Am I a Beta-Thalassemia Carrier ??

Hi, I am really glad that I found this very useful forum.

I am a 39 year old 1st time father-to-be. My wife is now 3 months pregnant. She was diagnosed as a Hb-E Variant Thalassemia Carrier. As a result, I was requested to be screened for Beta-Thalassemia carrier state. I come to know that Hb-E when combined with Beta-Thelassemia minor can have serious consequences.

 My Blood test results came as below :-

Full Blood count :- All within reference range. Particularly MCV is 89 and MCH is 32.

Hb-Electropherisis :- Hb A2 - 3.4 , Hb F - 0.6.

I was told that HB A2 t 3.4 % is considered borderline and anything that above 3.5 is deemed Beta-thalassemia. However, since my FBC is normal, I am probably not a Beta-thelassemia carrier

The doctor can't be too sure on that and it is now too late for DNA test to confirm anything. What is fellow forumers' opinion on this. Could someone with MCV as high as 89 and MCH as high as 32 be still a Beta Thelassemia carrier or minor ?? I am concerned because my Hb A2 of 3.4 is at Borderline.

Hi,

Welcome on the forum, The simplest way to know the status of thalassemia,if you have any, is the test called "heamoglobin electrophoresis".

Wish your wife good luck with the pregnancy.

ZAINI.

Hi Daddy123 and welcome to the site.

My husband and me are thal carriers . My Hb A2 is 3% which is also a boarder line. While all the blood analysis of my husband are normal ( HB, MCV,MCH and everything even the electrophoresis showed that he is normal ) It turned out that he is a silent carrier and usually silent carriers are revealed only in DNA tests.

Anyway, i think that the best thing you can do now is a CVS or aminosynthesis test for the coming baby to see if he/she inherited the mutation or not

Manal

Yes, I understand that I may be a silent beta-thalassemia carrier.

I wonder if I can derive from the borderline HbA2 of 3.4 and my high MCV ( 89 ) & MCH ( 32 ) that if I turn out to be a Beta-Thal carrier, it will likely be a very mild B+ mutation. I wonder if I can conclude that if a very mild B+ mutation were to combine with a HB-E mutation ( another mild Beta-mutation ), the worst end result will be Beta-Thal intermedia and it won't be Beta-Thal Major.

I have researched from the internet and understand that 2 of the most common silent Beta mutation ie. -101 C-T mutation & -92 C-T mutation typically would result in borderline Hb A2 of about 3.4 & MCV, MCH will be in normal range. I wonder if anyone knows if the above 2 mutations are common in South East Asia ( I am a Singaporen Chinese ). What would be the likely consequence if one of the above mutation were to combine with another HB-E Beta gene that My wife carries. Would the consequences be disastrous Anyone here can comment on this ??

By the way, I wonder if anyone knows that in a Amniocentesis pregnancy test, what do they do to determine if the fetus inherited mutated gene. Would the test be able to determine the severity of the Thal if found positive

Hi Daddy123

I think that Andy would better tell you what to expect when the two mutations combine. But as for the mutation you mentioned , i know there are more than you mentioned. For example, my mutation is IVS 1-6 ( boarder line ) and HB Knsos codon 27 is a silent carrier too. There are hundreds of mutations and even the same mutation can have a different effect on different persons depending on other factors found in the body.

Also you should know that amniocentesis or CVS test are not 100% guranteed but they have very high success rate to tell you what to expect in the coming child.

Manal

Hi Manal, I understand B-mutation IVS1-6 T-C would result in only Borderline HB A2. However, I have also read that it will also result in Borderline or decreased MCV & MCH. May I know what is the MCV & MCH in your FBC report. Are they low ?? Also, considering that you are double heterogeyous of IVS1-8 T-C & Hb Knossos, I would be very surprised if you also have normal or near normal Red-cell indices, MCV, MCH etc.

Also, is your hubby a silent alpha or Beta - thal carrier ? What is his HB A2 ? I have read that if HBA2 in the normal range but fall towards the lower end eg below 2.5, the chances of silent alpha thal is higher.

HI Daddy123,

I think you should still go for DNA testing, as it will give you a much better idea of whether you are a thalassemia carrier. As Manal pointed out, some silent carriers are only diagnosed through DNA analysis. This is relevant now and of course, relevant should you and your wife decide to have more children. I would also suggest a second hemoglobin electrophoresis to verify the Hb A2 reading, since it was borderline.

I would also suggest you read the post from ingreece at http://www.thalassemiapatientsandfriends.com/index.php?topic=1497.0;highlight=ingreece

We were told by the head of the -quite capable- hematological laboratory in the central pediatric hospital in Athens that despite my having had three previous hemoglobin electrophoresis scans in my life which came out as negative, I had a hidden unusual type of carrier anemia (Ed note: Lepore) which combined with my wife's quite typical carrier status came out as Thalassemia b-major.
Only a detailed molecular test could have brought this up and only if one knew what they were looking for.

The CVS (Chorionic villus sampling) should be able to reveal any chromosomal abnormality, including specific mutations. Predicting the health of a child by mutation combination is not so easy because thalassemia can be affected by other genetic mutations that can also be present. In the future this may be much easier but the database of mutations and combinations still needs to be created. As of now, the software to do so has been tested and proven to work, but it will take some years to to turn it into a useful tool for prediction. This task is complicated by the constant discovery of new thalassemia mutations throughout the world. You may however, be able to make an educated guess based on the specific mutations. In general, if the thalassemia gene is beta zero, the combination with HbE will cause a much more severe condition, equivalent to thal major. If it is a beta + mutation combined with HbE, it can be expected to be a less severe form, and likely classified as intermedia.

(I love these hometown links) http://www.urmc.rochester.edu/medicine/genetics/hemoENoA.aspx

Hemoglobin E/ beta-thalassemia: (E/beta-thal) The combination of HbE and beta0-thalassemia (no hemoglobin A present) produces a severe clinical disorder although a great variability of clinical expression is seen. At the severe extreme without treatment, a child with HbE/beta0-thalassemia will be small in stature with wasted extremities and poor body development with a protuberant abdomen. As the child grows there are marked skeletal abnormalities and retardation of growth and development. There is an increased incidence of infection and this is the most common cause of death from this disease. The interaction of HbE/beta+-thalassemia (some hemoglobin A present) results in a milder condition. The main form of treatment for all forms of symptomatic thalassemia is blood transfusion. For those patients dependent on blood transfusion, iron-chelating agents are required. Early management of complications, in particular infection, and good general medical care are important .

You have done a good job researching the possibilities. At some point you will most likely decide to have a DNA test. The information you have learned can be of some help in directing what should be looked for in the test.

Hi Andy, Thanks very much for your infomative reply.

As a matter of fact, I have done a second "hemoglobin electrophoresis" and the result of my HB A2 this time is 3.2 ( ref 1.9 to 3.2 ) and Hb F is 0.6 ( Ref 0.0 to 1.5 ). No other aberrant band is found.

A DNA test takes time and I think it is now too late considering my wife is 3-months pregnant.

In any case, if the chances of a mild Beta + mutation combined with a HB-E is likely at most result in an intermediate form of Beta-thal, doing an Amniocentesis test now would not make any difference to our decision to carry on the baby. I would not in this case be inclined to do a Amniocentesis as I was told that it carries a 1% risk of Miscarriage. Doing a CVS (Chorionic villus sampling) is also out of the question as my wife is now 3-months pregnant and it similarly carries a 1% risk for misscarriage.

This is not the case unless an Amniocentesis can predict for sure the severity of a B-thal and if yes, we can then reassess our options. But, do you think a Amniocentesis is capable of predicting that and for that matter, pin point out which Beta+ mutation I carry

Also for HB Lepore which one of the forumers is not able to detect despite doing 3 HB-Electropherisis, I have read that :-

"Hb Lepore Worldwide distribution but especially found in Middle and Eastern Europe
Fusion of db chains thought to arise during meiosis from erroneous recombination of misaligned d and b genes on separate chromosomes
Stable with normal functional properties except for a slightly Inc. oxygen affinity
Pathophysiology is similar to ß-thal with an excess of a-chains due to abnormal hybrid globin chains
Excess a-chains precipitate membrane damage and inflexibility leading to premature RBC destruction and Inc. bone marrow production of abnormal cells (ineffective erythropoiesis that contributes to the anaemia because the abnormal cells are destroyed in the marrow)

Homozygotes and heterozygotes have clinical similarities to ß-thal.

Blood Film (Homozygous form):
Microcytic, hypochromic anaemia (similar to ß-thal. )
Anisocytosis and poikilocytosis (with target cells)
Basophilic stippling
Post-splenectomy: nucleated RBCs and RBCs with a-chain precipitates
Bone Marrow:
Erythroid hyperplasia
Hb Electrophoresis:
HbA1 - Absent
8-30% Hb Lepore
HbA2 - Absent
HbF - Remainder (therefore Inc.)

Blood Film (Heterozygous form):
Microcytic, hypochromic RBCs with slightly Dec. Hb
Hb Electrophoresis:
HbA1 - Dec.
10% Hb Lepore
HbA2 - Dec.
HbF - Inc.

I pretty much rule out being Heterozygous of Hb-Lepore since my MCV & MCH is high, and that my HB F is not elevated. Am I right on that ?

http://www.ncbi.nlm.nih.gov/pubmed/8172199

Genotype of subjects with borderline hemoglobin A2 levels: implication for beta-thalassemia carrier screening.
Galanello R, Barella S, Ideo A, Gasperini D, Rosatelli C, Paderi L, Paglietti E, Sollaino C, Perseu L, Loi D, et al.

Clinica e Biologia Età Evolutiva, Università di Cagliari, Ospedale Regionale Microcitemie, Italy.

In this study, we have defined by molecular analysis, the alpha, beta, and delta globin genotype in a group of individuals with normal or thal-like red cell indices but borderline hemoglobin (Hb)A2 levels, who were identified in a program for beta-thal carrier screening. In 37 of 125 individuals with borderline HbA2 levels, we detected a molecular defect in the beta, in both the delta and the beta, or in the alpha globin gene. Specifically seven of these subjects were carriers of the -101 C T mutation, ten of the IVSI nt6 T C mutation, 16 were double heterozygotes for delta and beta thal, and two had the triple alpha globin gene and two the single alpha globin gene deletion. From these results, we may conclude that subjects with borderline HbA2, particularly when they marry a typical beta-thal carrier, should be extensively investigated in order not to miss heterozygous beta-thalassemia.

PMID: 8172199 [PubMed - indexed for MEDLINE]

This would also be the case with HbE. The high Hb A2 level is a red flag that says more screening is needed. If 37 of 125 were thal carriers, that means 88 were not. You need to find out where you fit. I found it interesting that alpha thalassemia was one cause of high Hb A2 levels, as alpha is also common in east Asians, and in one study done in Singapore, those of Chinese descent were more likely to be alpha carriers than beta carriers.

http://www.cababstractsplus.org/google/abstract.asp?AcNo=20053029781

Document Title:  Journal of Pediatric Hematology and Oncology,  2004   (Vol. 26)  (No. 12) 817-819

Abstract:

DNA technology provides a new avenue to perform neonatal screening tests for single-gene diseases in populations of high frequency. Thalassemia is one of the high-frequency single-gene disorders affecting Singapore and many countries in the malaria belt. The authors explored the feasibility of using PCR-based diagnostic screening on 1,116 unselected sequential cord blood samples for neonatal screening. The cord blood samples were screened for the most common reported [alpha]- and [beta]-thalassemia mutations in each ethnic group (Chinese, Malays, and Indians) in a multiracial population. The carrier frequency for [alpha]-thalassemia mutations was about 6.4% in the Chinese ([alpha]0 deletions=3.9%, [alpha]+deletions=2.5%), 4.8% in Malays, and 5.2% in Indians. Only [alpha]0 deletions were observed in the Chinese. The carrier frequency for [beta]-thalassemia mutations was 2.7% in the Chinese, 6.3% in Malays, and 0.7% in Indians. Extrapolating to the population distribution of Singapore, the authors found a higher overall expected carrier frequency for [alpha]- and [beta]-thalassemia mutations of 9% compared with a previous population study of 6% by phenotype. The highly accurate results make this molecular epidemiologic screening an ideal method to screen for and prevent severe thalassemia in high-risk populations.

Publisher: Lippincott Williams & Wilkins

Ideally the parents are both tested before CVS or amnio testing is done, as there is a small risk of miscarriage with CVS, but ideally, we would all know from birth if we carried a gene for any of the hemoglobinpathies. At this point, amnio can be used to determine if the baby carries any genetic defect, but I doubt anyone can tell you with 100% certainty what to expect if it proves to be HbE beta thal. I feel that personally I know too many transfusing HbE beta thals, to be able to advise someone that their child won't transfuse. If it is HbE beta thal, only the parents can decide what comes next.

I'm sorry if I confused the issue with the mention of Lepore. My intent was to demonstrate that some mutations do not show up with anything other than DNA testing. However, it should also be noted that Lepore is another gene that when mixed with beta thal is said to be usually an intermedia condition, but in fact is often most similar to thal major. 

Hi Daddy123

Actually i have just one mutation which is IVS 1-6 and though it is a boarder line in HBA2 but my MCV  and MCH are low in addition to iron defiency. Usually my MCV is 60 and MCH is 21.
My husband mutation is the silent one, HB Knossos and the HB electrophoresie showed that he is normal though not. But we did an HPLC and showed that his HBA2 is 4.6%

My son was the one who inherited both mutation and is diagnoised as a thal intermedia.

I would like to mention --though not applicable on your case-- that if there is an iron defiency, the result of HB A2 is not accurate

Manal

Hi Manal, what is your husband's MCV & MCH results ? I have read that Heterozygote Hb Knossos has borderline or low MCV & MCH. Does it hold true for your husband ??

http://globin.cse.psu.edu/html/huisman/variants/beta/Knossos.html

Hb Knossos is classified as a silent Beta Mutation but your husband's Hb A2 is 4.6 which in the Beta-thal range. I thought silent mutation refers to one that can not be detected by HB Electropherisis.

Actually i can't remember the exact figures as the last CBC he did was a long ago, but i can remember that they were borderline though the Hb was in the normal range.

When he did the HB electophoresis it showed that he is normal , but the HPLC showed this increase of the Hb A2

Manal

Hi Manal, sorry for my ignorance. I thought HPLC refers to HB electophoresis since it quantifies HBA2. By the way, what is HPLC in this case ? What is the purpose of the test as compared to HB electophoresis ?