Thalassemia Patients and Friends
Discussion Forums => Thalassemia Intermedia => Topic started by: TPF-Help on October 15, 2011, 07:35:00 AM
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Dear Andy,
I have some clarifications regards to my sons reports where we had tested his samples in two places:
1) HPLC report says that he is a "Homozygous Beta Thalassemia / Beta Thalassemia major suggest.
2) Another report DNA Mutation Analysis report says that he is a "Heterozygous IVS 1.5 (G-C) Mutation in beta globin gene detected.
There is a conflict in both the reports, the samples were tested before transfusion because his hb drop down to 4.2 g/dl at his 10th month of age.
HPLC DATA : 1) HbF - 69.1% 2) HbAo - 24.2% 3) HbA2 - 4.8%
Another HPLC had tested from peripheral blood in Gulf and the results are same as above : Heterozyougs IVS 1.5(G-C) in beta globin gene detected.
In India : based on the HPLC report they told that he is a major and tranfusion has been give on two times :
one time to rise his Hb from 4.2 to higher.
another time to maintain his Hb from above 9 to 12 which is after 18 days and now 60 days finish and we haven't transfuse him and his present Hb is 8.8%.
My son treatment is started here in Gulf recently where I am working, I had consult to an Expert doctor and we feel that we reached to a safe and right place.
I want to have a few comments on this issue and his management and conclusion.
Warm regards,
Sys
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Hi Sys,
The report says heterozygous IVS-I-5 (G->C). Is there a second mutation noted? If both genes are IVS-I-5 (G->C), it would be homozygous, but heterozygous infers two non-matching gene mutations. IVS-I-5 (G->C) is the most common mutation found in India, and when one has two genes like this, thal major occurs. Major also occurs when IVS-I-5 (G->C) is combined with many of the other mutations.
The presence of 24% HbA is confusing though, as majors normally have a much lower HbA level if they have any at all. This level looks more like thal intermedia but his early transfusion requirements would more likely place him as a major. An intermedia would not have an Hb under 6. However, if illness had been present, it could lower the Hb of an intermedia to the point where transfusions are necessary.
Where are you now located? Some of the Gulf nations have very good thal treatment, and have well trained doctors. What do the current doctors think? His Hb has held above 8 for two months, which again indicates intermedia. I would find it hard to believe the child is homozygous for IVS-I-5 (G->C). It may be that it is combined with a milder mutation that is allowing for some hemoglobin production. How old is he now?
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Dear Andy,
Thank you very much for your immediate reply....!!!
I would like to correct you once again : HPLC report is saying "Homozygous Beta Thalassemia" and
DNA Mutation is saying "Heterozygous for IVS 1.5 (G-C) Mutation in beta globin gene sequencing.
My son is now started 14th month, still I could not able to conclude him at this point of time.
My treating doctor is very professional and he wants to repeat HPLC once again and would like to observe him for one more month with a keen check-up on every 10-12 days without any stress on the bore marrow, this may be a touch decision but otherwise we never know he is a Intermedia / Major?
Please tell me some more details about the second mutation, which is required to be check from the patient or from parents blood sample?
Warm regards,
Sys
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Sys,
Heterozygous means that the two genes are not the same gene. When a DNA test says homozygous it means that the two genes are the same. (Homozygous beta thal is a general description and does not refer to the genetic report). Knowing which two genes are involved can help with the long term prognosis, but the information you have provided only refers to the one gene. Both genes would normally be reported in the DNA testing. If both genes were the IVS-I-5 (G->C) gene, then a severe thalassemia with an HbA of 5-8% could be expected. Your child has shown a much higher percentage of HbA, but at his age this can still change and I assume this is one reason the doctor wants to repeat the HPLC testing. At 14 months, this report should be more definitive because the changes that occur after birth should be completed by now. If the HbA is still higher than 10% it may be assumed that the second mutation is of a milder nature and the gap between transfusions may be longer. It may also mean that the child may be a candidate for hydroxyurea therapy, but this will not be clear until further testing is done. If the HbA has dropped significantly, it would be a sign that regular transfusions will most likely be required.
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Dear Andy,
Thanks for your prompt replies and detail updates.
In response to your reply earlie : Is about Second Mutation noted ? what is the name of this second mutation and how this has to be done, since we are planning to repeat my son's HPLC, the same time I can go for the second mutation ?
Do you think parents DNA mutation will be helpful to diagnose the case in detail, if so, what is the name of that that DNA Mutation analysis ?
Kindly do reply to me at the earliest please.
With regards,
sys
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Sys,
The report you provided only mentions the one gene and it says heterozygous, which means the two beta genes can't be identical.
DNA Mutation is saying "Heterozygous for IVS 1.5 (G-C) Mutation in beta globin gene sequencing.
Was there any other gene mentioned in your report? Perhaps mention of a codon?
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Dear Andy,
You are really a great...Thanks for immediate reply of my queries....!!!
The DNA report was having some limitations while we did the test for my son as they told me that second mutation not got ?
Limitations :
Only the coding regions of the beta globin gene and immediate flanking intron sequences were examined. Changes in the promoter region, farther into the introns, or in the other non-coding regions of the gene would not be detected. The sensitivity of the DNA sequencing is over 99% for the detection of nucleotide base changes, small deletions and insertions in the regions analyzed. Mutations in gene other than beta globin gene would not be identified. Miltiple exon deletions, multiple exon insertions, and complete deletion of one allele may not be identified using these methods.
You can better understand the above limitations and explain to me, and further more please let me know if as a parents we want to do our DNA test with regards to diagnose my son's case, then what is the name of that DNA test?
If we want to see other side mutation of my son then what is the name of that DNA test ? I hope you understand my query ?
With regards,
Sys
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Sys,
Heterozygous means that the two genes are not the same gene. When a DNA test says homozygous it means that the two genes are the same. (Homozygous beta thal is a general description and does not refer to the genetic report). Knowing which two genes are involved can help with the long term prognosis, but the information you have provided only refers to the one gene. Both genes would normally be reported in the DNA testing. If both genes were the IVS-I-5 (G->C) gene, then a severe thalassemia with an HbA of 5-8% could be expected. Your child has shown a much higher percentage of HbA, but at his age this can still change and I assume this is one reason the doctor wants to repeat the HPLC testing. At 14 months, this report should be more definitive because the changes that occur after birth should be completed by now. If the HbA is still higher than 10% it may be assumed that the second mutation is of a milder nature and the gap between transfusions may be longer. It may also mean that the child may be a candidate for hydroxyurea therapy, but this will not be clear until further testing is done. If the HbA has dropped significantly, it would be a sign that regular transfusions will most likely be required.
Hi,
Dear Andy,
Please required urgent help on the above comments which you had reply to me couple of months before.
I had repeat my son's HPLC after 85 days from the transfusion and his results are reveals very different:
1)HbF- 11.2% 2) HbA2 - 3.6% 3) HbA - 82.7%.
His previous HPLC - HbA - 24.2% at the time when he was first diagnosed and his HB was 4.2% g/dl.
I had given transfusion, when he falls at 5.9% which is after 85 days, and another time he falls at 6.3% which is after 15 days.
Kindly advise me urgently to help me in this matter, my son case is very confusing me. Do we need to check his Alpha status?
With regards,
Sys
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Hi Sys,
I can't imagine that alpha thal is also involved as he HbF level would not be high. The long interval between transfusions continues to suggest thal intermedia, but transfusion dependent intermedia. The electrophoresis is affected by the transfused blood, so it is not as useful a tool at this point. I think to ensure proper growth and development, a regular transfusion schedule will need to be implemented. Ideally, the Hb should not drop below 9. What has the doctor suggested as far as regular transfusion?
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Hi Sys,
I can't imagine that alpha thal is also involved as he HbF level would not be high. The long interval between transfusions continues to suggest thal intermedia, but transfusion dependent intermedia. The electrophoresis is affected by the transfused blood, so it is not as useful a tool at this point. I think to ensure proper growth and development, a regular transfusion schedule will need to be implemented. Ideally, the Hb should not drop below 9. What has the doctor suggested as far as regular transfusion?
Dear Andy,
Thanks for your quick reply of my query.
Doctor wants to maintain him from 6~8 and he is not treating as Thalassemia since his HbA is now more than 82% and wants to investigate more about alpha gene ? Requesting to do Parents HPLC , CBC and REtuculocyte for more study. Maintaining from 6~8 will be harm in the future ? His growth looks bit OK, Kindly advise....??
With regards,
Sys
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Dear Andy,
Thanks for your quick reply of my query.
Doctor wants to maintain him from 6~8 and he is not treating as Thalassemia since his HbA is now more than 82% and wants to investigate more about alpha gene ? Requesting to do Parents HPLC , CBC and REtuculocyte for more study. Maintaining from 6~8 will be harm in the future ? His growth looks bit OK, Kindly advise....??
With regards,
Sys
Hi,
Dear Andy,
Kindly give some feedback about my queries.....Also you are telling me that ....HPLC will not be helpful at this point?
According to the doctor..the HPLC value - HbA should be around 30-35% due to transfused blood but there is a tremendous change in the HbA of 82.7% which is quite confusing. How you identified that Alpha also involved?
Please reply to me at the earliest.
With regards,
Sys
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Electrophoresis is not accurate until 2-3 months after the last transfusion, so the value of the test is dependent on how long it was since the most recent transfusion. The test after 85 days should give a clear picture but the tests are completely different from the previous test. Is it possible for you to either post or send as a PM his complete report from the DNA test that concluded
"Heterozygous for IVS 1.5 (G-C) Mutation in beta globin gene sequencing
? This refers to only one of the two beta globin genes and identification of the other gene would help to clear things up.
I did not identify that alpha is involved. I said that it seems most unlikely that it could be involved because the level of HbF and HbA2 are too high to suspect alpha thal.
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Electrophoresis is not accurate until 2-3 months after the last transfusion, so the value of the test is dependent on how long it was since the most recent transfusion. The test after 85 days should give a clear picture but the tests are completely different from the previous test. Is it possible for you to either post or send as a PM his complete report from the DNA test that concluded ? This refers to only one of the two beta globin genes and identification of the other gene would help to clear things up.
I did not identify that alpha is involved. I said that it seems most unlikely that it could be involved because the level of HbF and HbA2 are too high to suspect alpha thal.
Dear Andy,
Thank you for your continuous support and prompt replies for my queries.
Please find attached herewith the DNA report and the HPLC report.
Expecting your comments upon reviewing of these reports.
With regards,
Sys
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The electrophoresis from the July 30 report indicates HbF, HbA and HbA2 levels that would indicate thalassemia intermedia. These levels are now completely different, with a much closer to normal HbA. The DNA report does only identify the one mutation. By itself, this cannot cause thal major. I suspect a second silent beta mutation. These are not as easily identified, but an expert may find that there is a small amount of a variant hemoglobin present. This will sometimes be found to be 2-3% of the total hemoglobin. Your current doctor may suspect this and I would talk to him in advance of HPLC testing to see if the test can find these variant hemoglobins that are not normally screened for. If a silent mutation is present, thal intermedia may be the correct diagnosis.
I have a question. Have both parents been tested as carriers or is it assumed that both are?
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The electrophoresis from the July 30 report indicates HbF, HbA and HbA2 levels that would indicate thalassemia intermedia. These levels are now completely different, with a much closer to normal HbA. The DNA report does only identify the one mutation. By itself, this cannot cause thal major. I suspect a second silent beta mutation. These are not as easily identified, but an expert may find that there is a small amount of a variant hemoglobin present. This will sometimes be found to be 2-3% of the total hemoglobin. Your current doctor may suspect this and I would talk to him in advance of HPLC testing to see if the test can find these variant hemoglobins that are not normally screened for. If a silent mutation is present, thal intermedia may be the correct diagnosis.
I have a question. Have both parents been tested as carriers or is it assumed that both are?
Dear Andy,
Thanks for your valuable comments :
It has been confirmed that we both are Thalassemia Trait or Thalassemia Carriers
My HPLC values are as follows :
1)HbF - 0.2 2) HbA2 - 4.4 3) HbA - 86.5
My Wife HPLC values are as follows :
1)HbF - 0.5 2) Hbs - 0.5 3) HbA2 - 4.8 4) HbA - 84.4
I am giong to do DNA studies for my family and mine.
How do we find the silent mutation based on which type of test we need to do ?
With regards to my son thalassemia management, we are not giving him regular transfusion.
Following doctors advise maintaining him from 6% ~ 8%, is it will be OK or we have to keep him above 9 ? Kindly advise please.
Thanks you once again.
With regards,
Sys
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Sys,
Your own HPLC reading comes only to 91% total. Your wife's shows a small amount of HbS (sickle cell). That is strange to see here and may be an error. These results are peculiar. Where were these tests done? A proper DNA analysis should determine if there are any silent variants. In fact, a proper HPLC should show if there are any small quantities of variant hemoglobin present. The DNA analysis should sort this out.
You have to be the judge regarding your son's health. Is he healthy and active at his current Hb level? If so, then transfusions may be avoided. If he is lethargic with slow growth, transfusions would be indicated.
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Sys,
Your own HPLC reading comes only to 91% total. Your wife's shows a small amount of HbS (sickle cell). That is strange to see here and may be an error. These results are peculiar. Where were these tests done? A proper DNA analysis should determine if there are any silent variants. In fact, a proper HPLC should show if there are any small quantities of variant hemoglobin present. The DNA analysis should sort this out.
You have to be the judge regarding your son's health. Is he healthy and active at his current Hb level? If so, then transfusions may be avoided. If he is lethargic with slow growth, transfusions would be indicated.
Hi,
Andy,
How are you ? Thanks for your valuable comments.
We had repeated our HPLC here for me and my wife as follows :
My Wife HPLC DATA in two countries as follows :
HPLC DATA UAE INDIA
HbA2 4.7% 4.8%
HbF 0.5% 0.5%
HbAo - 84.4%
HbS - 0.5%
My HPLC DATA UAE INDIA
HbA2 4.1% 4.4%
HbF 0.2% 0.6%
HbAo - 86.5%
With regards to my sons blood transfusions, my doctor did not keep him on regular transfusion, according to him his HbA - 82.5% and maintaining him Between 6%~8%. Is there will be any dysmorphic problem in the future when he reached to age 4 & above ? We are currently doing his "Beta Globin Gene Sequencing test" and then again we are going to repeat his HPLC one more time to see the figures before transfusion.
Kindly review the above data reply to my e-mail and please give me your valuable comments.
With regards,
Sys
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Again the test results are incomplete and I cannot comment until a proper electrophoresis is done. The numbers need to add to close to 100 and not 5 or 90. Were no results given for the HBA in the parents in the UAE test? I hope the gene sequencing reveals what is needed. Until we know what the TWO mutations are, instead of only one, there is nothing more I can comment.
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I hope the gene sequencing reveals what is needed. Until we know what the TWO mutations are, instead of only one, there is nothing more I can comment.
Dear Andy,
Please I need your urgent advise on this below subject :
Once again we had crossed three months gap from the transfusion.
Doctor's Recommenation :
* According to treating doctor, he has lot of patients maintaining their Hb level from 6% ~ 8% g/dl and living normal lives?
* They want to avoid transfusion if his Hb level is maintained above 6%~8% g/dl and RET within some range like >4% ~10%? For this reason the following Hb status on weekly basis has been tested :
* On: 07-12-2011 – Hb Level: 10.7% g/dl (Note : Transfusion given on 24-11-2011-200ml)
* On: 21-12-2011 – Hb Level: 11.5% g/dl.
* On: 03-01-2012 – Hb Level: 7.1% g/dl.
* On: 11-01-2012 – Hb Level: 6.4% g/dl - RET: 2.41%
* On: 16-01-2012 – Hb Level: 6.0% g/dl.
* On: 19-01-2012 – Hb Level: 6.3%g/dl.
* On: 25-01-2012 – Hb Level: 6.5% g/dl - RET: 4.21%
* On: 07-02-2012 - Hb Level : 7.5% g/dl - RET : 4.84%
* On: 21-02-2012 - Hb Level : 4% g/dl - RET : 5.47%
* On: 22-02-2012 - Hb Level : 4% g/dl - RET : 8%
* His growth looks OK but weight is now 8.4 Kg @ his current age : 17th Month.
* Beta Globin gene sequencing test reveals once again : IVS 1.5 (G-C), there is no other mutation detected.
* there are some RBC membrane damage which transfer from Mother side.
* According to Indian doctor’s advice, I have to maintain his Hb above 9% for the better quality of life even though he is Thalassemia Intermediate.
Your valuable comments will be highly appreciated.
With regards,
Sys
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Dear Andy,
Please I need your urgent advise on this below subject :
Once again we had crossed three months gap from the transfusion.
Doctor's Recommenation :
* According to treating doctor, he has lot of patients maintaining their Hb level from 6% ~ 8% g/dl and living normal lives?
* They want to avoid transfusion if his Hb level is maintained above 6%~8% g/dl and RET within some range like >4% ~10%? For this reason the following Hb status on weekly basis has been tested :
* On: 07-12-2011 – Hb Level: 10.7% g/dl (Note : Transfusion given on 24-11-2011-200ml)
* On: 21-12-2011 – Hb Level: 11.5% g/dl.
* On: 03-01-2012 – Hb Level: 7.1% g/dl.
* On: 11-01-2012 – Hb Level: 6.4% g/dl - RET: 2.41%
* On: 16-01-2012 – Hb Level: 6.0% g/dl.
* On: 19-01-2012 – Hb Level: 6.3%g/dl.
* On: 25-01-2012 – Hb Level: 6.5% g/dl - RET: 4.21%
* On: 07-02-2012 - Hb Level : 7.5% g/dl - RET : 4.84%
* On: 21-02-2012 - Hb Level : 4% g/dl - RET : 5.47%
* On: 22-02-2012 - Hb Level : 4% g/dl - RET : 8%
* His growth looks OK but weight is now 8.4 Kg @ his current age : 17th Month.
* Beta Globin gene sequencing test reveals once again : IVS 1.5 (G-C), there is no other mutation detected.
* there are some RBC membrane damage which transfer from Mother side.
* According to Indian doctor’s advice, I have to maintain his Hb above 9% for the better quality of life even though he is Thalassemia Intermediate.
Your valuable comments will be highly appreciated.
With regards,
Sys
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Sys,
The hemoglobin level has followed the path of thal intermedia, although the current Hb would classify the child as thal major. Regardless, the child must begin transfusions, as this is a dangerously low Hb level. Any further drop (<4) could cause the child to fall into a coma. Transfusions should begin with a goal of 9 as the minimum pre-transfusion Hb level. This is necessary to provide proper growth and development, along with a proper quality of life, as the doctor has stated.
I would say because of the one reading the mother had that showed a small percentage of HbS, that there is a second gene mutation that has not been diagnosed (perhaps sickle cell or a type of HbC that that resembles sickle cell in its manifestation, or another moderating gene that is preventing the second beta gene from properly functioning).
I wish I had a more positive report for you, but at this point, the phenotype, or actual physical condition must take precedence over any speculation about why.
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Sys,
The hemoglobin level has followed the path of thal intermedia, although the current Hb would classify the child as thal major. Regardless, the child must begin transfusions, as this is a dangerously low Hb level. Any further drop (<4) could cause the child to fall into a coma. Transfusions should begin with a goal of 9 as the minimum pre-transfusion Hb level. This is necessary to provide proper growth and development, along with a proper quality of life, as the doctor has stated.
I would say because of the one reading the mother had that showed a small percentage of HbS, that there is a second gene mutation that has not been diagnosed (perhaps sickle cell or a type of HbC that that resembles sickle cell in its manifestation, or another moderating gene that is preventing the second beta gene from properly functioning).
I wish I had a more positive report for you, but at this point, the phenotype, or actual physical condition must take precedence over any speculation about why.
Dear Andy,
Thank you very much for your comments......!!!
I am more panic now, I don't know what should I do....!!!
Treating doctor is telling me that he will monitor his growth, height and his Hb level should not come <6%.
So, we are going to see his Hb levels one more time before we put him on regular transfusion.
Also, doctor is telling me that they are having lot of patients maintaining their Hb from 6~8% and living normal life.
they are trying to avoid transfusions.
When he dropped to 4% g/dl on 22/2/2012, We did the following actions :
1) Given transfusion : 70ml on the first day.
2) Given transfusion : 150ml on the second day.
Now his current Hb level is now 9.8% after we gave transfusion.
His height is : 78
His Weight is : 8.5 Kg
Andy, please I am requesting you to reply to me urgently so that I will commit myself and request doctor to put my son on regular transfusion.
Thanks a lot in advance.
Sys
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Sys,
The hemoglobin level has followed the path of thal intermedia, although the current Hb would classify the child as thal major. Regardless, the child must begin transfusions, as this is a dangerously low Hb level. Any further drop (<4) could cause the child to fall into a coma. Transfusions should begin with a goal of 9 as the minimum pre-transfusion Hb level. This is necessary to provide proper growth and development, along with a proper quality of life, as the doctor has stated.
I would say because of the one reading the mother had that showed a small percentage of HbS, that there is a second gene mutation that has not been diagnosed (perhaps sickle cell or a type of HbC that that resembles sickle cell in its manifestation, or another moderating gene that is preventing the second beta gene from properly functioning).
I wish I had a more positive report for you, but at this point, the phenotype, or actual physical condition must take precedence over any speculation about why.
Dear Andy,
How are you ?
After a long gap I have Latest information about my son who has been detected:
1) Compoud heterozygous for HBB:c.92+5 G>C (i.e., IVS 1-5 (G-C) mutation & HBB:C.-136C>G
Chromosome location: 11p15 (the results are from transplantation center in INDIA).
In other LAB the report as follows:
1) Compoud heterozygous for HBB:c.92+5 G>C (IVS 1-5 (G-C) mutation & HBB:C.-86C>G
It has been noticed that one mutation is rare mutation.
His Hb Electrophoresis reports before transfusions @ 10th month of his age, because his hb drops down to 4.2 g/dl.
HPLC DATA: 1) HbF - 69.1% 2) HbAo - 24.2% 3) HbA2 - 4.8%
We are giving him regular transfusions:
• On every 4 Weeks.
• EXJADE started to control his ferritin level – since last 8 Months.
• His growth looks normal with a weight of: 11.2 kg and height: 88 cms.
• His current age is 2 Years + 8 Months.
Now, we started “Hydroxyurea – 2.8 ml / day to see the Hb levels and benefits.
Kinldy, I need your expert advice on this matter as soon as possible, what do you thinks about HU in his condition? Many patients are having different opionion about HU and its reaction.
Sys
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Because the HbF level is so high already, it does mean that hydroxyurea is more likely to work, but only using it can tell you for certain. An electrophoresis test should be done periodically to check the HbF level. If it has an increasing trend, it shows that the drug is having some effect. The reticulocyte count should also be checked to see if it has dropped, as that is one benefit often seen. The lower the retic count, the less the bone marrow is producing ineffective red blood cells, and this is also a main goal of transfusion, so the hope is that this will drop with the use of hydroxyurea. If there isn't a recent retic count, one should be done now as a baseline.
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Hi Andy,
Good day to you.
Please note that i have attach Xmnl polymorphism report of my daughter, can you please help me understand what does these report says. is she Thalassemia major or minor and how to read these reports.
Regards
Sushil Thakur
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The report says that the XMN1 polymorphism is absent. It recommends that testing be done for the other two genetic modifiers.
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Hi Andy,
so does that means that we can not say whether child is Intermedia or Major as per this report? what are other two genetic modifiers for which i should go to get them tested?
Regards
Sushil Thakur
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The other two tests are listed on the report after Recommendation. This report states nothing about the status of the child, as it is simply a report that states that the polymorphism isn't present. The presence of HbO when combined with a beta mutation can result in either intermedia or major. The Hb level suggests transfusion dependent intermedia, so it doesn't really make much difference. The testing for polymorphisms is to determine if trying a drug like hydroxyurea to boost the HbF is worth it.
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Andy and tpl
I guess my daughters case is similar. The DNA sequence test is still pending and I just keep wondering and have few simple questions
Knowing that my daughter was transfused two weeks back when she was sick and hemoglobin dropped to 6.5. She does not have any e hemoglobin. Abnormal hemoglobin
Here HBf and HBa before transfusion was 66 and 33%
Question
Can HBa continue to increase naturally without transfusion. She is now 14 months old
Do adults with thal trait or minor have hbf.
I am trying to find out if there is any hope to stabilize her hemoglobin without future transfusions?
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Tpf
How is your child now? Any update on transfusion