized geographical location of Saudi Arabia the
biggest country on the Arab peninsula at the connection point of three largest
and oldest continents in the world, and those tribes try to keep their own
ancestry genes. According to the previous estimation of consanguineous marriage
in Saudi Arabia were about 69% in the South as the highest, and 41.5% in the
Western area as the lowest [26]. However, these noticeable rates are likely to
be kept at arisen points in Saudi Arabia [27]. Unsurprisingly, the
consanguineous marriage considered at the significant rates within Arab
countries from 20-60% (Figure 1) [4].
The traditional issues could be an important part of hemoglobinopathy
increment. The Saudis are similar to most Arabs who are well known for
maintaining their traditional practices with respect to marriage and are not
easily convinced to change their traditions. This is when a subsets of about
2,375 high-risk couples (Sickle cell and thalassemia), that already have
received genetic counseling session; about 89.6% among them have continued with
their marriage plans, ignoring their high risk status [28]. Moreover, rejection
on the grounds of test incompatibility, creates a very severe conflict between
the families specifically in the case of consanguineous marriages, increases
the situations complexity. More efforts need to be addressed in regards to
decrease the incidence of the disease and population knowledge towards
hemoglobinopathies. Although, the screening programme seems to be successful
according to the above results as both carriers and cases have significantly
decreased in some parts of the country compared to the others, the incidence
remains higher. Therefore, genetic counseling programs have to be developed and
increased especially by the expert genetics counselors. The careless couples at
high risk could be talked through strong law procedures, which guarantee the
excision of at high-risk marriage projects to be completed [29].
Up to this end, some recommendations are required to be stated.
Firstly, educational program must be introduced, expanded, simplified and
evaluated to suit the Saudi population. Secondly, the government has to create
effective coordination and cooperation between the involved Ministries, i.e.,
Health, Justice and Interior to allow more effective follow up of incompatible
couples to understand the effect and consequences of screening. Thirdly, the
national screening program for inherited disorders has to be established and
started as early as from secondary school age to avoid later personal
stigmatism and family breakdown. Finally, the number of screening centers
should be increased and developed technologically with improved genetic
councilors especially in high population and diseases prevalent areas [30].
CONCLUSION
The pre-marital screening program in Saudi Arabia
appears to be achieving its objective. There was a significant reduction in
incompatible marriage certificates. The carrier incidence was the highest in
Eastern area, followed by the Southern area and the incidence has been
calculated in each region. Further recommendations were presented. The optimum
time for screening setup would be at secondary school. The continuation of this
program is highly recommended, as it will apparently decrease the incidence of
the screened diseases.
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