Dr.Abdolreza Afrasiabi Thalassemia & Heamophilia Genetic Reaserch Center Shiraz Medical University
Hemoglobin tetramer
Hemoglobin Structure % A 1 α 2 β 2 94-97% A 2 α 2 δ 2 2.5% A 1C α 2 (β-n-glucose) 3% F α 2 γ 2 <1% Gower-1 ζ 2 ε 2 0* Gower-2 α 2 ε 2 0* Portland ζ 2 γ 2 0* * Indicates early embryonic form not seen in adults
There are 3 main categories of inherited Hemoglobin abnormalities: Structural or qualitative: Genetic mutation involving amino acid deletions or substitution.(hemoglobinopathy). Quantitative: Production of one or more globin chains is reduced or absent (Thalassemia). (HPFH): Hereditary persistence of Fetal Hemoglobin. Complete or partial failure of γ globin to switch to β globin.
Heterogenous group of disorders due to an imbalance of α and β globin chain synthesis α thalssemia: α-globin chain production decreased β thalassemia: β globin chain production decreased Quantitative deficiency: 0 thalassemia: No β -globin chain is made β + thalassemia: decreased b-globin chain is made
Beta ( ) thalassemia: - The disease manifests itself when the switch from to chain synthesis occurs several months after birth - There may be a compensatory increase in and chain synthesis resulting in increased levels of Hb-F and A 2. - The genetic background of thalassemia is heterogenous and may be roughly divided into two types: 0 in which there is complete absence of chain production. This is common in the Mediterranean. + in which there is a partial block in chain synthesis. At least three different mutant genes are involved: +1 10% of normal chain synthesis occurs +2 50% of normal chain synthesis occurs +3 - > 50% of normal chain synthesis occurs
Lab findings include: Prepheral Smear - hypochromic, microcytic anemia - marked anisocytosis and poikilocytosis - schistocytes, ovalocytes, and target cells - basophilic stippling from chain precipitation - increased reticulocytes and nucleated RBCs chronic hemolysis leads to increased bilirubin and gallstones hemoglobin electrophoresis shows increased Hb-F, variable amounts of Hb A2, and no to very little A.
β-thalassemia minor
Solubility test (Sickledex): Test to identify HbS. HbS is relatively insoluble compared to other Hemoglobins. Add reducing agent HbS will precipitate forming and opaque solution compared with the clear pink solution seen in HbS is not present.
Alpha ( ) thalassemia The disease is manifested immediately at birth There are normally four alpha chains, so there is a great variety in the severity of the disease. At birth there are excess chains and later there are excess chains. These form stable, nonfunctional tetramers that precipitate as the RBCs age leading to decreased RBC survival. The disease is usually due to deletions of the gene and occasionally to a functionally abnormal gene.
I. Silent carrier state II. III. IV. Alpha thalassemia trait Hemoglobin H disease Hemoglobin H constant spring V. Homozygous constant spring VI. Hydrops fetalis
Lack of alpha protein is so small Generally causes no health problems Diagnosed when individuals has a child with Hb-H or alpha thalassemia trait Hb constant spring is an unusual form of it and caused by mutation of alpha-globin with no health problems
Reduced MCV and MCH with normal Hb A2 in lab data Physicians often mistake with iron deficiency anemia
Created by the remaining beta globin Lack of alpha protein is great enough to cause sever anemia and health problems such as an enlarged spleen, bone deformities, and fatigue
One parent is constant spring carrier and other carrier of alpha thalassemia trait Affected individual have a more sever anemia and suffer more frequently from enlargement of the spleen and viral infections
When two constant spring carriers pass their genes on to their child. The condition is less sever than Hb H-constant spring and more similar to Hb-H disease.
There are no alpha gene in the individual s DNA Gamma globins produced by the fetus to form an abnormal Hb called Hb Barts. Most individuals die before or shortly after birth
Co inheritance with heterozygous beta-thal and alpha-thal in particualr -alpha/-alpha genotype may be normalize MCV and MCH while Hb A2 levels remain elevated. Interaction of delta-thal and beta-thal trait may reduce Hb A2 to borderline or normal level while MCV and MCH are reduced. phenotype of deltabeta-thal is similar to alpha but alpha/beta globin chain synthesis is <0.9 for alpha and >1.2 in deltabeta carrier.
1) Megaloblastic Anemia due to B12/Folic Acid deficiency 2) Liver disease (Lipid Metabolism) 3) Unstable Hb, Sickle Trait, S/B, S/a 4)hyper Thyroedism 5) Viral Treatment in Acquired immune deficiency HIV 6) Combined a/b with Normal index
1) Delta Beta Thalassemia (Hetero/Homo) 2)Hb H disease 3) Unstable Hb, Sickle Trait, S/B, S/a 5) Iron deficiency 6)Hb D
1) Hb A 2 Hb G in S window in HPLC or Capillary System a) Mutation in Delta gene (16 Gly Arg) With increased Hb F <5% b) Deletion in 5 B gene c) Intronic mutation can cause pre mature splice site
Parental Options
Procurement removal of AF transabdominally with US* at 14-16 weeks gestation determined via last menstrual period (LMP) *Ultrasound (US): locates the placenta (anterior or fundal in 70%) assess amount of AF date pregnancy via BPD, femur length, chest size locate fetus assess anatomy (brain, spinal cord, stomach, kidneys, HR)
Procurement (cont) removal of 10-20 cc fluid which contains amniocytes and fluid use 20-21 gauge spinal needle, strict asepsis w/ or w/o local anesthetic AF is produced by the fetus amniocytes are fetal in origin: skin, amnion, eyes, GU tract, GIT, respiratory system
Risks 1-3% overall for experienced doc Fetus: infection (<1/200) limb defects due to disruption of fetal development; severe arm/leg anomalies oromandibular hypogenesis amniotic puncture leading to amnionitis Mom: ½-1½% miscarriage risk cramping/bleeding infection (<1/200)
Problems/complications cannot do AFP for NTD; must do MSAFP at 15+ weeks mosaicism Rh limb defects Greatest advantage TIME