Haemoglobin Disorders I Flashcards
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
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.
_____________ are the commonest monogenic diseases because almost ___% of the worldwide population are carriers.
Haemoglobinopathies
7
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
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
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
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
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.
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.
Hb AS
Also distributed across the Mediterranean, Middle East, and Indian Subcontinent.
T/F
T
Hb AS
The distribution of the defect is thought to be due to ___________________________________
partial protection for carriers from plasmodium falciparum malaria.
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
The world distribution of haemoglobinopathies overlaps the geographic distribution of malaria.
T/F
T
It is believed that carriers of α thalassaemia are protected against malaria
T/F
T
It is believed that carriers of ___ thalassaemia are protected against malaria
α
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
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
The most common inherited Hb disorder:
___________________ is the most common
Homozygous sickle cell anaemia (Hb SS)
The most common inherited Hb disorder:
the doubly heterozygote conditions of ________ and _______ also cause sickling disease.
Hb SC and Hb Sβthal
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
Hb C confers a relative protection against malaria.
T/F
T
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
Types of genetic defects causing Haemoglobinopathies
The most common genetic disorder of haemoglobin is those caused by _______ followed by _________.
point mutation
deletion
Thalassaemia
_____________ of _________◦β thalassaemia
________ of ________◦α thalassaemia
Other variant
Reduced production of β chains
Reduced production of α chains
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 ______
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
T
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
T
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.
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.
6
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
C
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
B
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
E
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.
I don’t know
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
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
