Chances of having thal in siblings

Hi folks,
Although there is a thread already started by sn196 regarding thal/HbH in siblings, I'm creating another one to talk about chances of having a thal kid if one of the parent is thal intermedia.
I'm thal intermedia with Hb-E and my wife is normal(does not carry any thal trait). She's pregnant and is in 9th week .

My concern is : Is there any chance that the kid can have thal intermedia?

Based on my understanding, there's a 50% chance of having thal trait and another 50% chance having Hb-E. So, the worst possible case in this situation is a "thal trait" as heterozygous Hb-E condition does not affect that much as compared to being thal-minor.

Also in this case, is CVS (Chorianic Villus Sampling) test useful? Will be be worth the risk?

Can somebody help me understand this better, also please correct me if my understanding is wrong?
 

Thanks in advance,
Hallu

     

Congratulations on the pregnancy. I don't think there is much for you to worry about.

Your child will have either an HbE gene or a beta thal gene and the other gene will be normal. In most cases if the child has the beta gene it will be a minor. As you said, if it's the HbE gene, there will be no problem, other than in the future, the child should know the status of any prospective mate before having children. In some rare cases where there is a severe deletion of the beta hemoglobin gene, a condition sometimes classified as intermedia can occur. This is rare and unlikely to happen in your case, as you are classified intermedia. As I recall, your intermedia did not become a problem until well into adulthood, which would indicate that the gene deletion is not complete. I think it would be very unlikely that your children will have any problems.

CVS does pose a small risk of problems. Keep in mind that the inherited gene can be no worse than your own. Your history does not indicate a severe or complete deletion of the Hb gene, and in fact many HbE beta thals require lifelong transfusion, which has not been the case with you. I would encourage you to make sure your wife has a healthy stress-free pregnancy and that she makes sure she always takes her folic acid.

Hi Andy/All,
Firstly thanks a lot for educating me on this. Yes, so far I haven't run into any *major* problem other than an enlarged spleen + being weak all time. I thank god for taking care of me .

After reading your reply, I get a little nervous though and I'll explain you why. Please correct me if anyone finds that my understanding is wrong.

My father is heterozygous beta thal, mutation IVS1-1. My mother is Hb-E, and also there's a mutation in her which is not very common and doctors could not figure out. The basis of this argument(of having some mutation) is: if she didn't have any mutation other than Hb-E, then I would be thal-minor and not intermedia. I think Hb-E is considered benign. Right?

As per my understanding, I have IVS1-1 mutation(from father), and some other "unknown mutation" + Hb-E, which makes me BetaThal-Intermedia with Hb-E.
I guess IVS1-1 is complete absence of beta chain...isn't it? Mutation of my mom is milder and does not cause complete absence of beta chain.

You said, "in a rare case if there's a complete absence of beta chain, then it might be like intermedia". Do you or anybody in group think that based on the info state above, there's a chance of it? Should we go for CVS to eliminate chance of intermedia, if there is ? Will it be worth the risk?

Sorry if I sound a lil fussy or if i'm digging too much. But I guess, you'll will understand my situation.

Thanks,
Hallu.

The reason you are intermedia is the combination of HbE and beta thal. It is not beta thal alone that does this. I know we have several members in this group with the same combination as you, and thankfully, you are better off than them as they have required transfuions since childhood. HbE is benign when it is by itself. When combined with a beta thal gene, it becomes a condition very similar to intermedia, although in reality, many of these intermedias would be classified as majors by their transfusions requirements. Six year old Teddy from Dubai has the same. One beta thal gene and one HbE gene. He has required transfusions and desferal from an early age and most definitely has the symptoms of major. It may be the amount of mutation or deletion of the thal gene that makes the difference. I know it seems that if HbE is benign when it is found by itself then it shouldn't make a difference when combined with only one thal gene, but it does make a huge difference, causing the HbE beta thal condition.

So the answer to your question is no. The other mutation in your mom may have some potential to cause a problem, but it is the combination of HbE and the beta thal gene that has made you an intermedia. This can manifest in a wide range of symptoms appearing to be anything from minor to major, but it is the combination of the two genes that is the cause.

http://www.thalassemia.com/variant_hemo.html

there are mutations such as that leading to hemoglobin E, which do not produce disease even in the homozygous state. However, hemoglobin E combined with other variant beta globins can produce mild to severe anemia. Many variant hemoglobins exist worldwide. Hemoglobins E and S are significant because they can be co-inherited with thalassemia trait to produce a disease that requires treatment. Hemoglobin E is very common among Southeast Asians; California Newborn Screening Program found that 1 in 12 Southeast Asians, and 1 in 4 Cambodian newborns had Hgb E trait. Hgb EE (homozygous) has not been shown to have serious medical implications. Hgb E-Beta thalassemia has a wide range of clinical manifestations, from mild anemia to significant anemia requiring chronic tranfusions.

But as far as your original question, since you can only pass one of these two genes on to your children, they cannot have the same condition as you.

And thanks for asking. We are here to help and educate and any question helps educate not only the members of this group but also many people who stop by the group looking for answers to specific questions. If there is anything that is still not quite clear, please do not ever hesitate to ask. This can be very confusing stuff and HbE beta thal certainly fits that description, just as intermedia does. There is still much that isn't fully understood about why these genes operate the way they do but we are always getting closer to answers.

 Andy is right... Hb E + Thal will lead to E Beta thal.. which can have various manifestations.. sometimes it can remain as intermedia and these kids might not need transfusions all their life and can adjust to a very low Hb ( maybe 6-7 ) and carry out all their normal activities. It has also been seen in Sri  lanka that after splecnectomy, E Beta thals can survive without blood transfusions.

But most of the time, it has all the manifestations of a Thal major. They require transfusions every 10-15 days. Some doctors think that if the spleen is taken out in these kids, then the transfusion requirement slows down most of the time.

My daughter is E Beta Thal. She is 29 years old and has required regular transfusions all her life. After splenectomy, the transfusions frequency is 2 units every 5-6 weeks. She leads a perfectly regular life. But she cannot do without transfusions after 5-6 weeks, when she begins to feel tired etc.

E beta thal is very very common among the Bengali community .. that is the eastern part of India.

Shikha Mitra

Wow! This information is an eye opener.
I used to think that my intermedia is because of beta chain IVS1-1 mutation from my father + some other *mild mutation* from my mother. And in addition to that I'm Hb-E and hence I'm Beta Thal Intermedia-Hb-E.
But now based on the info provided by you guys, my intermedia is because of combination of beta thal + Hb-E (Though I'm not sure how's the other *mild mutation* affecting me). This is a new piece of info and is very helpful to correct my understanding on the subject.
I owe a big - Thanks! - to you guys for sharing this with us. I’m really grateful to you all and especially Andy: Hats off to you!!!

Finally if I sum up my understanding, kid would be either like my father (beta thal(IVS1-1)) Or like my mother (Hb-E + some *mild mutation*)) And CVS won’t be recommended in this case as it’s risky (as risk would outweigh the benefit)…right?

Thanks,
Hallu

Exactly right. Your kids can only get one of those two genes from you so testing in advance would have little purpose and one of every 100 cvs ends in miscarriage so there is some risk.

It does seem strange that HbE alone is so innocuous but when together with the beta thal gene, it can cause serious transfusion dependent anemia. An interesting note is that Lisa, the founder of this group was not a classic thal major herself. She had one beta thal gene, but also carried the Lepore trait. Again, this is normally classified as intermedia but in both her and her father's case (he had the same combination), the condition was definitely transfusion dependent anemia, as severe as thal major.

This Hb E Beta Thal can be heterogenious type of clinical picture, I have diagnosed 40 year old male Hb E Beta thal for first time. The history came to me, he had always sevre jaundice, and he had gall stones and surgically removed gall bladder. Even with all this they never diagnosed hemoglobinopathy in this patient, before he was refered to us.

My point here is in this situation or other thalassemic situation from patient to patient there are so much variations becuase of severity of mutations. In general we can conclude clnical symptoms on these cases but it very much depend on case to case.

Hi all,
   I found this conversation very interesting. I looked up my genetic testing which was done 10 years ago, and I also am heterozygous for the IVS -I-1 mutation. I also have intermedia. They weren't sure how I got intermedia since my mother was not a Thal carrier. They thought she might have something in her genes that caused me to have a more severe anemia, even though I am heterozygous. My father had Thal minor. I just had genetic testing done again at Children's Memorial Hospital in Chicago, to see if they can find anything else because the technology is more advanced now.
   My hemoglobin never went over 9 as a child, and oftentimes went down in the 6-7 range.  I started regular transfusions 3 years ago at age 52. I will let you guys know what they find once I get my report from Children's. Interesting that Hallu and I have similar genes.  My father was of Greek heritage.
     Good luck with the pregnancy!  Jean

Thanks Jean for the wishes. I hope that everything goes well.

This is really interesting stuff. Even my understanding was wrong until Andy/Shikha corrected it. I think intermedia as such is a confusing concept and people are not very clear on it. I remember, when my thal was discovered my family was told that I have thal minor (and not intermedia). The only classification they had that time was Minor and Major. I was 10 yrs old that time.

It'll be interesting to know your finds on same. You must be inheriting some blood disorder gene from your mother, which makes you an intermedia.
Since, we've touched this topic, I would also like to ask another question related to this.
Does anyone know what "XMN Polymorphism" means? In my reports, I see I'm "+/+" for that. My guess is, it has got something to do with gamma gene. I don't know whether it has any connection with thal gene or not. Also, it this some kind of disorder?

Any inputs will be welcomed.

Thanks,
Hallu

Hallu,

XMN Polymorphism is a common gene sequence variant and is believed to be involved in the expression of the gamma globin gene. The interesting thing I learned researching this, is that XMN Polymorphism is associated with heightened levels of fetal hemoglobin (HbF). It is believed that this higher production of HbF results in a milder thalassemia. This could be an explanation for why you have not been transfusion dependent.

Have you ever had your HbF checked? I would be very interested in those results to see if it backs up this theory.

If you care to read highly technical explanations, you can google XMN Polymorphism. I found a very good but also very technical page at http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=384958

Andy,
Based on my recent electrophoeresis report, my HB composition is:
HbF : 47% HbE : 33% HbA : 17.4% HbA2: 1.5%
It doesn't add to 100% exact but it is close (98.9%). I'm missing 1.1% somewhere and I'm unable to recall which reading is wrong. But I think this gives a pretty good idea of the composition. Can you or anyone here interpret how severe is my thal based on these readings?
Strangely, these reading were different at the time my thalassemia was detected. That time(when i was 10 yr old) my HbF was 20.1% and HbE 28%. I don't know reading for HbA/A2 that time, as that report is lost and I have only an incomplete report stating HbF and HbE.

Regarding, higher level of HbF and XMN Polymorphism: I think all Beta thals have high levels of HbF. Does that mean all Beta thals have gamma gene sequence/XMN Polymorphism?
You are right that HbF helps in keeping total Hb high. I think Hydroxyurea treatment also attempts to raise HbF. However, once I met someone whose HbF was very very high(but no HbA) but was still transfusion dependant. This stuff is difficult to understand but is very interesting to chase.

The article you provided was too technical for me. I will have to read it again(and possibly again ) to understand better.

Hallu,

Not all thals have the XMN Polymorphism. It is theorized that those who do are less likely to need to transfuse. HbF is usually raised in thals but is often under 10%. The percentages don't tell the whole story though, as the total hemoglobin level will better indicate the need to transfuse or not. Was the person you met with high HbF who transfused, a major? The high percentage of HbF would not necessarily mean he would also have a high Hb total. If your HbF is 80% but your total Hb is only 6, chances are you would need to transfuse.