XMN Polymorphism

hello to All

This is Prathhit 's Genotypiung report which was done on Jan 24, 2003

Genotyping for Beta thalassemai Mutation
The Beta gene mutation identified  Cap+1(A-C) inherited  from mother & -alapha/alpha alpha[PCR,RDB]- HETEROZYGOUS ALPHA/BETA THALASSMEIA
IVS-1;5(G-C) - inherited  from father -heterozygous beta-thalassemia

So the conclusion was XMN1 polymorphisn - HOMOZYGOUS NEGATIVE FOR THE SITE.

At tht time the doc who concluded the test said if he was homozygous psitive, hydrea wud hv worked better, but this result they r not sure.

Still we went ahead and tried for prat, cos Prat's Hema wanted to. It worked. He has been on hydrea since nov 2002.

Hi Puja,

Sorry for being late.
I don’t know much about XMN polymorphism. But sure there is term in Priya`s genetic report which says that she has -/+.And one Dr. from Ganga Ram Hospital ( New Delhi ) told me that Hydrea in this case doesn’t work as effectively as it works when polymorphism is +/+.
But in her case Hydrea has help her to maintain HB between 7-7.8  but not above that.

Mr. Andy if you can shed some light into it.

Take Care

Dimple

The fact that the doctors themselves are not sure if hydroxyurea will work demonstrates how complex and confusing this topic is. While the  XmnI polymorphism can be used to predict that hydroxyurea may work, there are other factors that may have an effect, as seen with your cases. The article below explains some of the factors that determine the severity of thalassemia.

From http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=11132233&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlus

Genetic factors affecting clinical severity in beta-thalassemia syndromes.
Winichagoon P, Fucharoen S, Chen P, Wasi P.

Thalassemia Research Center, Institute of Science and Technology for Research and Development, Mahidol University, Nakornpathom, Thailand. stpfc@mahidol.ac.th

PURPOSE: Heterogeneity in the clinical manifestation of beta-thalassemic diseases may occur from the nature of beta-globin gene mutations, alpha-thalassemia gene interaction, or differences in the amount of hemoglobin (Hb) F production. This study was conducted to determine whether these genetic determinant factors can predict phenotypic severity of patients with beta-thalassemia and to assess the relationship between the genotype and phenotype of the disease. MATERIALS AND METHODS: A total of 144 patients with beta-thalassemia were divided into mild (46 patients), intermediate (55 patients), and severe groups (43 patients). DNA analysis based on polymerase chain reaction technique was performed to characterize types of beta-thalassemia mutation, interaction of alpha-thalassemia, and XmnI polymorphism 5' to Ggamma-globin gene. RESULTS: Two alleles of mild beta-thalassemia mutation (beta+/beta+-thalassemia or beta+-thalassemia/Hb E) resulted in a mild clinical symptom whereas two alleles of severe beta-thalassemia mutation (betao/betao) produced a severe clinical phenotype. Compound heterozygosity for mild and severe alleles of beta-thalassemia (betao/ beta+-thalassemia or betao-thalassemia/Hb E) led to variable severity of anemia. Coinheritance of alpha-thalassemia alleviated the severity of beta-thalassemia disease in those patients with at least one allele of the mild beta-thalassemia genotype. DNA polymorphism at position-158 nt 5' to the Ggamma-globin gene was demonstrated by XmnI restriction enzyme. Homozygote of the XmnI site, +/+, was found to have a strong linkage with high Hb F levels and high hemoglobin production in two patients who had mild clinical symptoms. However, some patients who had XmnI site -/- also had mild clinical symptoms because the XmnI- was found to be associated with beta+-thalassemia mutation. CONCLUSION: Types of beta-thalassemia mutation and coinheritance of alpha-thalassemia in the patient who has at least one allele of the mild beta-thalassemia genotype are predictive for the clinical severity of the disease. However, a mild clinical symptom in some patients with betao/beta+-thalassemia or betao-thalassemia/Hb E who do not have a detectable alpha-thalassemia haplotype and no linkage with XmnI++ suggests that there are other confounding factors responsible for the severity differences of the disease.

PMID: 11132233 [PubMed - indexed for MEDLINE]

Not everything about thalassemia is understood and much that is understood is incomplete. Even though some patients may be better candidates for hydroxyurea in theory, it does not mean that other patients should not try it. If your child can avoid transfusion by using hydroxyurea, it is the preferable treatment of the two.

I found the case below to be very interesting as a clear demonstration of how much things can vary in thal. One would normally expect severe thalassemia when the patient has two completely non-functioning beta hemoglobin genes, but in this case, the patient has mild thal with moderate but manageable anemia.

From http://lib.bioinfo.pl/meid:8881

Ann Biol Clin (Paris). ;64 (4):341-5 16829478      
[Beta(o)/beta(o) thalassemia with a mild phenotype]
[My paper] C Hémar , O Nibourel , P Maboudou , C Méreau-Richard , C Badens , J Rousseaux , C Rose
We report the case of a 30 years old patient of Algerian origin, presenting a beta-thalassemia major with a phenotype of intermediate severity. Its genotype is beta(o)/beta(o), leading to a complete absence of beta-globin synthesis. This genotype is usually responsible for major clinical complications and a severe anaemia requiring regular transfusions. However, the patient presents with a mild form of the disease and a moderate relatively well tolerated anaemia. This phenotype was found related to a high level of synthesis of foetal haemoglobin, dependent most probably on an homozygous state for the polymorphism (XmnI -158, C>T) in the promoter of the Ggamma gene. This observation shows that it is important to keep in mind that beta-thalassemia major may have a mild or intermediate phenotype because of polymorphisms of the beta locus.

In this case, the XmnI polymorphism is such that the level of fetal hemoglobin produced naturally is sufficient to avoid transfusion.  One day they will be able to accurately predict what to expect in thals by what their exact mutations and related mutations are, but the science is not close to exact enough to say positively that fetal Hb induction won't work on a patient.

Andy,
    I have a question... my son is 22 months old and has Beta Thalassemia Major. He has not had to have a transfusion yet. The last time we had his hb checked it was at 8.3... but he was sick and that was the lowest that it has ever been. It usually stays in the 9 or 10s.  He was found to be heterozygous for the CT Polymorphism (XMN 1) at nt 158 5' to the GY globin gene.  Can you tell me if this means that we should consider him intermediate? His fetal hemoglobin was at 98% when he was last tested in July of 2015. I'm just wondering if this means he won't have to have regular transfusions, or will his high fetal hemoglobin keep him in the less severe area for ever?

Thanks,
Lisa

Lisa,

Although I cannot say for sure, it is certainly good that your son has not required a transfusion so far. It is also great that he is expressing such high levels of fetal hemoglobin. Although it is difficult to say whether or not he will produce such high levels of fetal hemoglobin inevitably, I think for now it is best to wait and see the pattern.

I think that when gene therapy and other treatments such as luspatercept are available, even if your son's fetal hemoglobin rates decline to some extent - he will still be a great candidate to succeed with the treatments. 

Best  ,

Sharmin

Lisa,

It's difficult to guess whether or not a child will need transfusion. Some won't have a drop in Hb low enough to require transfusions until age 3-4. The presence of the polymorphism may be why the fetal hemoglobin production is so high. While only time will tell if this level maintains, please be aware that the presence of this polymorphism makes it far more likely that the Hb can be raised by hydroxyurea use. This can be sought as an alternative to transfusion if his Hb does drop below 7. Sharmin brought up Luspatercept. This drug will be ideal for your son once it is approved, as his Hb will most likely never drop to true thal major levels of 3-4, so the boost in Hb from Luspatercept should be enough to keep him transfusion free permanently.

Thank you Andy and Sharmin for your replies.  So  do you think that if he gets to be 5 and has not had a transfusion by then he will likely only have to have transfusions when needed instead of regularly like most Thal Major patients?

Lisa

That is one possibility. This could change as an adult, but by then new treatments will be available that should greatly reduce the need for transfusions in many and and eliminate it entirely in many others. I think treatment will change greatly in the next 20 years.

Oh no Andy...

20 years......

Lokkhi,

Many new treatments will have appeared by then. Don't despair. I think we will see a major new treatment in less than 5 years and more will come after that.

Dear Andy. my child has Cap+1 & Del 619 mutations. 2 years back i have started Hydroxyurea 4 him. he had a gap of almost 40 days in transfusion but his platlet count dropped drastically due to which i have suspended the medicine. now again i started with wheatgrass but no gap happened. somebody told me that Cap+1 is very good for Hydroxyurea but the other mutation has very poor response. so again i suspended after trial of 03 months. wat is ur opinion should i restart. is it true that Cap+1 is very good 4 Hydoxyurea.

Hafiz,

The mutations can give you some indication if hydroxyurea will work, but nothing can be considered absolute just by looking at the mutations. In the end, the only thing that matters are the results. If your child maintains an adequate Hb level with hydroxyurea, it should be continued. If it has little effect, then transfusion would be the solution, as needed.