Inheriting a blood disorder

Inheriting defective genes that code for the protein chains that form part of haemoglobin can result in thalassaemia.

Dr Hazren Mohamed, 25, is intimately familiar with the environs of the Hospital Kuala Lumpur (HKL) Paediatric Institute and Hospital Ampang, Selangor.

And it is not just because he is a doctor undergoing his first year of housemanship at Hospital Ampang.

Dr Hazren has been visiting first, the HKL Paediatric Institute, then Hospital Ampang, once a month ever since he was seven years old.

The reason for his visits is blood transfusions, needed to treat his thalassaemia intermedia disorder.

He is one of six siblings, children of two β-thalassaemia carriers.

Offspring of such parents have a one-in-four chance of developing thalassaemia intermedia or thalassaemia major, due to their inability to produce sufficient β-globin chains.

Aside from Dr Hazren, one other sibling – his elder brother Amran Halim Mohamed – also had thalassaemia.

A common problem

Thalassaemia is an inherited autosomal recessive blood disorder.

According to consultant haematologist Datin Dr Gnanasothie Duraisamy, around 3 to 5 per cent of the Malay, Orang Asli and Chinese populations in Malaysia are affected by this genetic condition.

However, it is rare in Tamils, or Indians originating from the southern part of India.

There are two forms of thalassaemia: α-thalassaemia and β-thalassaemia. This is due to the structure of haemoglobin — the iron-containing, oxygen-transporting component of red blood cells.

Haemoglobin is composed of heme, which contains iron and gives the red blood cell its colour, and globin, which consists of two pairs of linked polypeptide chains.

Each polypeptide pair is made up of an α-globin chain and a β-globin chain.

The α-globin chain is coded for by two pairs of genes located on chromosome 16 of human DNA, while β-globin chains are produced by a pair of genes on chromosome 11.

Each parent contributes one half of the gene pairs to their child.

Healthy people have all their six pairs of genes working hard at producing the required α- and β-globin chains throughout their lives. But when one or more of the genes do not work or are defective, you have thalassaemia.

A four-gene mixture

Because there are four genes involved in producing the α-globin chain, α-thalassaemia presents itself when two or more of the α-globin genes stop producing its polypeptide chains.

Those who have one non-functional α-globin gene are considered carriers, as they can potentially pass down a copy of the defective gene to their children.

However, as they still have three other genes producing the α-globin chains, they have sufficient normal haemoglobin to live a regular life.

Even those with two non-functional α-globin genes do not usually present with any symptoms, and are unaware that they have what is called thalassaemia trait.

These people are usually picked up when they have to undergo a full blood count, as their haemoglobin levels tend to be on the lower end of normal (above 11g/dL), and both their mean corpuscular volume (MCV) and mean corpuscular haemoglobin (MCH) levels are low (<76fl and <26pg respectively)

According to Dr Duraisamy, results such as these, coming from a Malay, Chinese or Orang Asli patient, should immediately lead the doctor to request for haemoglobin electrophoresis or a haemoglobin analysis to check for thalassaemia. The analysis consists of high liquid performance chromatography (HPLC) and a reticulocyte smear.

She says that women with thalassaemia trait – both α and β – also tend to present with anaemia when they get pregnant, and that is usually the best time for their genetic condition to be picked up.

However, she adds that doctors need to be vigilant about detecting these cases as they can be easily confused with pregnancy-induced iron-deficiency anaemia, due to their similar presentations.

Meanwhile, the absence of three functioning α-globin genes results in Haemoglobin H disease.

The condition is named after the abnormal haemoglobin that is produced due to the lack of sufficient α-globin chains.

When there are not enough α-globin chains, the β-globin chains start to pair up with each other instead, resulting in haemoglobin H. This haemoglobin cannot carry oxygen well, and also damages the red blood cell membrane, thus, accelerating cellular destruction.

Patients with Haemoglobin H disease frequently need regular blood transfusions in order to survive.

Those unfortunate enough to inherit four defective α-globin genes usually develop a condition called hydrops fetalis, and die at birth or in the womb.

“It is called hydrops fetalis because the body looks like a bag of water, and it occurs mainly in Chinese in Malaysia,” says Dr Duraisamy.

Clinically complex

As there are only two genes involved in β-thalassaemia, its inheritance pattern is more straightforward. However, its clinical presentation is a bit more complex compared to α-thalassaemia.

Genetically speaking, having one defective β-globin gene means that the person has thalassaemia trait, like Dr Hazren’s parents.

Just like α-thalassaemia, those with β-thalassaemia trait produce sufficient β-globin chains to lead a fairly normal life, and as such, are usually unaware that they have a defective gene.

Again, these cases are usually picked up when they need to do a full blood count, which will show a haemoglobin level towards the lower end of normal, and low MCV and MCH, and when the pregnant woman inevitably develops anaemia.

And then there are those whose β-globin genes are both defective.

But, as can be seen with Dr Hazren and his brother Amran, even though they both had the same genotype or genetic condition, their presentation of the disease was different.

Amran, the elder sibling and third of the six children, started showing symptoms of the condition when he was a few months old.

His mother, Kamaliah Hasbullah, recalls: “For the first three months when he was breastfeeding, he was okay. Then he started having fever off and on, refused to eat, and he looked pale and yellow.”

For months, she kept taking him to various clinics for treatment until he became so pale at the age of eight months that he resembled a “mayat” (corpse), she says.

At that point, the doctor in the Sentul clinic she had taken him to took one look at him and ordered her to take him to the hospital immediately.

There, Amran’s haemoglobin levels was discovered to be so low that it was only between 2-4g/dL (normal levels for children should be >11g/dL).

He was subsequently diagnosed with thalassaemia major, and received his first blood transfusion there and then.

In contrast, Dr Hazren, the second youngest child, went undiagnosed until he was about seven years of age.

Says Kamaliah: “When I saw that he was pale when he was around five to six months old, I knew he got it too; but he was chubby and had good appetite.”

It wasn’t until family and friends started to “tegur” (chide) her because Hazren was so pale (due to anaemia) and yellow (jaundice, due to excess bilirubin in the body) that she finally took him to see the doctor.

He was then diagnosed with thalassaemia intermedia, due to his milder symptoms.

The differences in the age of presentation as seen by Dr Hazren and Amran, and the severity of their condition, is due to variations within defective β-globin genes.

Some genes (βο) cannot produce any β-globin chains at all, while some genes (β+) still manage to produce minimal amounts of the chain.

So, those with two defective β-globin genes could either have βο/ βο, βο/β+ or β+/β+, with the corresponding differences in the amount of β-globin chain production and severity of the disease.

Thalassaemia intermedia and thalassaemia major are clinical classifications of the disease, which depend on the haemoglobin levels of the patient, and the need for blood transfusions.

The haemoglobinopathies

To complicate matters further, patients who come under the heading of thalassaemia need not only have defective α- and β-globin genes.

While thalassaemia-causing genes are inherited, some patients might instead, have a point mutation on one of the globin genes, resulting in that gene producing faulty globin chains.

For example, Haemoglobin Constant Spring is a form of haemoglobin produced when the α-globin gene is mutated to produce an extra long chain.

This longer chain is inherently unstable, and results in the same symptoms as Haemoglobin H disease when it occurs along with only one normal α-globin gene (out of the four).

(For the curious, the name Constant Spring is derived from the district of the same name in Jamaica where this variant of haemoglobin was first isolated in a Chinese family.)

Another result of a common example of β-globin gene mutation in Malaysia is Haemoglobin E (HbE).

This form of haemoglobin occurs due to a change in one amino acid along the β-globin chain, leading to decreased production and an unstable form.

When this mutation occurs along with a normal β-globin gene, the person is considered to have thalassaemia trait, and does not usually have any serious symptoms.

The problem arises when the mutation occurs alongside a defective β-globin gene inherited from a thalassaemia trait parent. A person with this genetic profile would develop thalassaemia intermedia.

Treating thalassaemia

The general treatment for serious thalassaemia cases is blood transfusions, in order to supplement their own defective red blood cell supply.

Both Amran and Dr Hazren were at the hospital once every month for their doctor’s appointment, followed by an infusion of packed cells, which comes from blood donors.

Because of the regular blood transfusions, thalassaemia patients have to receive chelation therapy. This is to remove excess iron in the body caused by the intake of extra red blood cells.

According to Dr Duraisamy, the body can only absorb and remove about 1-2mg of iron a day; however, 200ml of packed cells contain about 250mg of iron.

Over time, if untreated, the excess iron accumulates in organs such as the spleen, liver and heart, which eventually leads to organ failure and death.

This was the cause of Amran’s death at the age of 19 in 2001.

The main form of chelation therapy in Malaysia is a drug called deferoxamine.

Dr Hazren shares that it is administered subcutaneously over a period of 10-12 hours, usually at night while the patient sleeps, via a transfusion pump once every 24 hours.

This method is painful and troublesome, as the patient has to prepare the infusion, sterilise the injection site, and inject himself. The alternative is to go to the hospital to get transfused every day.

“My brother was non-compliant, like many other patients,” shares Dr Hazren. “He’d do it whenever he felt like it, maybe one or two times a week.

“And I think when he was away studying (a diploma course) in Ipoh, he was even less compliant.”

The medication and transfusion pump are not cheap either. Dr Hazren says that the medication costs about RM140 (S$56) per box, and he used to finish four boxes a month, while the pump cost over RM1,000.

But beginning in 2006, the Health Ministry started sponsoring the treatment for all thalassaemia patients at government hospitals around the country. Before that, Dr Hazren was fortunate enough to be sponsored by his father’s employer.

There are also two forms of oral chelation therapy available for those willing to pay for it.

Dr Hazren is currently on deferasirox, which he started taken over two years ago. “It is much easier because of my studies and my job now.”

He is also fortunate that Hospital Ampang is sponsoring his treatment under their own budget, as they only have enough money to sponsor two thalassaemia patients.

For most other patients, the drug costs about RM5-6,000 a month.

The exceptions are for patients aged below eight, those who are not currently receiving optimal treatment, and those experiencing side effects with other chelation drugs.

Health Minister Datuk Seri Liow Tiong Lai announced in May that the Government would sponsor deferasirox for these groups of patients.

Dr Hazren was also previously on another oral medication called deferiprone; however, he suffered from severe joint pain on that drug and had to stop taking it after six months.

The oral medications, although convenient, can cause quite severe side effects.

Preventing future cases

Another important area, particularly for those with thalassaemia trait, is the area of genetic counselling.

It is estimated that around one in every 20 Malaysians carries a defective thalassaemia gene without knowing it.

Around RM11.7mil has been allocated by the Government this year to expand prevention and control programmes. This includes a continuation of free screenings for thalassaemia in government clinics and hospitals.

The main aim of screening is to identify and counsel thalassaemia traits and carriers on passing down the thalassaemia genes to their children.

Says Dr Duraisamy: “Having a child with thalassaemia major is very psychologically, emotionally, and financially draining.

“You have to bring him or her to the hospital every month for treatment, and it can be very emotionally draining.”

With the carrier rate so high among Malaysians, she advises couples to get tested before they commit themselves in a relationship.

In order to prevent cases of thalassaemia major or intermedia, it is usually advised that β-thalassaemia traits should not marry another β-thalassaemia trait or those with the Hb E gene; and α-thalassaemia traits should not marry another α-thalassaemia trait.

However, α-thalassaemia traits can marry β-thalassaemia traits or HbE gene carriers, and HbE gene carriers can marry another HbE gene carrier.

Dr Duraisamy also stresses that family members of anyone who has been confirmed as a thalassaemia trait or patient should also get tested for thalassaemia, if they do not know their status.

Kamaliah, who says that no one, not even her husband, knows how much she suffered for her children, adds half-jokingly that “If I had known about our condition then, I would have rejected (my husband’s proposal).”

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