HbF Gene Variant Linked to Moderated symptoms of beta-thalassemia

It is amazing how quickly these new discoveries are coming. This is a major factor in explaining the difference in severity of cases where the thal mutations are similar but the severity is not.

http://www.nia.nih.gov/NewsAndEvents/PressReleases/PR20080130thalassemia.htm

Sunday, January 30, 2008

Contact:
Megan Homer
(301) 496-1752
Nianews3@mail.nih.gov

Beta-thalassemia is a serious, potentially life-threatening disease that affects red blood cells, cells that carry oxygen via hemoglobin throughout the body. As part of the SardiNIA Study of Aging, supported by the National Institute on Aging (NIA), a component of the National Institutes of Health (NIH), scientists have found a genetic variant in the BCL11A gene that can explain why some people with beta-thalassemia seem to be protected from most dangerous symptoms. The findings appear this week in Proceedings of the National Academy of Sciences.

While all those affected in the Sardinia study population have the same mutation in adult hemoglobin, the carrier of oxygen in the red cells, some people experience less extreme symptoms than others — mild enough that these individuals do not need to undergo regular blood transfusions, usually a necessary treatment for beta-thalassemia. People with this blood disorder do not have enough hemoglobin binding to oxygen within their red blood cells and are therefore weakened. They are also at risk for "hemolytic crisis," a condition in which their red blood cells are destroyed faster than their bodies can make new ones. It has been known that some individuals escape hemolytic crisis because they retain a high level of fetal hemoglobin (HbF), which is turned off at birth in most people. The persistence of fetal hemoglobin seems to substitute for the lack of adult hemoglobin sufficiently to moderate the course of the disease.

Now it has been shown that variation in the BCL11A gene, discovered through a genome-wide scan of 4,305 research participants in Sardinia and representing a founder population with a high frequency of beta-thalassemia, is strongly associated with elevated levels of HbF and is specifically more common in the individuals with less severe disease. Also in this study, researchers found the same BCL11A variant associated with persistent HbF levels among 1,242 patients from the Cooperative Study of Sickle Cell Disease, another disorder in which adult hemoglobin levels are depleted. The study raises the possibility that manipulation of BCL11A levels might be studied as a potential therapeutic intervention to alleviate hemoglobin deficiencies that occur in people with beta-thalassemia and sickle cell anemia.

andy ..
my son hdf-91% since 2 years. is this helpful then? or im not understanding this...

Hi,
 I am new to this group.Its a blessing to find this site

My daugther born last month has EBeta thal.

Her HB F is 95.5 % and Hb E 5 % , no Hb A or A2 at 21 days.

does it mean it is good that Hb % is high?

Thank you.

Hi Hopefulmommy and welcome,

I think it's too early to conclude anything from your daughter's Hb level. The fetal hemoglobin (HbF)  levels are still high from  birth and take a few months to drop down. Her long term prognosis will be greatly affected by her ability to produce HbF as she gets older. If she can maintain an ability to produce HbF, it will help to moderate her condition and also make her a candidate for HbF inducers such as hydroxyurea. The absence of any HbA is an indicator that the beta thal gene is minus or zero, so the outcome will be somewhat dependent on the ability to produce HbF long term. However, HbE beta thal is very unpredictable, even when the genotype is known. Siblings with identical genes can have very different phenotypes. ie. One might be transfusion dependent and one might not be. Time will tell how your child does, and as I said, she may be a candidate for hydroxyurea if her HbF production is good.

We will join you in hopefulness that your daughter falls into the non-transfusing category.

Hello Andy,


Thank you so much.
Yeah, I am slowly coming to know about the unpredictability of EBeta Thal.

But is it a reality that E/B0 Thal is much more severe condition that regular thalassemia major?

Also, does gene switching ever happen? As there is  no Hb A in my daughter's blood does it mean that her genes for HbA can never be switched on  and she can not have her on Hb A?

Also, as she is my first chilld and she has got the disease I was wondering something.

I  am thal minor and my husband Hb E carrier, no genetic testing doen yet. I was wondering why is has fallen in disease category and not in the 75% safe zone? Are the chances of having unaffected kid/or carrier status kid for E and BEta carrier parents similar to both thal carrier parents?  I want to plan early for next baby if we she needs any kind of help.

Another thought is , should I start having wheat grass f rom now, so that she can keep high on Hb F through breast milk? Is there anything I can do now/with my diet to make any difference for her good health.

Thank you and best regards,
hopefulmommy

Hi Hopefulmommy and welcome

I know that in holistic medicne, breast feeding the baby from another mum ( not the real mum) has the ability to alter or affect the genetic coding .I know that this sounds crazy, but many holistic medicne doctors admit it

manal

Hi Hopefulmommy,

The chances of you and your husband having an HbE beta thal are the same as if two thal minors have a child, 25% with each pregnancy. As you have already experienced, the odds are meaningless in the real world. Do not believe that because you already have one HbE beta thal, that you won't have another. I know quite a few families that have produced three thal majors, so odds are something to be chanced only in Las Vegas. Genetic counseling is very important and In Vitro Fertilization should be considered.

I have never heard of any case of HbE beta thal that is worse than thal major. Generally when they are transfusion dependent, the transfusions are not quite as frequent as with thal major. HbE beta thal zero does not produce any hemoglobin A because no beta globin is being produced to combine with the alpha globin to make normal hemoglobin. If the beta hemoglobin mutation is plus, it means some beta globin is being produced so you would see some HbA. However, even with HbE thal beta 0, it is not possible to predict the clinical outcome. The ability to produce HbF will be one factor that moderates the condition, but there are other factors that are not understood which can also moderate HbE beta thal. Even though it seems that combining HbE with beta 0 should lead to the most severe condition, only about half of those affected have a condition as severe as thal major.

http://asheducationbook.hematologylibrary.org/cgi/content/full/2007/1/79

The most serious Hb E syndrome is Hb E ß0-thalassemia. The compound heterozygote state of Hb E ß-thalassemia results in a variable phenotype ranging from a complete lack of symptoms to transfusion dependency. In review of 378 patients with Hb E-ß0-thalassemia from Thailand, the hemoglobin concentrations ranged from 3 to 13 g/dL, with an average of 7.7 g/dl. Approximately one-half of the patients are phenotypically similar to patients with thalassemia major who require regular transfusion therapy, and the other half resembles thalassemia intermedia.

Wheatgrass is safe for any age. For a child as young as yours, you might want to try a small dose of the extract daily. I don't think a child that young would willingly take wheatgrass juice since it does not taste good at all. The course of HbE beta tha can be significantly altered in many cases through the use of HbF inducers, so it may provide some help in maintaining an acceptable hemoglobin level.

Because the expertise of the lab can come into play when analyzing hemoglobins, I would suggest another hemoglobin electrophoresis after six months to both verify that there is no HbA and also to see what course the HbF levels have taken.

About Hb fetal...


In our daughter's treatment (Lepore, 2 and a half years old) we were told that one of the -admittedly secondary- goals of the transfusion regiment was to reduce her high Hb fetal which when she started transfusions (18 months old) was extremely high (70-80%).
This is now down to 7-8% which seems to have our doctors happy.
I was told that lowering this percentage means that her own bone marrow is suppresed and that has the benefit of avoiding bone deformations.

From what I understand some individuals have such a high percentage of Hbf (which is if antyhing more efficient in oxygen transportation) that they can avoid or minimise transfusion.

Should we have looked into this?

Doesn't having a high fetal hemoglobin percentage mean that bone marrow is working overtime?


Thanks and God bless

Hi InGreece,

When your daughter's fetal Hb was 70-80% what was her total hemoglobin level? I assume fairly low if transfusion was started.

I don't understand what the concern was about the high HbF percentage unless it was being used as a test of bone marrow activity. If the HbF wasn't enough to raise the total Hb to acceptable levels, I don't think it could cause any harm but it would be an indicator that there was excess bone marrow activity. Of course, transfusion will both dilute this high HbF % and also suppress bone marrow activity. Whether you should have followed the HbF induction route depends on her clinical picture. If her Hb was in the typical range for majors, HbF induction would not be sufficient to avoid transfusion and there would be excess bone marrow activity. This may very well change in time as new HbF inducers are developed. The work of Dr Susan Perrine is of specific interest because of its potential to raise Hb levels several points.

The goal in fetal hemoglobin induction is raising hemoglobin levels which in turn, helps regulate bone marrow activity. Rather than increase it, the rising hemoglobin level will adjust the bone marrow activity closer to normal, depending on how high the Hb can be raised.

Hi Andy

This issue of fetal HB is always confusing me because i don't get it as why in majors we decrease it as it is an indication of high bone marrow activity and in intermedias we tend to increase it and increasing it in intermedias means that their bone marrow is being suppressed (that is what hydrea does)?

Why an increase in fetal Hb is sometimes not reflected on the total Hb??

manal

Hi Manal,

Because (so far) fetal hemoglobin inducers don't raise the HB anywhere close to enough to eliminate transfusion dependency in majors, the bone marrow would remain overactive, leading to bone expansion. However, with intermedias, the hope is that by raising the Hb a point or two, that it be sufficient to suppress bone marrow expansion. That is one of the main criteria for deciding if an intermedia needs transfusions. If the condition can be managed without significant bone marrow expansion, then transfusion is usually avoided.

The problem with understanding fetal Hb concentrations is that it can be confusing when you talk percents rather than actual hemoglobin volumes. The Hb value is an actual total of the hemoglobin whereas the percent of fetal Hb is simply the percent of the Hb that is HbF.

If the Hb is 3 and the fetal Hb is 70%, 2.1 of the 3 is HbF. 70 % sounds like a lot but 2.1 doesn't. Now if the total Hb is 8 with the fetal Hb  raised to 30% the total HbF is now 2.4 even though the per cent of total Hb is much lower. If an increase in HbF doesn't raise the total HB, it means the other hemoglobins have actually dropped.

Hydroxyurea is unique among the fetal hemoglobin inducers in that it is a bone marrow suppressor, beyond what raising the Hb level will do to suppress bone marrow activity. This actually makes it less efficient than it could be in raising Hb. The ideal inducer would raise the Hb high enough to suppress excess bone marrow activity by raising the Hb high enough to eliminate excess bone marrow activity.

Thank you Andy, the example made it really easy to understand, but

If an increase in HbF doesn't raise the total HB, it means the other hemoglobins have actually dropped.

1- any rise in HB F as a result of inducers will normally lower the other hemoglobins since they all should add 100% , right so this is expected

2- This brings another question, assume an intermedia took an inducer (hydra) for a certain time and the HB F increased with a certain percentage then stopped this medicne. Will his body maintain this increase in fetal HB??

3-When the percentage HB A is lowered due to taking hydra, will it increase again after stopping it ?

4- what is the importance of HB A2 to our bodies, shouldn't it be more easy to increase its amounts in the body rather than trying to switch on the gamma genes to produce the fetal HB

Too long, i know...

manal

Manal,

1) No. A rise in HbF does not lower other hemoglobins. The total Hb will rise as more HbF is added to the total. You are getting confused by percentages. Percentages are not volume. They tell you how much of a specific volume of hemoglobin is which type of Hb. The percentage that the other hemoglobins will be is lower because they are now less percent of the total but their volume hasn't changed. The percentage of each type of hemoglobin does not tell you anything at all about the total volume of hemoglobin.

Take a glass of water to represent hemoglobin. If you have one ounce of water and add an ounce of juice (to represent HbF), then 50% of the total is juice, but you only have two ounces. If you take a 9 ounce glass of water and add the same one ounce of juice, the juice content is only 10% of the total of ten ounces, yet each glass contains the exact same amount of juice. The percentage doesn't tell you anything about the total volume. It is the volume of hemoglobin that is added by HbF induction that matters. The percentage that is of total Hb is barely relevant.

2) If you stop giving hydroxyurea, you can't expect it to keep inducing hemoglobin. The Hb will drop unless some other factor has changed. The percentage increase of HbF isn't what matters. It is the total volume of hemoglobin that matters. It would be nice if there was some way to just prime the pump, so to speak, and stimulate the hemoglobin production and stop giving the stimulus, but so far that isn't the case.

3) Hydroxy suppresses bone marrow activity. It is not a very efficient drug from that stand point. If you stop taking it, whatever the state was prior to taking it, should return.

4) HbA2 is made from combining delta and alpha globins. Not much is produced and unlike HbF, there is no point in human life when it is. There isn't anything to turn on as with HbF. A baby in the womb relies totally on HbF and the goal is to stimulate this again to produce enough HbF to compensate for the lack of normal adult hemoglobin (Hb). You are asking the delta gene to do something it has never done at any point in the life of a human, whereas turning the gamma back on is asking to do something that was active when the human was a fetus. It would be unlikely that anything could modify the delta gene enough to make a serious impact on total Hb.

Thank you Andy sooooo much for your effort, it is totally clear now.

I hope that these gamma genes can produce more hb than it used to in the womb, to be able to compansate an adult rather than a a fetus

manal

Hello All and Andy,

I am feeling absolutely disturbed with my daughters results.

Her Hb levels:

at 3 days - 17.3

at 21 days - 15.3

at 1 month 10 days - 11.7

I cant think anything to calm my self or stop worrying .

Should I start giving her wheat grass shots? What can I do.

My daughter is EBeta Thal, 95% HbF no HbA and the rest Hb E.

Please help.

Thank you so much.