Beta Thalassemia: Etiology and Pathogenesis

by Carlo Raj, MD

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    00:00 Let’s go on to beta thalassemia.

    00:05 So if alpha thalassemia you felt as though was a little complicated, that’s okay.

    00:09 It was, because you’re dealing with 4.

    00:11 Beta? Heck of a lot easier.

    00:13 Because in beta, you only have two alleles total, okay? Whereas in alpha, you have two alleles from each parent.

    00:19 Here, you have one allele from one parent, another allele from another parent.

    00:25 If I were you, I would know chromosome 11, that’s important.

    00:28 Now, I’m going to give you a few scenarios in which the boards really like because they want to test your knowledge in concept of beta thalassemias.

    00:37 You will see what I’m referring to.

    00:38 So that means that there’s really only two patterns.

    00:40 You miss one, that’s minor or you miss two, that’s major.

    00:45 But clinically, you need to be able to identify the nomenclature, so I’ll walk you through that specifically.

    00:51 There's your normal gene, chromosome 11 shall we say for beta.

    00:57 If there is a mutation, maybe it’s a splicing defect.

    01:00 What does that mean? Do you see the bottom picture where you see the mutant type of splicing mutation? Remember, you have introns and extrons and normally should remove your introns.

    01:09 Correct? Remember that from genetics.

    01:12 Well what happens in splicing is the fact that intron remains.

    01:15 Do you see that white area, that bar, the white bar that's empty? That’s the splicing defect.

    01:20 So you are not able to have proper splicing.

    01:23 And beta thalassemia primarily caused by splicing mutations in beta globin genes.

    01:28 So you want to keep that in mind.

    01:29 This is just a graphic illustration of a splicing mutation in beta thalassemia.

    01:35 How many alleles total please? Two, one from mother and one from father.

    01:39 You have minor or major, minor and major, that’s it.

    01:42 None of this trait and none of this HbH and such.

    01:47 Now, the nomenclature does become important here.

    01:49 I need you to pay attention.

    01:52 If you find a beta as what you see here, if you find a beta with no superscript, hematologically or clinically that means a perfectly normal beta, beta, beta gene, okay? Or beta allele.

    02:08 However, as soon as you see a superscript, let me lay down the law for you, if you find a superscript that means there’s a mutation of some type.

    02:16 Is that clear? So be very careful because this looks like it’s beta plus.

    02:20 And if you didn’t know any better and you didn’t speak this language of hematology, you’ll think, “Oh! There is presence of beta.” No, no, no.

    02:29 In order for you to have a normal beta allele, this means there should be no superscript.

    02:34 But the fact that you find beta plus, means there’s mutation and expression here is going to be variable.

    02:41 Meaning to say variably decreased.

    02:44 So it won’t be normal, it will be subnormal.

    02:47 But if it’s beta not, meaning beta zero as you see here, no beta allele was present at all.

    02:56 Now for simplicity purposes, on your board exam, let me tell you, if there’s one beta with no superscript, that’s from mother.

    03:05 And let’s say from the father, you picked up a beta with either the superscript plus or a superscript of the zero, by the definition as far as your concerned with your medical education, that is beta thalassemia minor.

    03:22 I don’t care nor should you with that second beta that has been mutated if it’s a plus or a zero.

    03:28 But because you have one beta that is perfectly normal, that is minor.

    03:32 As I told you, this will be the only part where it becomes a little tricky.

    03:36 But if you understand the nomenclature, then you will be in good shape.

    03:38 What if you had both betas that has some kind of superscript? As far as your concerned, that means it’s major.

    03:46 In other words, that’s your Cooley.

    03:47 Hopefully, they'll just give you beta zero, beta zero.

    03:50 It’s major, you’re done.

    03:51 Or they will give you beta and beta zero, that’s minor.

    03:55 But if not by chance, at least you know how to now interpret it.

    03:58 Speaking of which, let’s go through.

    04:00 I’m going to first give you the most common and then I will talk about the one that rarely shows up.

    04:07 So let’s talk about beta thalassemia minor.

    04:10 You will notice the following, exactly what I was referring to.

    04:13 So now that we discussed it, let’s take a look at it, so that permanently stays in your head.

    04:18 First, take a look at the beta with no superscript.

    04:21 Perfectly normal betas.

    04:24 Next, you see the betas with superscript 0/not and beta plus superscript.

    04:32 Either/or for you, at this juncture of your medical education, that to you should mean beta thalassemia minor.

    04:39 Asymptomatic with mild anemia.

    04:41 I’m going to skip over intermediate for a second, and then I’m going to give you this one.

    04:46 You definitely want to know this and I’ll tell you why, why, why.

    04:51 There are 2 betas, both have superscript.

    04:54 What does that mean? Major, that’s it.

    04:56 "But Dr. Raj, beta plus means variable expression." I don’t care neither should you.

    05:01 This is beta thalassemia major.

    05:03 What does that mean? Severe anemia, severe anemia.

    05:06 Now the only time, if you want to take a look at the middle, there is a bunch of variations.

    05:09 The one on the middle is called thalassemia intermedia.

    05:12 It exist, but I’m just going to mention it and know that it exist.

    05:17 But your focus should be minor and major.

    05:20 I will definitely walk you through on what it means to be transfusion dependent.

    05:23 I have to, I have to.

    05:25 But before we move on now, I need you with me right now to predict what’s going to come next.

    05:32 You tell me what beta globin is.

    05:34 Which hemoglobin or hemoglobins contain beta? There’s a new one hemoglobin that contains beta.

    05:43 Whereas an alpha, all relevant hemoglobins have alpha: Hemoglobin A, A2, F, okay? Here however, beta globin is only which one, A’s and B’s? Hemoglobin A.

    05:57 Interesting, right? Because -- Let me review real quick -- If you’re missing three alpha alleles, you can’t produce any other hemoglobin.

    06:07 You have to literally produce some other globin.

    06:10 Versus here, if you have beta thalassemia major, let’s stick to that, where you do not produce much hemoglobin A.

    06:19 May I ask you? Could you produce hemoglobin A2? Let’s see, that’s made up of alpha and delta.

    06:26 Oh, yeah, I can.

    06:27 Good.

    06:28 And what about hemoglobin F? Oh, that’s alpha and gam-- Oh, yeah, I can too! So those are going to compensate.

    06:35 So you end up producing more hemoglobin F and hemoglobin what? A2.

    06:40 But what happened to hemoglobin A? Oh, that diminished.

    06:43 I’m going to show you all this.

    06:44 Don’t worry.

    06:45 We’re just going to talk about this and then we’ll look at it.

    06:50 Always do this, every single question, you think about what you’re going to answer then you take a look at the answer choices.

    06:57 Don’t do it the other way around.

    06:57 If you take a look at the answer choices first, you’ll get confused.

    07:00 I can guarantee that.

    07:02 Efficiently, you look at the vignette, you read through the clinical situation and each line either rule in or you rule out that’s relevant for your patient.

    07:10 You’re literally the doctor, the clinician, a detective.

    07:14 You’ll predict what’s going to happen.

    07:15 If it’s there, fantastic.

    07:17 Do you know how much time you spent? Like you literally spent not much time in an efficient way.

    07:21 You need to train yourself, it’s a marathon.

    07:23 The boards are not -- It’s not a sprint.

    07:26 You can't cram from this.

    07:28 There is no way, no way.

    07:30 So now my point is this, 97% is your normal hemoglobin A and what happens in beta thalassemias? That 97% will diminish as we shall see on hemoglobin electrophoresis.

    07:41 Okay, pathogenesis, what does this mean to you? Well, you tell me.

    07:45 You’re going to have a decrease in hemoglobin.

    07:47 Tell me about your patient.

    07:48 Symptomatic, kind of behaves like your? Well, there's fatigue especially upon exertion.

    07:53 What else may happen? You have decreased hematocrit.

    07:55 What about your iron studies? Yeah, leave it alone.

    07:58 Okay, iron studies here only dealing with globins.

    08:01 So very similar in terms of alpha.

    About the Lecture

    The lecture Beta Thalassemia: Etiology and Pathogenesis by Carlo Raj, MD is from the course Microcytic Anemia – Red Blood Cell Pathology (RBC).

    Included Quiz Questions

    1. Hemoglobin A
    2. None of the hemoglobins mentioned contain beta globin chains.
    3. Hemoglobin Barts
    4. Hemoglobin F
    5. Hemoglobin A2
    1. Chromosome 11
    2. Chromosome 21
    3. Chromosome 18
    4. Chromosome 13
    5. Chromosome 16
    1. ββ0
    2. β+β+
    3. β+β0
    4. β0β0
    5. ββ
    1. Cooley’s anemia
    2. Macrocytic anemia
    3. Silent carrier of α-thalassemia
    4. Alpha thalassemia trait
    5. Beta thalassemia minor

    Author of lecture Beta Thalassemia: Etiology and Pathogenesis

     Carlo Raj, MD

    Carlo Raj, MD

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    By Anas J. on 17. December 2017 for Beta Thalassemia: Etiology and Pathogenesis

    helpful lec thumps up for me is better than the ophthalmo lecs by the same doc