2 month old diagnosed with Homozygous Beta+/beta+ thalassemia

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.

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 .

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.