In this post, we shall be discussing about the inherited disease called Sickle cell Disease.

Description:

Sickle cell disease (SCD) is a group of disorders caused by an inherited mutation in hemoglobin beta gene, HBB, which encodes haemoglobin subunit β. The incidence of SCD is around 300,000 to 400,000 newborns annually around the world (2018). Most of the cases are observed in sub-Saharan Africa. The symptoms of SCD starts appearing in babies as early as at 4 months old, but mostly occurs after the 6-month due to the presence of the fetal hemoglobin. The person born with this mutation is expected to live for around 40-60 years.

(Just for info: Have a look at this article listing few celebrities with SCD)

Fig 1: Sickle Red Blood Cells at 40x Magnification (Image source: MicroscopyU)

Causes:

Hemoglobin (Hb) is the protein present in red blood cells, that is involved in the delivery of oxygen from the lungs to the tissues and carbon dioxide from the tissues to the lungs. It is composed of 4 subunits, two α and two β subunits (fig 2a). Each of the subunit contains an iron-containing heme group. The genes coding for α chains (HBA1 and HBA2) are located on the chromosome 16 and that for β chain are located on the short (p) arm of chromosome 11 at position 15.4 (11p15.4).

Mutations in the genes of both α and β subunits cause variety of disorders. One such disorder is sickle cell diseases. It is caused due to a point mutation, i.e. missense mutation converting GAG to GTG in the haemoglobin beta gene. This leads to the substitution of ‘acidic’ glutamic acid with a ‘hydrophobic’ valine at the position six. This abnormal beta globin is called hemoglobin S or HbS. The hemoglobin in the person with SCA have the abnormal hemoglobin S subunits instead of the normal β subunits (fig 2b). The HbS causes a set of symptoms, which is collectively called as Sickle Cell Disease.

(Just for info: Read our post on types of mutations.)

Fig 2: The (a) normal and the (b) sickle hemoglobin.

SCD is an autosomal recessive disease and is manifested only when the person has two copies of the mutated gene. If a person has only one copy of the mutated gene and the other one is normal, the person is a carrier for sickle cell disease and can pass on the gene to the next generation. This condition is called ‘sickle cell trait‘.

(Just for info:Read more about Sickle Cell Trait in this paper.)

RBCs contain almost nothing but only haemoglobin at a high concentration and typically is biconcave in shape. In the lungs, the haemoglobin within the RBCs pick up oxygen and releases at the peripheral tissues. The normal haemoglobin is usually a single free molecule in both the oxygenated and deoxygenated form.
On the other hand, sickle hemoglobin are single molecules when oxygenated but once it releases oxygen in the tissues, i.e. in the deoxygenated state, the molecules interact with each other. They tend to stick together due to hydrophobic interaction and eventually undergo polymerization to form a long chains or polymers.

(Just for info:Read this paper about Treating sickle cell disease by targeting HbS polymerization.)

Fig 3: The polymerization of the deoxygenated HbS.

The fibres in turn form a 14 polymers structure. These fibres grow from a single start site known as a nucleation site, and grow in different directions.

Fig 4: Structure of HbS 14 polymer fiber model (Image cropped from: Lu et al. 2016).

The rigid polymers formed, changes the shape of the biconcave RBC into various different shapes, the most frequent being the cresent-like or sickle-shaped cells, giving the disease its name (fig 5).

Fig 5: The representation of how HbS polymers change the shape of the RBC.

When the RBC reaches the lung and the hemoglobin gets oxygenated again and return back to their single form. However, unlike the normal hemoglobin, the membrane of the sickle RBC can undergo only a limited number of these oxygenation-deoxygenation cycles.

The sickle shaped RBCs have two features:

1. They die prematurely.

Sickle cells live for about only 10 to 20 days, whereas normal red blood cells can live up to 120 days. They also get destroyed by the spleen because of their shape and rigidity. Due to early destruction of the RBCs, the affected person experiences a lack of red blood cells or anemia. This anemia due to the sickled RBCs is called as sickle cell anemia.

2. They have abnormal shape and are rigid.

The rigid red blood cells clog the small blood vessels. They also interact with the inflammatory activated vascular endothelial cells and neutrophils. Due to this there are vaso-occlusive events, which in turn leads to ischemic-reperfusion (injury due to lack of oxygen) damage of organs such as lung, heart, eye, kidney or brain.

Fig 6: Vaso-occlusion caused by sickle RBCs (Frenette and Atweh, 2007)

Other associated pathological events include binding of increased neutrophil adherence, nitric oxide and increased platelet activation.

Opportunistic infectious organisms like chlamydia, Streptococcus pneumonia, and Mycoplasma predominate can infect the organs like lungs, etc.

Diagnosis:

The diagnosis is based on hemoglobin electrophoresis that quantifies the types of hemoglobin. To detect other symptoms, complete blood count (CBC) with differential, reticulocyte count, complete metabolic panel, LDH level, bilirubin level can be performed. Appropriate tests should be performed to check the functioning of the other organs.

(Just for info: Read this interesting article ‘Mystery solved: How sickle hemoglobin protects against malaria‘)

Management/ Treatment:

One approach to treating sickle cell disease is to induce the production of fetal hemoglobin (HbF) which is made up of two α and two γ subunits. HbF inhibits the polymerization of sickle hemoglobin. The drug, hydroxyurea induces fetal hemoglobin production in some patients and improves the clinical condition.

(Just for info: Read this paper titled ‘Fetal hemoglobin in sickle cell anemia’)

Hydroxycarbamide results in increase in both HbF and total hemoglobin and relieves the patients from the various symptoms of SCD. Blood transfusions and haematopoietic stem cell transplantation are also done to reduce help manage the disease.

(Just for info: Read this article ‘US (FDA) Approves New Drug to Manage Sickle Cell Disease’ in Nov 2019.)

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Read other posts by The Biotech Notes:

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Biofilms and diseases.

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References:

Sedrak and Kondamudi. Sickle Cell Disease. [Updated 2019 May 6]. In: StatPearls. Treasure Island (FL): StatPearls Publishing; 2019.

Chakravorty and Williams (2015) Sickle cell disease: a neglected chronic disease of increasing global health importance. Arch Dis Child. 2015 Jan; 100(1): 48–53.

Kato et al. (2018) Sickle cell disease. Nat Rev Dis Primers 4, 18010.

Russo et al. (2019) Current challenges in the management of patients with sickle cell disease – A report of the Italian experience. Orphanet J Rare Dis 14, 120.

Billett (1990) Hemoglobin and Hematocrit. In: Walker HK, Hall WD, Hurst JW, editors. Clinical Methods: The History, Physical, and Laboratory Examinations. 3rd edition. Boston: Butterworths. Chapter 151.

Keenan and Shvartsman (2017) Mechanisms and causality in molecular diseases. History and philosophy of the Life Sciences 39: 35.

Platt et al (1994) Mortality in sickle cell disease. Life expectancy and risk factors for early death. N Engl J Med. 330(23):1639-44.

LuLu et al. (2016) Probing the Twisted Structure of Sickle Hemoglobin Fibers via Particle Simulations. Biophysical Journal 110 (9): 2085-2093.

Frenette and Atweh (2007) Sickle cell disease: old discoveries, new concepts, and future promise. J Clin Invest. 117(4):850-858.