Thread: a doubt!!!

is thallasemia a hemoglobinopathy????

No i dont think it is..Hemoglobinopathies are where u have abnormal Hb...But in thalassemia the pathology is one of deficient globin synthesis..

I don't think so Fathima.....@Sailee--> thalassemia is a Hemoglobinopathy....

Hemoglobinopathies
(Hemoglobin Disorders)


Hemoglobin is produced by genes that control the expression of the hemoglobin protein. Defects in these genes can produce abnormal hemoglobins and anemia, which are conditions termed "hemoglobinopathies". Abnormal hemoglobins appear in one of three basic circumstances:

Structural defects in the hemoglobin molecule. Alterations in the gene for one of the two hemoglobin subunit chains, alpha (a) or beta (b), are called mutations. Often, mutations change a single amino acid building block in the subunit. Most commonly the change is innocuous, perturbing neither the structure nor function of the hemoglobin molecule. Occasionally, alteration of a single amino acid dramatically disturbs the behavior of the hemoglobin molecule and produces a disease state. Sickle hemoglobin exemplifies this phenomenon.

Diminished production of one of the two subunits of the hemoglobin molecule. Mutations that produce this condition are termed "thalassemias." Equal numbers of hemoglobin alpha and beta chains are necessary for normal function. Hemoglobin chain imbalance damages and destroys red cells thereby producing anemia. Although there is a dearth of the affected hemoglobin subunit, with most thalassemias the few subunits synthesized are structurally normal.

Abnormal associations of otherwise normal subunits. A single subunit of the alpha chain (from the a-globin locus) and a single subunit from the b-globin locus combine to produce a normal hemoglobin dimer. With severe a-thalassemia, the b-globin subunits begin to associate into groups of four (tetramers) due to the paucity of potential a-chain partners. These tetramers of b-globin subunits are functionally inactive and do not transport oxygen. No comparable tetramers of alpha globin subunits form with severe beta-thalassemia. Alpha subunits are rapidly degraded in the absence of a partner from the beta-globin gene cluster (gamma, delta, beta globin subunits).

@drgauravkatiyar:I've referred quite a few books now..Could you please check this out Sir..Robbins lists them(hbinopathies and thalassemia) as separate..Even my biochem textbook(Vasudevan) says thalassemis cannot be considered a hbinopathy.But Harper isn't very clear on this.
Where is this article from btw?

thalassemia ALFA OR GAMMA is a lack of gene in the synthesis of Hemoglobin, so it must be considered as a Hemoglobinopathy. in any country and in any book.

@Fathima...please refer harrison..there they have given a table for classification of hemoglobinopathy..thalassemia is there...

thank-u all 4 answering my question.
i take it tat it IS a hemoglobinopathy.
but the question is: why is there so much confusion regarding tis?? and why hav textbooks got it wrong?? my biochem. txtbuks say tat it is NOT but my physio. buks say tat it IS.

Thank you drgaurav.I referred Harrison.You are correctAnd wolverine too is.

Originally Posted by sailee

but the question is: why is there so much confusion regarding tis?? and why hav textbooks got it wrong?? my biochem. txtbuks say tat it is NOT but my physio. buks say tat it IS.

May be it's because whoever first framed the definition of Hbinopathies framed it wrong He(or she or they) called it a disorder affecting only the structure of Hb.Now the def has been modified to
Hemoglobinopathies are disorders affecting the structure, function, or production of hemoglobin.
Sadly our biochem textbooks love the older version too much to switch to the new one saileeMine has even dedicated a special box to discuss how and why Hbinopathy and thalassemias are different

That's the def from harrison Fathima...all this confusion is because some books are not updated...
May be in near future present def will be wrong...lol

The hemoglobinopathies are generally classified into two major groups.


The first, the thalassemias, are caused by quantitative deficiencies in the production of globin chains. These quantitative defects in globin synthesis cause microcytic and hypochromic anemias.


The second group of hemoglobinopathies consists of those caused by structural abnormalities of globin chains. The most important of these, hemoglobins S, C, and E, are all the result of point mutations and single amino acid substitutions in -globin. Many, but not all, infants with hemoglobinopathies are identified by routine neonatal screening.

Source:
CURRENT Pediatrics > Chapter 28. Hematologic Disorders


--------------------------------


------Thalassemias ------vs---- Hemoglobinopathies



Definitions


Thalassemia:
A quantitative disorder of hemoglobin synthesis resulting from genetic mutations in one or more globin genes causing a reduction in normal hemoglobin synthesis.






Hemoglobinopathy:
A qualitative disorder of hemoglobin synthesis resulting from a genetic mutation of one or more globin genes causing an abnormal version of hemoglobin to be synthesized.



-----------------

Thalassemias]-------------------[vs-----------------Hemoglobinopathies

1. Genetic mutation---------------------------------------------------1. Genetic mutation

2. Globin gene(sgene(s)-----------------------------------------------2. Globin gene(sgene(s)

3. Lack of gene expression --------------------------------------------3. Normal gene expression

4. Decreased normal Hb------------------------------------------------4. Release of abnormal Hb

5. Anemia-------------------------------------------------------------5. Low oxygen saturation

6. Low RBC, Hb, and Hct & MCHC---------------------------------------6. Hb polymerization

7. Increased RBC divisions---------------------------------------------7. Vaso--occlusion

8. Smaller RBC - Low MCV ---------------------------------------------8. Hemolysis

9. Increases Hb/RBC - Normalization of MCH and MCHC--------------- ---9. Anemia - Normal MCV, MCH, & MCHC



Thalassemia

��Normal Globin genes
��Chromosome 16 (alpha--like)
---��Alpha
---��Zeta
��Chromosome 11 (beta--like)
---��Beta
---��Delta
---��Gamma
---��Epsilon


α−Thalassemia Lab Diagnosis

�� Peripheral Blood
�� Microcytic hypochromic anemia
�� Target Cells (��surface:volumesurface:ratio)
�� Hemoglobin Electrophoresis
�� �� in αα−−containing hemoglobins
�� HbA, A, A2, F,
�� �� in non--α containing hemoglobins
�� HbBarts(γ4)
�� HbH (H β)




Hemoglobinopathies


��Definition

��A genetic point mutation resulting in one nucleotide change and a single amino acid substitution, addition, or deletion that functionallyamino functionallychanges changes the Hgb moleculethe molecule

��Three Common hemoglobinopathies

��Hgb SHgb S
��Hgb CHgb C
��Hgb EHgb E

��Less Common Hemoglobinopathies

��Hgb D
��Hgb M
��Hgb S
CHgb SC
��Hgb SD



β -Thalassemia Point Mutations

Promoter Mutation (Start Site)
---RNA polymerase has decreased binding
Mutated Stop Codon
---Extended mRNA and extended protein
Nonsense mutation
---Causes added stop codon or frame shift
Splice Site Mutation
---Lengthens the mRNA and the protein


Nonsense Mutation

Normal mRNA/Stop (UAA, UAG,UGA)
---AUA-GAU-UUC-CGA-AUC-CCA-UAA-TCA
Add Stop Codon
---AUA-GAU-UUC-UGA-AUC-CCA-UCA-TCA
Frame Shift Mutation
---AUA-GAU-UUC-GA-AUC-CCA-UCA-TCA
Result
---Short mRNA>>Short protein>>Degradation
---Altered mRNA>>Longer or shorter>>Degradation



Hemoglobinopathies

Point mutation
Single nucleotide change
Changes one codon
Changes one amino acid
Alters quaternary structure
Changes intracellular molecular interactions
Causes hemoglobin polymerization
DOES NOT REDUCE HB SYNTHESIS



Sickle Cell Anemia
NORMAL
0 1 2 3 4 5 6
MET VAL HIS LEU THR PRO GLU
ATG GTG CAC CTG ACT CCT GAG
SICKLE
ATG GTG CAC CTG ACT CCT GTG
MET VAL HIS LEU THR PRO VAL


Deoxyhemoglobin S Polymer Structure

A) Deoxyhemoglobin S
14-stranded polymer
(electron micrograph)
D) Charge and size prevent
6β Glu from binding.
C) Hydrophobic pocket
for 6β Val
B) Paired strands of
deoxyhemoglobin S
(crystal structure)
Dykes, Nature 1978; JMB 1979
Crepeau, PNAS 1981
Wishner, JMB 197


---------------------


Thalassemia
Genetic mutation
---Globin gene(s)
Lack of gene expression
Decreased normal Hb
--Anemia
----Low RBC, Hb, and Hct
--Increased RBC divisions
--Smaller RBC
---Low MCV
Less Hb/RBC
Low MCH and MCHC
---


Hemoglobinopathies

Genetic mutation
---Globin gene(s)
Normal gene expression
Release of abnormal Hb
---Low oxygen saturation
---Hb polymerization
----Vaso-occlusion
Hemolysis
---Anemia
---Normal MCV, MCH, &
---MCHC




What others Say?


CURRENT Pediatrics >

Chapter 28. Hematologic Disorders

Daniel R. Ambruso, MD, Taru Hays, MD, Neil A. Goldenberg, MD


Congenital Hemolytic Anemias: Hemoglobinopathies


The hemoglobinopathies are an extremely heterogeneous group of congenital disorders that occur in many different ethnic groups. The relatively high frequency of these genetic variants is related to the malaria protection afforded to heterozygous individuals.


The hemoglobinopathies are generally classified into two major groups.


The first, the thalassemias, are caused by quantitative deficiencies in the production of globin chains. These quantitative defects in globin synthesis cause microcytic and hypochromic anemias.


The second group of hemoglobinopathies consists of those caused by structural abnormalities of globin chains. The most important of these, hemoglobins S, C, and E, are all the result of point mutations and single amino acid substitutions in -globin. Many, but not all, infants with hemoglobinopathies are identified by routine neonatal screening.



The normal developmental changes that occur in globin-chain production during gestation and the first year of life. At birth, the predominant hemoglobin is fetal hemoglobin (hemoglobin F), which is composed of two -globin chains and two -globin chains.

Subsequently, the production of -globin decreases and the production of -globin increases so that adult hemoglobin (two chains and two chains) predominates after 2–4 months.


Because -globin chains are present in both fetal and adult hemoglobin, disorders of -globin synthesis (-thalassemia) are clinically manifest in the newborn as well as later in life. In contrast, patients with -globin disorders such as -thalassemia and sickle cell disease are generally asymptomatic during the first 3–4 months of age and present clinically after -chain production—and therefore fetal hemoglobin levels—have decreased substantially.









-Thalassemia

Essentials of Diagnosis & Typical Features



Most of the -thalassemia syndromes are the result of deletions of one or more of the -globin genes on chromosome 16. Normal diploid cells have four -globin genes; thus the variable severity of the -thalassemia syndromes is related to the number of gene deletions.

The severity of the -thalassemia syndromes varies among affected ethnic groups, depending on the genetic abnormalities prevalent in the population. In persons of African ancestry, -thalassemia is usually caused by the deletion of only one of the two -globin genes on each chromosome.


Thus, in the African population, heterozygous individuals are silent carriers and homozygous individuals have -thalassemia trait. In Asians, deletions of one or of both -globin genes on the same chromosome are common; heterozygous individuals are either silent carriers or have -thalassemia trait, and homozygous individuals or compound heterozygous individuals have -thalassemia trait, hemoglobin H disease, or hydrops fetalis.

Thus, the presence of -thalassemia in a child of Asian ancestry may have important implications for genetic counseling, whereas this is not usually the case in families of African ancestry.






-Thalassemia

Essentials of Diagnosis & Typical Features

-Thalassemia Minor:

Normal neonatal screening test.
African, Mediterranean, Middle Eastern, or Asian ancestry.
Mild microcytic, hypochromic anemia.
No response to iron therapy.
Elevated level of hemoglobin A2.


-Thalassemia Major:

Neonatal screening shows hemoglobin F only.
Mediterranean, Middle Eastern, or Asian ancestry.
Severe microcytic, hypochromic anemia with marked hepatosplenomegaly.



General Considerations

In contrast to the four -globin genes, only two -globin genes are present in diploid cells, one on each chromosome 11. Some -thalassemia genes produce no -globin chains and are termed 0-thalassemia. Other -globin genes produce some -globin, but in diminished quantities, and are termed +-thalassemia. Persons affected by -thalassemia may be heterozygous or homozygous. Individuals heterozygous for most -thalassemia genes have -thalassemia minor.


Homozygous individuals have -thalassemia major (Cooley anemia), a severe transfusion-dependent anemia, or a condition known as thalassemia intermedia, which is more severe than thalassemia minor but is not generally transfusion-dependent. -Thalassemia major is the most common worldwide cause of transfusion-dependent anemia in childhood. In addition, -thalassemia genes interact with genes for structural -globin variants such as hemoglobin S and hemoglobin E to cause serious disease in compound heterozygous individuals.


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[HIDE]http://www.qabs.com/files/Session%2026%20Thalassemias%20vs%20Hemoglobinopath ies%20Presentation.pdf[/HIDE]

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