**2.2 Overview of inherited hemoglobin disorders**

Inherited hemoglobin disorders include all disorders that are passed down through families and affect the normal properties of blood in humans. **Figure 4** summarizes the general classification IDH.

Hemoglobin disorders can be broadly classified into two general categories [24].

1.Those in which there is a quantitative defect in the production of one of the globin subunits, either total absence or marked reduction. These are called the thalassemia syndromes (quantitative disorders of globin chain synthesis/ accumulation: β-Thalassemia and α-Thalassemia

#### **Figure 4.**

*Flow chart of general classification inherited disorders of Hemoglobin. Note: In this chapter we are interested in inherited hemoglobin disorders that are common enough to be of public health significance and particularly in those with a link to malaria (G6PD, α –thal, β-thal, HbS, HbC, HbE). Adapted from table of classification of hemoglobin disorders from Forget al. (2013). [Forget BG, Bunn HF: Classification of the disorders of hemoglobin. Cold Spring Harb Perspect Med 2013, 3:a011684].*

*Inherited Disorders of Hemoglobin and* Plasmodium falciparum *Malaria DOI: http://dx.doi.org/10.5772/intechopen.93807*

	- Sickle cell disorders: Sickle Cell trait, Sickle cell anemia disease, SC disease, sickle β-thalassemia disease
	- Hemoglobin with decreased stability (unstable hemoglobin variants): G6PD deficiency

Hemoglobin includes four globin chains:


Human Hemoglobin genes are located in the α-globin and β-globin gene clusters in chromosomes 16 and 11. Due to spontaneous mutation, hemoglobin gene variants are present at low prevalence in all sizeable populations [5].

They fall into two broad groups structural variants that change the amino acid sequence and produce an unusual hemoglobin, [8] and thalassaemias that lower or abolish production of globin chains [12].

Morbidity and mortality rates from SCD and β-thalassemia are still very high and represent an important challenge. Increased understanding of pathophysiological aspects has lead to significant improvements in the treatment and prevention of these diseases [25]. However most hemoglobin gene variants are rare and many are harmless, but some are common because carriers are less likely than others to die from *falciparum* malaria.

We are interested in inherited hemoglobin disorders that are common enough to be of public health significance and particularly in those with a link to malaria.

#### *2.2.1 Sickle cell disorders*

**2.2 Overview of inherited hemoglobin disorders**

*Human Blood Group Systems and Haemoglobinopathies*

accumulation: β-Thalassemia and α-Thalassemia

*hemoglobin. Cold Spring Harb Perspect Med 2013, 3:a011684].*

summarizes the general classification IDH.

**Figure 4.**

**10**

**Figure 3.**

Inherited hemoglobin disorders include all disorders that are passed down through families and affect the normal properties of blood in humans. **Figure 4**

*Representation of the blood-stage of* P. falciparum *life cycle in the human host and the malaria-protective*

*variants that have important roles in the red blood cell (RBC). Image adapted from [1].*

Hemoglobin disorders can be broadly classified into two general categories [24].

1.Those in which there is a quantitative defect in the production of one of the globin subunits, either total absence or marked reduction. These are called the thalassemia syndromes (quantitative disorders of globin chain synthesis/

*Flow chart of general classification inherited disorders of Hemoglobin. Note: In this chapter we are interested in inherited hemoglobin disorders that are common enough to be of public health significance and particularly in those with a link to malaria (G6PD, α –thal, β-thal, HbS, HbC, HbE). Adapted from table of classification of hemoglobin disorders from Forget al. (2013). [Forget BG, Bunn HF: Classification of the disorders of*

SCD is a group of inherited RBC disorders; it is by far the most common IDH worldwide. SCD is caused by a variation in the gene that codes for hemoglobin, the protein in our red blood cells that helps carry oxygen to all parts of the body. The altered protein found in people with SCD is called hemoglobin S and occurs in people who have inherited the hemoglobin S (HbS), the red blood cells become hard and sticky [12].

**Hemoglobin S** results from an amino acid substitution at the sixth residue of the β-globin subunit: β6-Glu ! Val. RBCs of persons with HbAS typically have 40% HbS and 56–58% HbA [24]. The frequency of allele S is up to 0.2 in some parts of sub-Saharan Africa [26–28]. In equatorial Africa, where malaria is endemic, the prevalence of HbAS is much higher and can reach over 30% in some populations because of the survival advantage of HbAS heterozygotes from complications of *P. falciparum* malaria. Individuals with HbAS are typically asymptomatic; severe hypoxia is required for them to experience manifestations of SCD, called sickling.

Persons who have inherited the HbS gene from only one parent are Heterozygote for the Sickle gene (AS). They carry the gene certainly, but they usually do not have the disease and are more tolerant of malaria infection, making them more likely to survive the disease [12, 29].

SCD is most common in Africa where limited resources and these resources carefully targeted are often directed towards sectors other than health. However, it should be noted that the symptoms of SCD are often serious, substantially reducing life expectancy and often requiring intensive treatment throughout the patient's life.

• α+ - thalassemia, in which one pair of the genes is deleted or inactivated by a

• α 0-thalassemia, in which both pairs of genes are deleted or inactivated.

*Inherited Disorders of Hemoglobin and* Plasmodium falciparum *Malaria*

The frequency of a α thalassemia is generally 41% in regions where malaria is prevalent and in some populations, such as in Nepal, parts of India, and Papua New Guinea, it is over 80% [36]. However, in sub-Saharan African populations, a α-thalassemia frequencies do not exceed 50% despite intense malaria selection and some authors [37] suggested that this might occur because of negative epistasis with the S allele.

The β-thalassemias are characterized by a quantitative deficiency of β-globin chains, can be sub classified into those in which there is a total absence of normal bglobin subunit synthesis or accumulation. The βthalassemias are divided into two

there is a partial deficiency of β-chain production) [24]. The molecular basis of the β-thalassemias is very heterogeneous, with over 200 different mutations having been described [38]. In general, the mutations causing β-thalassemia are point mutations affecting a single nucleotide, or a small number of nucleotides, in the bglobin gene. The frequency of carriers of β-thalassemia variants is from 5 to 20% in some areas, although not as high as the frequency of α-thalassemia variants [39].

*2.2.3 Glucose-6-phosphate dehydrogenase deficiency and* P. falciparum *malaria*

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is a genetic disorder

The deficiency makes red cells more susceptible to oxidative haemolysis, this disease that can cause jaundice in newborn babies and haemolytic anemia (when red blood cells break up) throughout life. This is, usually caused by an infection or exposure to certain foods or chemicals [41, 42]. One of the chemicals that can trigger severe symptoms in people with G6PD deficiency is Primaquine, the only drug currently available to clear the relapsing life stages of the *Plasmodium vivax*

G6PD and a number of other human genetic traits including sickle cell anemia and related haemoglobinopathies are predominantly found in populations living in malaria endemic countries and have been suggested to provide the host protection

G6PD deficiency can be common in populations with high levels of malaria infection, indeed the prevalence is even higher (8%) in malaria-endemic countries [8]. Malaria control programs need to know this to inform their policies on using

**2.3 Epidemiology of inherited hemoglobin disorders and** *P. falciparum* **malaria**

the parasite has had largely time to adapt and evolve with the human host [40]. Immune processes and genetic traits have contributed to reducing the profligacy of

For a very long time, human beings have interacted with malaria parasites and thus

from severe forms of malaria [30, 43–45] and asymptomatic malaria [27].

Primaquine as a treatment and as a malaria control measure.

This X-linked genetic condition is characterized by reduced G6PD enzyme activity, which can remain asymptomatic. Red blood cells obtain reduced glutathione (GSH) solely from the G6PD/reduced nicotinamide adenine dinucleotide phos-

thalassemia,

main varieties (β0-thalassemia, there is no β-chain production and β<sup>+</sup>

point mutation,

*DOI: http://dx.doi.org/10.5772/intechopen.93807*

*2.2.2.2 β-thalassemia*

that results in impaired enzyme activity.

phate (NADH) pathway [7, 12, 30, 40, 41].

parasite from the liver.

**13**

**Hemoglobin C** results from a variation in the gene that codes for hemoglobin (β6-Glu ! Lys), the protein in our RBC that helps carry oxygen around the body, It causes hemolytic anemia, splenomegaly in homozygous state and provides a degree of protection against malaria infection [12, 26]. Persons with hemoglobin C trait (Hb AC) are phenotypically normal, with no clinical evident limitations or symptoms. However, their heterozygous status, gives them a degree of protection against developing severe malaria HbC is common in malarious areas of West Africa, especially in Burkina Faso, the prevalence of HbAC is much higher and can reach over 21% [26, 28, 30, 31].

**HbS and HbC** caused by point mutations in the beta-globin gene, offer both substantial malaria protection. Despite the fact that the blood disorder caused by homozygosity for HbC is much less severe than that caused by homozygosity for HbS [9, 12, 26, 32], it is the sickle mutation which has come to dominate many oldworld malarious regions, whilst HbC is highly restricted in its geographical distribution [33]. It is probable that this discrepancy (blood disorder between HbC and HbS) may be due to sickle cell heterozygotes enjoying a higher level of malaria protection than heterozygotes for HbC. A probable higher fitness of HbS heterozygotes relative to HbC heterozygotes could certainly have allowed the sickle cell allele to spread more rapidly. However, observations that carrying either HbC or HbS enhances an individual's capacity to transmit malaria parasites to mosquitoes could also shed light on this hypothesis [32].

**Hemoglobin E** results from a glutamate to lysine substitution in codon 26 (β26 Glu-Lys and GAG-AAG). Besides being a structural variant, the E variant also causes the production of an abnormal mRNA with less b-globin being synthesized. It is synthesized at a slightly reduced rate and has a homozygous phenotype similar to heterozygous β thalassemia [34].

HbE is the second commonest abnormal hemoglobin after sickle cell hemoglobin (HbS). HbE is common in South-East Asia, where its prevalence can reach 30–40% in some parts of Thailand, Cambodia and in Laos [35].

#### *2.2.2 Thalassemia syndromes*

The thalassemia syndromes are inherited disorders characterized by absence or markedly decreased accumulation of one of the globin subunits of hemoglobin. Individuals with thalassemia disease are not able to make enough hemoglobin, which causes severe anemia [24].

There is two primary types of thalassemia disease: alpha (α) thalassemias and beta (β) thalassemia disease. In the α-thalassemias, there is absent or decreased production of α-globin subunits, whereas, in the β-thalassemias, there is absent or reduced production of β-globin subunits. Thalassemias affecting the production of delta (δ)- or gamma (γ)-globin subunits are also been described but are rare and not clinically significant disorder

#### *2.2.2.1 α-thalassemia*

The α-thalassemia syndromes are usually caused by the deletion of one or more α-globin genes and are sub classified according to the number of α-globin genes that are deleted or mutated [24].

There is two primary types of α-thalassemia:

*Inherited Disorders of Hemoglobin and* Plasmodium falciparum *Malaria DOI: http://dx.doi.org/10.5772/intechopen.93807*


The frequency of a α thalassemia is generally 41% in regions where malaria is prevalent and in some populations, such as in Nepal, parts of India, and Papua New Guinea, it is over 80% [36]. However, in sub-Saharan African populations, a α-thalassemia frequencies do not exceed 50% despite intense malaria selection and some authors [37] suggested that this might occur because of negative epistasis with the S allele.
