Thalassemia Patients and Friends
Discussion Forums => Thalassemia Intermedia => Topic started by: sk_ut on April 26, 2010, 02:31:14 AM
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Hello All,
The mutation is IVSI-5 G-C (which is a beta+ mutation).
We think this is thal-intermedia.
Can anyone shed more light on this particular mutation and how severe this is?
I have also read that the onset on anemia is later for intermedia.
Anything I should be looking for in my daughter for me to know that she is getting anemic.
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Hi,
This is the most common hemoglobin mutation on the Indian sub-continent and is likely to be intermedia, but predicting the phenotype or outcome, is not simple because other factors sometimes act as moderating factors. These include the co-existence of alpha thalassemia mutations and the presence of the persistence of fetal hemoglobin gene. If one of these is also present, the condition could be somewhat ameliorated. Some intermedias do not need to transfuse, but this is often a matter of wait and see unless the hemoglobin does drop at an early age.
Has hydroxyurea been suggested? This is definitely worth investigating because it may be enough to keep the child transfusion independent if the phenotype is not severe.
Some typical things to watch for are lethargy, pale skin and white lips. If a previously energetic child becomes listless, it is time to check the Hb level.
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Andy,
Thanks for the prompt response. This is very helpful.
The child is very energetic and seems normal right now.
The hematologist did a CBC last week (my daughter is 9 weeks) and the Hb level was 9 and MCV was around 65.
I afraid the hematologist we are seeing is not a specialist in beta thals.
Few questions I had are
1) Can we start Hydroxyurea even for an infant (just 2 months)
2) Our Ped recommended giving multi-vitamin drops with Iron - is that safe?
3) At what age does intermedia become transfusion Dependant?
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Iron is not advisable as it does absolutely nothing to raise the Hb level in thalassemia and just adds to the eventual iron load. It is advisable to start the baby on liquid folic acid. This is safe and does help build red blood cells. Hydroxyurea has been shown safe in infants, but is probably not yet necessary. I would suggest talking to the doctor about this in advance, but to wait until the Hb drops to below 8, so you have a better idea of the severity of the thalassemia. The age of transfusion dependency in intermedia varies greatly, with some intermedias never needing transfusions.
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As Andy has pointed, put your child on liquid Folic Acid,the doctor will let you know the dosage. My daughter takes 0.5ml, she is 2 yrs.
Try to get the iron free multivitamin, my daughter takes the iron-free Polyvisol.
It is very difficult to predict how low the Hb will drop and when,most doctors and parents of older thal kids will tell you that.Basically, you need to see how the things go with time.
Symptoms of low Hb are lethargy, excessive sleep, poor feeding,more crankiness, pale lips.
My daughter has E/ B+(IVS-1-5 GC), she is 2 yrs and her Hb is currently around 7.5-8 and till now she has not needed transfusion.But depending on how things proceed, doctors will decide. IVS-1-5 GC is a severe B+ mutation, which is very common in India as Andy mentioned. This mutation is found in majors as well as intermedia. Does your daughter have this mutation on both sides?
If you are in the US, any of the Comprehensive Thal care centers will provide you excellent care and guidance.(See Cooley's Anemia Foundation site)
Whichever way things go, always remember that today there are thousands of people who are living great and healthy lives with Thal, regular transfusions or without regular transfusions.
Wish you all the best and may God bless your baby.
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Thanks for the encouraging information...
Yes my daughter has the B+ mutation on both sides. I am not aware of the E mutation.
Would this be found on the DNA testing they did on our daughter?
Is the E mutation less severe than B+/B+?
I will start her on the folic acid. The last test revealed Hb of 9 and MCV of 65.
We are hoping it continues to stay that way.
We are based in Texas.
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HbE is a different mutation of the beta globin gene and would have shown on the electrophoresis, but if the child is B+B+, there is no possibility of HbE involvement. However, the outcome of B+B+ is often similar to HbE beta thal.
Two things that you should do. Contact Eileen Scott at the Cooley's Anemia Foundation and register. CAF can advise you in many areas, including finding appropriate care and dealing with insurance issues. Second, the absolute best care for thals in the US is found at the Centers of Excellence and their satellite centers. There is one in Dallas. Contact Dr Quinn. This is the most important thing you can do for your child. I would definitely talk to Dr Quinn about the subject of hydroxyurea, should the Hb drop. Many intermedia thals avoid transfusion by using hydroxyurea. In the coming years, we will also be seeing new drugs that stimulate fetal hemoglobin production better than hydroxyurea does. Contact these people now. Regardless of whether or not transfusions become necessary, intermedias do have special health concerns that are best served by doctors who treat thalassemia.
Cooley's Anemia Foundation
330 Seventh Avenue, #900
New York, NY 10001
(800)522-7222
Fax: 212-279-5999
Patient Services Manager
Eileen Scott
eileen.s@cooleysanemia.org
Children's Medical Center - Dallas
1935 Medical District Drive
Dallas, Tx 75235
Charles T. Quinn, M.D.
Office: 214-456-2382
Fax: 214-456-6133
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Andy,
Unfortunately Dr. Quinn is leaving Dallas to go to Cincinnati.
I have tried reaching him several times with no luck.
I am also in touch with Eileen Scott on the phone.
Thanks for pointing them though.
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I'm sure Eileen can keep you posted on who takes Dr Quinn's place. Please let us know if you find out who the new doctor is.
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Where in Texas are you located? Send me a personal message and I can link you with some Thal folks in Texas who might be able to guide you.
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Hello sk_ut,
I am sorry I did not see your post earlier. You are right Dr Quinn. has left Children's in Dallas.
My 19 months old son was his patient, from birth. He last appt, with Dr. Quinn, was last week. He is also a Thal- intermedia. His situation is very similar as hopefulmommy's daughter.
Dr Z. Rogers (she is also in Children's) will be seeing my son, from onwards. We will surely miss Dr Quinn. He is a very nice. We are looking forward to meet Dr Rogers in our next appointment. If you need any additional infromation pls. send me a personal message, I will be glad to help you out. I am guessing you are based in Dallas, is that correct?
I am sure, as everybody else has already mentioned your baby will be fine, so pls. do not worry. May god bless your baby.
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Zora Rogers, MD
Associate Professor
Specialties: Pediatric Hematology-Oncology
Clinical Interests: Hematology; ITP; Sickle Cell.
Research Interests: Characterization of the natural history and improvement of the treatment of children and adolescents with non-malignant hematologic diseases such as aplastic anemia, myelodysplastic syndromes, and histiocytosis; Development of optimum management approaches to major clinical events in children with sickle cell disease (febrile illness, chest syndrome, painful crisis, avascular necrosis, stroke); Use of hydroxyurea, stem cell transplantation and other therapies, particularly in young children, to prevent the morbidity of sickle cell anemia.
Publications: View Publications
Clinical Practice Location: Children's Medical Center - Dallas
1935 Medical District Drive
Dallas, Tx 75235
Appointments: 877-445-1234, Fax: 877-445-1234
Insurance Plans Accepted
Medical School:University of California At San Diego, School of Medicine, La Jolla (1983)
Residency:Los Angeles County, University of Southern California Med Center, Pediatrics (1983 - 1986)
Fellowship:Los Angeles County. University of Southern California Medical Center, Research Fellow in Pediatric Hematology/Oncology (1986 - 1987)UT Southwestern, Pediatric Hematology/Oncology (1987 - 1990)
Board:American Board of Pediatrics
American Board of Pediatrics Subboard of Pediatric Hematology/Oncology
Honors:Phi Beta Kappa (1978)
American Cancer Society (1988)
American Cancer Society (1989)
Language:English
Some searching also found that Dr Rogers has been active in research into various aspects of hemoglobinopathies. I don't feel like I'm going out on a limb to say that she will be a suitable replacement for Dr Quinn. I am particularly happy to see that she has much experience with the use of hydroxyurea.
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Hi andy,
I would like to share that my daughter is diagnosed with Thal Major . she is carrying mutations 619 BP deletion/Cap Site +1 with ploymorphism -/-.
Doctors say she is major since she is transfuison dependent but i have read articles where menationed cap site mutaion cannot be a major but can be intermedia only . Also she is now transfused 7 times and her pre -transfusion HB is at 10 .
I have asked doctors for hyroxyurea but they are saying since polymorphism is -/- it will not help .
So i am bit confused about this pls advice .
Also let me know if i can do another HPLC test for her and at what duration like after 1-2 months i can go for this test .
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This will take a bit of time to investigate. Can you provide some more information? At what age was she first transfused? What was her Hb before her first transfusion? What is her current transfusion frequency?
Transfusion dilutes the blood with the blood of the donor, and an HPLC will be affected by this. Levels of HbF and HbA2 will most likely be lower as a result. It is advised to wait 90 days after a transfusion to repeat an HPLC, so this may not be practical. HPLC is believed to be very accurate. Is there any reason you might expect a mistake was made?
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Hi Andy,
When she was 4 months old she was detected with mutation mentioned by me . At that time her HB was 5 and MCV was 68 and RBC 2.33 . So she was given first transfusion at that time . Her transfusion frequecy is 6 weeks (42 days) we have kept it constant and her pre-transfusion HB is 10.2 , HCT 29.7,MCV 86.9, MCHC 34.4,MCH 30 and rdw 18.
One important thing when she was first diagoned her HPLC report showed HBF 56 and
HB A2 3.7 and HB-A - 41
Also when i see her fingers to check blood flow look ok to me but her lips look slightly whitish.
Pls advise.
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The 619 BP deletion is a beta zero deletion, so that gene produces zero beta globin. The Cap +1 mutation is a silent mutation that is not easily detected, so once again we see that thalassemia can occur even when tested by electrophoresis. This leads to the recommendation that when there is any question or any possibility of thal trait, a DNA test should be done to verify the status.
It was thought that the silent mutation would not lead to any severe thalassemia, but...
http://www.ncbi.nlm.nih.gov/pubmed/17900295
Eur J Haematol. 2007 Nov;79(5):417-21. Epub 2007 Sep 27.
The clinical significance of the spectrum of interactions of CAP+1 (A-->C), a silent beta-globin gene mutation, with other beta-thalassemia mutations and globin gene modifiers in north Indians.
Garewal G, Das R, Awasthi A, Ahluwalia J, Marwaha RK.
Department of Haematology, Postgraduate Institute of Medical Education and Research, Chandigarh, India.
Abstract
OBJECTIVES: To assess the clinical significance of the interactions of CAP+1 (A-->C), a silent beta-globin gene mutation, with other beta-thalassemia mutations and globin gene modifiers in north Indians. METHODS: The clinical phenotypes associated with compound heterozygosity for the CAP+1 (A-->C) mutation with other beta-thalassemia mutations, together with the potential effect of the genetic modifiers alpha-thalassemia and the Xmn-1(G)gamma C-->T polymorphism were studied in 30 patients. The frequency of the CAP+1 (A-->C) polymorphism was determined and an analysis of the red cell indices, HbA(2) levels, iron status, and alpha-globin genes was carried out in 35 heterozygotes. RESULTS: Based on an analysis of 1075 beta-thalassemia alleles the CAP+1 (A-->C) mutation constituted 3.2% of north Indians. There was a wide spectrum of phenotypic severity in compound heterozygotes; 18 of 30 were transfusion dependent. There was a very high frequency of the -/- genotype of the Xmn-1(G)gamma polymorphism in compound heterozygotes. Analysis of 35 heterozygotes indicated that approximately half were hematologically normal and therefore genuine 'silent' carriers. CONCLUSIONS: Compound heterozygotes for CAP+1 (A-->C) and other severe beta-thalassemia alleles are phenotypically severe enough to necessitate appropriate therapy and counseling. The unexpected severity of these interactions may be due, in part, to the high frequency of beta-thalassemia alleles associated with the Xmn-1(G)gamma- allele in Indian populations. It is concluded that the CAP+1 (A-->C) mutation can pose serious difficulties in screening and counseling programs in populations in which it occurs at a significant frequency.
PMID: 17900295 [PubMed - indexed for MEDLINE]
As it turns out, many patients with the Cap+1 mutation are transfusion dependent. I cannot argue against transfusing a child whose Hb is only 5.
However, recent studies have shown that the effect of hydroxyurea in thalassemics cannot be accurately predicted based on genotype alone. In addition, hydroxyurea provides other benefits besides HbF induction.
http://emedicine.medscape.com/article/206490-treatment
In a small study, Italia et al evaluated the clinical and hematologic response to hydroxyurea in 79 beta-thalassemia patients in western India with variable clinical severity and correlated the findings with genetic factors.16 One group consisted of 38 beta-thalassemia intermedia patients, and a second group consisted of 41 beta-thalassemia major patients. Both groups were administed hydroxyurea therapy and followed up for 20-24 months. Findings consisted of the following16 :
* Fifty-eight percent of the frequently transfused patients in the beta-thalassemia intermedia group became transfusion independent. Sixteen percent demonstrated a 50% reduction in post-therapy transfusions versus 32% in the beta-thalassemia major group, both correlating with a greater mean fold increase in HbF and gamma mRNA expression levels.
* Forty-one percent of the beta-thalassemia intermedia group also had associated alpha-thalassemia, and 72.7% were XmnI (+/+).
* Of beta-thalassemia intermedia patients who had a clinical and hematologic response to hydroxyurea therapy, 41% had a link to haplotype (- + + - + + - - +) as opposed to haplotype (+ - - - - - - - +), which was more common in patients without such a response. However, response was not associated with the beta-thalassemia mutations.
* Both beta-thalassemia groups showed a significant decrease in serum ferritin.
Overall, the investigators found that clinical response to hydroxyurea in the beta-thalassemia intermedia group was better in patients with alpha-thalassemia, XmnI (+/+), and a higher mean fold increase in gamma mRNA expression.16 In those with beta-thalassemia major, one third showed a partial response.
Prediction of the outcome when using hydroxyurea is not as certain as we have previously been led to believe. Only a trial of at least one year can give you a picture of what hydroxyurea can do for a patient. Recent studies have also shown that hydroxyurea should be administered in combination with L-carnitine and magnesium for optimum results. We have several threads regarding the use of hydroxyurea which can be found by searching our site. One thread in particular is at http://www.thalassemiapatientsandfriends.com/index.php?topic=3352.msg34138#msg34138
I will point out what Dore mentioned after attending the recent conference in Berlin.
What was said on the conference in Berlin is that all thals should try hydrea.
Your daughter is transfusing on a six week schedule which is more like what is expected with transfusion-dependent thalassemia intermedia. I think this already makes her a good candidate for hydroxyurea therapy. I hope you are also giving her a daily folic acid supplement. I would also strongly recommend a daily natural vitamin E supplement, and strongly does not adequately express my feelings on the subject of vitamin E.
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Hi andy,
Thanks for your great response .We are also following up homepathic treatment for her to control her serrum ferratin at early age . One more advice needed from you.
1. For a one year old kid what advice do yoy give how to control iron overload and any thing we can take care of.
2. I have heard if we combine hydorxyurea with cenouthus americanus homeo medicine would yield good effects.
3. How long do you think new treatment based on gene therapy will arrive , since we do'nt want to go for bone marrow transplant due to problems related to graft vs host issue and other infection related issues .
Pls advice .
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A low iron diet should be utilized. Red meat is probably the one thing to be avoided as much as possible because of its high quantity of easily absorbed iron. The iron from plant sources is not so readily absorbed and can also be somewhat inhibited by drinking tea with meals. Dairy products also have some ability to block iron absorption. Avoid citrus fruit and juice with meals because it increases iron absorption. Instead, take citrus between meals only. A diet high in antioxidants is extremely important as antioxidants counter the damage done by iron. Natural vitamin E is one very safe and effective antioxidant. The supplement called IP6 (Inositol hexaphosphate), is both an iron chelator and a powerful antioxidant. This comes in capsules which can be opened and stirred in with water or juice (no milk products for this use) and taken on an empty stomach. This increases the absorption of IP6.
I have previously done a post about a study that showed that homeopathic treatment combined with hydroxyurea produced better results. You can see this post at
http://www.thalassemiapatientsandfriends.com/index.php?topic=1685.msg13954#msg13954
I think the benefit to the spleen is quite important.
There is a good article about fetal hemoglobin inducers from the natural world at http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2686630/
Inducers of HbF from natural sources
Inducer Source Biological effects References
Bergaptene A. marmelos Erythroid differentiation of K562 cells Lampronti et al. (65)
Angelicin A. arcangelica HbF production Lampronti et al. (78)
Rapamycin S. hygroscopicus HbF production Mischiati et al. (114)
Fibach et al. (116)
Resveratrol Red wine, grape skin and darakchasava HbF production Rodrigue et al. (101)
Mithramycin Streptomyces species HbF production Bianchi et al. (51)
It takes many years for any new drug or therapy to get through trials and be approved for general use. Gene therapy will take some time to run trials and prove efficacy and safety. However, many patients will be able to take advantage of trials once it gets to stage 3 trials. Of course, we are only now entering the stage 2 trials and the biggest obstacle is funding, so it is difficult to estimate. If funding was in place, it would move much more quickly, but we live in a world where priority is given to funding weapons of destruction rather than funding directing towards the benefit of humanity. It's a shameful situation.