Haemoglobin Disorders I Flashcards by Iseoluwa Ojo

What are the haemoglobinopathies?

The haemoglobinopathies are a group of disorders passed down through ___________ in which there is __________ or __________ of the haemoglobin molecule.

families (inherited)

abnormal production or structure

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What are the haemoglobinopathies?

Haemoglobinopathies are caused by mutations in _________, which encode for the _________ of haemoglobin, causing decreased or defective production of ________,___________ and ________

globin genes

globin proteins

haemoglobin, haemolysis, and anaemia.

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_____________ are the commonest monogenic diseases because almost ___% of the worldwide population are carriers.

Haemoglobinopathies

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What are the haemoglobinopathies?

They have originally emerged from the _______ regions, large parts of ———— and ______ .

However, the ————- and _________ contributed to their spread from those areas to all over the world.

Mediterranean

Asia and Africa

slave trade and international migration

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Classification of Haemoglobin Disorders

Haemoglobin disorders are be broadly classified into two general categories

__________ disorders of globin _________

_________ disorders of globin chain _________

Qualitative; structure

Quantitative; synthesis/accumulation

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Geographic distribution of the haemoglobinopathies

Commonest genetic defect worldwide with an estimated _________ carriers.

Inherited haemoglobin disorders were originally characteristic of the ______ and ______ but are now common worldwide due to migration.

269 million; tropics and subtropics

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Geographic distribution of the haemoglobinopathies

In populations in which _______ is (or was) endemic, 3 to 40% of individuals carry one of these significant variants.

malaria

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Geographic distribution of the haemoglobinopathies

Haemoglobin disorders are distributed across South-east Asia in a line stretching from _______ down the___________ to __________

Southern China

Malaysian Peninsula

Indonesian islands.

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Hb AS is very widespread and is found in up to one in _____ West Africans, (______%).

It is maintained at this level because of _______________________

four; 25

the protection against malaria that it offers.

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Hb AS

Also distributed across the Mediterranean, Middle East, and Indian Subcontinent.

T/F

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Hb AS

The distribution of the defect is thought to be due to ___________________________________

partial protection for carriers from plasmodium falciparum malaria.

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β thalassaemia syndrome is found in the ———— region especially Greece, Italy, some part of Spain

While

α-thalassaemia is more common in the _______/________.

Mediterranean

Far East/ South-east Asia

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The world distribution of haemoglobinopathies overlaps the geographic distribution of malaria.

T/F

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It is believed that carriers of α thalassaemia are protected against malaria

T/F

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It is believed that carriers of ___ thalassaemia are protected against malaria

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It is believed that carriers of α thalassaemia are protected against malaria and that _______ is responsible for elevating and maintaining their gene frequencies.

natural selection

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The most common inherited Hb disorder:

α plus (α+) thalassaemia, is usually (harmful or harmless?) .

However, people who inherit combinations of haemoglobins ______,____,_____,______,______, or ________ may have a serious haemoglobin disorder.

harmless

S, C, E, D Punjab, β thalassaemia, or α zero (α0) thalassaemia

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The most common inherited Hb disorder:

___________________ is the most common

Homozygous sickle cell anaemia (Hb SS)

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The most common inherited Hb disorder:

the doubly heterozygote conditions of ________ and _______ also cause sickling disease.

Hb SC and Hb Sβthal

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The most common inherited Hb disorder:

Haemoglobin C defect is most frequent in ______. The highest frequency is found in _______ and _______ followed by ________ part of ______.

This is due to the fact that these areas were or are still afflicted with ______

West Africa

Burkina fasso & Ghana

western part of Nigeria

malaria

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Hb C confers a relative protection against malaria.

T/F

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Types of genetic defects causing Haemoglobinopathies

o________ of a globin gene
o__________ of a globin gene
o_______ of genes
oProduction of ________
oAbnormal ____________
o_________ resulting in dysfunction of the genes
oMutations affecting ____________giving rise to elongated but unstable globin chain.

Deletion

Partial deletion

Fusion

non-functional mRNA

gene transcription

Point mutations

termination of translation

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Types of genetic defects causing Haemoglobinopathies

The most common genetic disorder of haemoglobin is those caused by _______ followed by _________.

point mutation

deletion

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Thalassaemia

_____________ of _________◦β thalassaemia

________ of ________◦α thalassaemia

Other variant

Reduced production of β chains

Reduced production of α chains

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β-Thalassaemia __________ deficiency - So reduced Hb ____ BUT retained production of other β-type chains, so increased ◦_______ production (Hb____) ◦_______ production (Hb_____)

β chain A Delta (δ) ; A2 gamma (γ ) ; F

β thalassaemia β gene Encoded by _____ gene pair (Xlinked or Autosomal?) (recessive or dominant?)

a single ; Autosomal; recessive

β thalassaemia Heterozygotes have β thalassaemia ______ Homozygotes have β thalassaemia major (thalassaemia _____)

trait MAJOR

β thalassaemia they are (ALIVE or DEAD?) at birth

ALIVE

Inheritance of β thalassaemia β-thalassemias are caused by ________ or, more rarely, ______ in the β globin gene on chromosome ____, leading to ____ (β+) or ______ (β0) synthesis of the β chains of hemoglobin (Hb).

point mutations deletions 11 reduced absent

Inheritance of β thalassaemia Transmission is (Xlinked or autosomal?) (dominant or recessive?)

Autosomal recessive

Inheritance of β thalassaemia dominant mutations have also been reported. T/F

β thalassaemia genes If the mutation causes total shutdown of the β chain production ◦No β chain produced: _____ If the mutation reduces β chain production (but does not shut it down) ◦some β chain produced : ______

β0 β+

Genetic combinations β / β+ _____zygote ◦____cytosis, ◦Hb _____ ◦raised _____ and _____ β / β0 _____zygote ◦____________cytosis, ◦Hb _______ ◦raised _____ and _____

hetero; Micro; normal; A2 and F hetero; More severe micro; normal; A2 and F

Genetic combinations β +/β+ ◦_____cytosis, ◦——- anaemia β +/ β0 _____________◦____cytosis, ____ anaemic ◦ β 0/ β0 ◦____________: _______ dependent ◦_______ cytosis, _____ changes,

micro; +/- thalassaemia intermedia; micro ; variably Thalassaemia Major; transfusion; micro red cell

thalassaemia intermedia is when ???? thalassaemia major is when?

One gene is not producing beta chain Atall and the second gene is producing a reduced amount of beta chain Both genes are shut down

Clinical features of β Thalassaemia Severe anaemia becomes apparent at _________ after birth when __________________ should take place.

3-6 months the switch from γ- to β-chain production

Clinical features of β Thalassaemia Enlargement of the liver and spleen occurs as a result of ___________,_________ and later because of ________.

excessive red cell destruction extramedullary haemopoiesis iron overload

Clinical features of β Thalassaemia The large spleen increase blood requirements by ___________ and _________, and by causing ____________

increasing red cell destruction and pooling expansion of the plasma volume.

Clinical features of β Thalassaemia _________ but not as much as in SCD.

Jaundice

Clinical features of β Thalassaemia Expansion of bones caused by ______________ leads to a thalasaemic ______: _________,________,_________ and to thinning of the cortex of many bones with a tendency to fractures and bossing of the skull with a ‘___________’ appearance on X-ray.

intense marrow hyperplasia facies mongoloid, gnathopathy, small stature hair-on- end

Clinical features of β Thalassaemia The patient can be sustained by _________ , but _______ caused by repeated transfusions is inevitable unless _________ is given.

blood transfusions iron overload chelation therapy

Clinical features of β Thalassaemia Each 500ml of transfused blood contains approximately _____mg iron. To make matters worse, _____________________ is increased in β-thalassaemia, probably secondary to _______________ and inappropriately low serum _______ levels.

250 iron absorption from food ineffective erythropoiesis hepcidin

Clinical features of β Thalassaemia Iron damages the liver and the endocrine organs with failure of ______, delayed or absent _____, ______,______, and _________

growth puberty diabetes mellitus, hypothyroidism and hypoparathyroidism

Clinical features of β Thalassaemia Skin pigmentation as a result of _______ and _________ gives a ________ appearance at an early stage of iron overload.

excess melanin and haemosiderin slately grey

Clinical features of β Thalassaemia Most importantly, iron damages the ____. In the absence of intensive iron chelation, death occurs in the ______ or _____ decade, usually from _______ or ________

heart second or third congestive heart failure or cardiac arrhythmias.

Clinical features of β Thalassaemia Infections can occur for a variety of reasons. In infancy, without adequate transfusion, the anaemic child is prone to _____ infections. _____,________, and _______ infections are likely if _______ has been carried out and ___________ is not taken.

bacterial Pneumococcal, Haemophilus and meningococcal splenectomy prophylactic penicillin

Clinical features of β Thalassaemia Transfusion of viruses by blood transfusion may occur T/F

Clinical features of β Thalassaemia Liver disease in thalassaemia is most frequently a result of _______ but _______ is also common where the virus is endemic. __________________ has been transmitted to some patients by blood transfusion.

hepatitis C hepatitis B Human immunodeficiency virus (HIV)

Clinical features of β Thalassaemia Osteoporosis may occur in well-transfused patients. It is more common in _______ patients with ______ abnormalities and with __________ resulting from ineffective erythropoiesis.

diabetic; endocrine marrow expansion

Clinical features of β Thalassaemia Growth ________, delayed ________________

retardation secondary sexual characteristics.

Laboratory Diagnosis of β Thalassaemia There is a severe ____chromic, ____cytic anaemia, _____ reticulocyte percentage with normoblasts, ______ cells and _________ in the blood film.

hypo; micro ; raised target; basophilic stippling

Laboratory Diagnosis of β Thalassaemia Haemoglobin electrophoresis reveals absence or almost complete absence of Hb ______, with almost all the circulating haemoglobin being Hb ____. The Hb ——- percentage is normal, low or slightly raised in β thalassaemia.

Hb A; Hb F Hb A2

Laboratory Diagnosis of β Thalassaemia ________________ is now usually used as first-line method to diagnose haemoglobin disorders. _______ is used to identify the defect on each allele.

High performance liquid chromatography DNA analysis

Blood film in B-thalassemia ——chromic ——-cytic _____ cells ——— red cells( _______) _________ are seen in the same red cells

Hypo; micro Target Nucleated; normoblasts Howell-jolly

Management of beta thalassemia ___________ are needed to maintain the haemoglobin over ___g/dL at all times. This usually requires ________ units every ————-  Fresh blood, filtered to __________, gives the best red cell survival with the fewest reactions.  Regular ______ (e.g. 5 mg/day) is given if the diet is poor.

Regular blood transfusions; 10 2-3 units; 4-6 weeks. remove white cells folic acid

Management of beta thalassemia _____ therapy is used to treat iron overload. The most established drug is _________. The complex is mainly excreted in the _____ but up to one-third is also excreted in the ______.

Iron chelation deferroxamine urine; stools

Oral Iron chelators are not available. T/F

F Oral Iron chelators are now available.

Management of beta thalassemia ________, 200mg/day, increase excretion of iron produced by deferoxammine. ———— may be needed to reduce blood requirements.

Vitamin C Splenectomy

Management of beta thalassemia ________ therapy is given either as replacement because of end-organ failure or to stimulate the pituitary if puberty is delayed. ________ will require insulin therapy. Patients with osteoporosis may need additional therapy with increased _______ and ______ in their diet, together with a _______ and appropriate endocrine therapy.

Endocrine Diabetics calcium and vitamin D biophosphonate

Splenectomy should be delayed until the patient is over ____ years old because of the high risk of dangerous infections post-splenectomy. The vaccinations and antibiotics to be given.

Management of beta thalassemia Immunization against _______ should be carried out in all non-immune patients.

hepatitis B

Management of beta thalassemia __________________ offers the prospect of permanent cure. The success rate (long-term thalassaemia major-free survival) is over ____% in well- _______ (younger or older?) patients without _______ or ________

Allogeneic bone marrow transplantation 80 chelated; younger liver fibrosis or hepatomegaly.

Management of beta thalassemia A human leucocyte antigen (HLA) matching ______ (or rarely other family member or matching unrelated donor) acts as donor. Failure of transplant can happen resulting in recurrence of thalassaemia or death

sibling

Inheritance of alpha thalassaemia More complex as encoded by ___ gene pairs (so ___ genes per person, not ___)

2; four; two

alpha thalassaemia trait (α+ ) ____ gene deletion : (____) _________ _______ Hb _________ or _________ MCV

One α α/ α- Silent carrier normal normal or slightly reduced

Cis- _____ gene deletion: (_____/_____) _______ _______ anaemia MCV ______, RBC count is _____ x 1012/L. Hb electrophoresis is _______, DNA analysis needed for diagnosis

Two α α /- - α0 trait; Usually no low; >5.5 normal

Trans- ____ gene deletion: (_____/____) Homozygous __________ _______ anaemia MCV ______, RBC count is _____ x 1012/L. Hb electrophoresis is _______, DNA analysis needed for diagnosis

Two α -/ α- thalasaemia trait Usually no low; >5.5 normal

Three gene deletion: (_____/______) •___________ disease, •______ Hb, Hb 7-11g/dl , •may or may not be __________ •unlike in beta thalassaemia, there is ________ for alpha

- -/α - Haemoglobin H Reduced transfusion dependent no substitute

Three gene deletion: (- -/α - ) •_____cytic _____chromic anaemia, fragmented cells, _____ cells , ________, _____cytosis

micro; hypo target; polychromasia poikilo

Three gene deletion: (- -/α - ) •_____megaly presence of ________________ on film (“_______” cells)

spleno beta tetramers β4 (HbH) golf ball

_____________ Four gene deletion: (______/____) Four gene deletion ◦___ alpha chain production ◦ ________ with life ◦ fetus _______ ◦_________ form instead γ4- Hb Barts

Barts Hydrops fetalis - -/ - - no incompatible dies in utero gamma tetramers

With regards to haemoglobinopathies? A) alpha thalassaemia are caused by deletions in the alpha globin gene B) beta thalassaemia is not clinically apparent until 6 months of age C)HbS forms as a result of a point mutation in codon 7 of the beta globin gene D)sickle cell disease is the commonest genetic disorder in Nigeria E) they are blood cell disorders which cause haemolytic anaemia

Caused by deletion of all four alpha globin genes ? A) beta thalassaemia major B) Hb Barts hydrops fetalis C) Diamond-Blackfan anaemia D)alpha thalassaemia trait E)hereditary spherocytosis

Deletion of one or two alpha globin genes? A) Hereditary spherocytosis B) Hb Barts hydrops fetails C) Diamond-Blackfan anaemia D) alpha thalassaemia major E)alpha thalassaemia trait

Concerning β thalassaemia A) Mutations reduce or eliminate the production of β-globin chains. B)Gene deletions may cause β thalassaemias but are more common in α thalassaemia C)Either no β chain (βo) or small amounts (β+) are synthesized. D)The main pathology involved is excess β chains which precipitate in erythroblasts and in mature red cells causing the severe ineffective erythropoiesis and haemolysis that are typical of the disease. E)Production of γ-chains helps to ‘mop up’ excess α chains and to ameliorate the condition.

D in Beta thal. There is a decreased production of beta globin chain which is why there is usually an increased gamma and delta chain to compensate.

As regard the α-Thalassaemia Syndromes They are usually caused by gene deletions. The clinical severity depends on the number of genes that are missing or inactive. Loss of all four α genes is compatible with life. Hb H disease (β4) is three α gene deletions and leads to moderately severe microcytic, hypochromic anaemia with splenomegaly. In foetal life, Hb Barts (γ4) occurs when all four α genes are deleted. α-thalassaemia traits are caused by loss of one or two genes

D in Beta thal. There is a decreased production of beta globin chain which is why there is usually an increased gamma and delta chain to compensate.

The following may be clinical manifestation of β-Thalassaemia Growth retardation and delayed secondary sexual characteristics. Leucocytosis Bleeding tendency Tendency to fractures and bossing of the skull with a ‘hair-on-end’ appearance on X-ray. Skin pigmentation

T F F T T

Haemoglobin Disorders I Flashcards

(77 cards)