Say you've always been interested in pyruvate kinase deficiency and its inner workings. Or you have a relative with this rare disorder. What if it wasn't just a deficiency but also exerts a protective effect over another type of disease? The Internet holds a vast plethora of information.. so where to start? By reading this article, of course!
Pyruvate kinase deficiency (PKD) is the defect of the enzyme pyruvate kinase and can affect survival rate
as well as morphology of erythrocytes. Cases of PKD occur across the globe but have a higher number of
reported cases in northern Europe, Japan and the United States.
In hereditary PKD, PKD is resultant from a mutation of the PKLR (pyruvate kinase, liver and red blood
cell) gene which is located on the long (q) arm of chromosome 1 at position 21 in humans. There are
more than 100 types of genetic defects in the PKLR gene and most of which occur as a result of missense mutations. However, insertion, deletion and splicing mutations have also been shown to contribute to the mutation. It is passed on from parent to child as both an autosomal dominant and autosomal recessive trait, however, the latter is more common.
Acquired PKD, on the other hand, may result from acute leukemia, pre-leukemia, refractory
sideroblastic anemia (any anemic condition that is unsuccessfully treated by any other means outside
of blood transfusions), polycythemia vera (disorder of bone marrow that leads to over production of
erythrocytes) and chemotherapy complications. This is more common and results in milder effects than
its hereditary counterpart.
Individuals with this disease may find themselves victims of hemolytic anemia as a result of lack of
normal pyruvate kinase. Other symptoms include fatigue, lethargy, jaundice, pale skin, an enlarged
spleen and severe cases may result in death. Complications also arise from such a disease and they
include cholecystolithiasis (gall stones) due to buildup of bilirubin (produced as a result of hemolytic
anemia), sepsis by encapsulated bacteria in children and thromboembolic disease in adults after
splenectomy, ischemic stroke (stroke that results from stop of blood flow to a part of the brain), iron
overload and alloimmunization during pregnancy as a result of multiple transfusion therapy.
The enzyme pyruvate kinase in erythrocytes converts phosphoenolpyruvate to pyruvate which is one of
two glycolytic reactions in the erythrocyte that produces ATP. Reticulocytes (immature erythrocytes)
have mitochondria and thus, can generate ATP via oxidative phosphorylation. However, mature
erythrocytes do not have mitochondria and as such, require glycolytic activity to produce ATP (required
for sodium pump which maintains intracellular electrolyte concentration via the ATP cation pump and
biconcave disc shape of erythrocytes). In the case of PKD, the erythrocytes are lacking in ATP due to
reduced pyruvate kinase enzyme function. As a result, the cells distort and swell, giving them a spherical
shape (spherocytes). The distorted erythrocytes either lyse or get prematurely destroyed by the
spleen and liver, leading to anemia. However, PKD individuals have a greater ability to release oxygen
into tissues as PKD influences increase in 2,3-disphosphoglycerate (2,3-DPG) (right shift in oxygen-
dissociation curve).
As the disease is not life-threatening in most cases (low severity), most individuals do not require
treatment. Blood transfusions may be carried out in cases of low erythrocyte count (which occurs only
in early childhood, periods when physiological stress is present – i.e. infection, pregnancy). Supplements
such as folic acid and B vitamins help to increase erythrocyte production and relieve symptoms. If
anemia is severe, splenectomy can be carried out to reduce erythrocyte destruction. However, in the
case of young children, it is delayed as long as possible in order to allow maturity of the immune system.
Prophylactic antibiotics and pneumococcal vaccine should also be administered to young patients post
splenectomy (refer to complications above).
Patients who have a family history of PKD and wish to start a family can undergo genetic counseling
in order to prevent their children from inheriting this disease as carriers of the defective gene can be
diagnosed by detecting decreased erythrocyte PKD activity.
So then, after all that has been said and done, what has PKD got to do with malaria - the disease that at one point was so highly prevalent in tropical and subtropical countries?
To answer that question, we must first start with malaria, which we all know is a type of disease caused by parasites (Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale, Plasmodium malariae and Plasmodium knowlesi have all been known to infect humans) that infects us by first replicating in certain types of mosquitoes (gets infected when it takes blood from an infected person) and then entering our body through mosquito bites. People down with malaria usually have high fevers, shaking chills and flu-like symptoms. It is indeed a serious illness as delay of prompt treatment can even cause kidney failure, seizures, mental confusion, coma and eventually, death.
Why is it such a cause of worry? Despite the fact that there are anti-malarial drugs available for consumption, there is currently no known malarial vaccine. This is due to the fact that the malaria parasite is able to constantly make changes to its surface and thereby evade the body's immune system which in turn makes it a challenge to produce a vaccine to these ever-changing surfaces.
However, studies show that PKD actually exerts a shield-like effect over malaria affected individuals. This is something amazing in itself as it is a natural defence against a serious illness.
To find out how exactly PKD reduces the effects of malaria, do refer to the scientific article on our blog.
References:
>> The New York Times, 2012. Pyruvate Kinase Deficiency. [online] Available at: <http://health.nytimes.com/health/guides/disease/pyruvate-kinase-deficiency/overview.html> [Accessed 12 December 2012].
>> Medscape Reference, 2011. Pyruvate Kinase Deficiency. [online] Available at: <http://emedicine.medscape.com/article/125096-overview> [Accessed 12 December 2012].
>> St. Edward’s University, 2012. Pyruvate Kinase Deficiency and Hemolytic Anemia. [online] Available at: <http://www.cs.stedwards.edu/chem/Chemistry/CHEM44/alarid/pyrkin.html#biochemistry> [Accessed 12 December 2012].
>> PubMed Health, 2012. Pyruvate Kinase Deficiency. [online] Available at: <http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0002177/> [Accessed 12 December 2012].
>> Homerton University Hospital, 2012. Pyruvate Kinase. [online] Available at: <http://www.homerton.nhs.uk/our-services/pathology/guide-to-laboratory-tests-and-directory/haematology-tests/pyruvate-kinase/> [Accessed 12 December 2012].
>> Office of Rare Diseases Research, 2011. Pyruvate Kinase Deficiency. [online] Available at: <http://rarediseases.info.nih.gov/GARD/QnASelected.aspx?diseaseID=7514> [Accessed 12 December 2012].
>> Patient.co.uk, 2011. Pyruvate Kinase Deficiency. [online] Available at: <http://www.patient.co.uk/doctor/Pyruvate-Kinase-Deficiency.htm> [Accessed 12 December 2012].
>> Centers for Disease Control and Prevention, 2012. Malaria. [online] Available at: <http://www.cdc.gov/malaria/about/faqs.html> [Accessed 20 January 2013]
Images obtained from:
>> http://ghr.nlm.nih.gov/dynamicImages/chromomap/PKLR.jpeg
>> http://www.vetmed.vt.edu/education/Curriculum/VM8304/vet%20pathology/CASES/CELLINJURY2/ SPHEROCYTOSIS.JPG
>> http://cdn.c.photoshelter.com/img-get/I0000AIEUK4DZsL8/s/600/600/85636DS.jpg
>> http://chemistry.berea.edu/~biochemistry/2010/cd/paper.html20_files/image002.jpg
Pyruvate kinase deficiency (PKD) is the defect of the enzyme pyruvate kinase and can affect survival rate
as well as morphology of erythrocytes. Cases of PKD occur across the globe but have a higher number of
reported cases in northern Europe, Japan and the United States.
In hereditary PKD, PKD is resultant from a mutation of the PKLR (pyruvate kinase, liver and red blood
cell) gene which is located on the long (q) arm of chromosome 1 at position 21 in humans. There are
more than 100 types of genetic defects in the PKLR gene and most of which occur as a result of missense mutations. However, insertion, deletion and splicing mutations have also been shown to contribute to the mutation. It is passed on from parent to child as both an autosomal dominant and autosomal recessive trait, however, the latter is more common.
 |
| Point mutation of PKLR gene at long (q) arm of chromosome 1 at position 21. |
Acquired PKD, on the other hand, may result from acute leukemia, pre-leukemia, refractory
sideroblastic anemia (any anemic condition that is unsuccessfully treated by any other means outside
of blood transfusions), polycythemia vera (disorder of bone marrow that leads to over production of
erythrocytes) and chemotherapy complications. This is more common and results in milder effects than
its hereditary counterpart.
Individuals with this disease may find themselves victims of hemolytic anemia as a result of lack of
normal pyruvate kinase. Other symptoms include fatigue, lethargy, jaundice, pale skin, an enlarged
spleen and severe cases may result in death. Complications also arise from such a disease and they
include cholecystolithiasis (gall stones) due to buildup of bilirubin (produced as a result of hemolytic
anemia), sepsis by encapsulated bacteria in children and thromboembolic disease in adults after
splenectomy, ischemic stroke (stroke that results from stop of blood flow to a part of the brain), iron
overload and alloimmunization during pregnancy as a result of multiple transfusion therapy.
The enzyme pyruvate kinase in erythrocytes converts phosphoenolpyruvate to pyruvate which is one of
two glycolytic reactions in the erythrocyte that produces ATP. Reticulocytes (immature erythrocytes)
have mitochondria and thus, can generate ATP via oxidative phosphorylation. However, mature
erythrocytes do not have mitochondria and as such, require glycolytic activity to produce ATP (required
for sodium pump which maintains intracellular electrolyte concentration via the ATP cation pump and
biconcave disc shape of erythrocytes). In the case of PKD, the erythrocytes are lacking in ATP due to
reduced pyruvate kinase enzyme function. As a result, the cells distort and swell, giving them a spherical
shape (spherocytes). The distorted erythrocytes either lyse or get prematurely destroyed by the
spleen and liver, leading to anemia. However, PKD individuals have a greater ability to release oxygen
into tissues as PKD influences increase in 2,3-disphosphoglycerate (2,3-DPG) (right shift in oxygen-
dissociation curve).
As the disease is not life-threatening in most cases (low severity), most individuals do not require
treatment. Blood transfusions may be carried out in cases of low erythrocyte count (which occurs only
in early childhood, periods when physiological stress is present – i.e. infection, pregnancy). Supplements
such as folic acid and B vitamins help to increase erythrocyte production and relieve symptoms. If
anemia is severe, splenectomy can be carried out to reduce erythrocyte destruction. However, in the
case of young children, it is delayed as long as possible in order to allow maturity of the immune system.
 |
| Splenectomy |
Prophylactic antibiotics and pneumococcal vaccine should also be administered to young patients post
splenectomy (refer to complications above).
Patients who have a family history of PKD and wish to start a family can undergo genetic counseling
in order to prevent their children from inheriting this disease as carriers of the defective gene can be
diagnosed by detecting decreased erythrocyte PKD activity.
So then, after all that has been said and done, what has PKD got to do with malaria - the disease that at one point was so highly prevalent in tropical and subtropical countries?
To answer that question, we must first start with malaria, which we all know is a type of disease caused by parasites (Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale, Plasmodium malariae and Plasmodium knowlesi have all been known to infect humans) that infects us by first replicating in certain types of mosquitoes (gets infected when it takes blood from an infected person) and then entering our body through mosquito bites. People down with malaria usually have high fevers, shaking chills and flu-like symptoms. It is indeed a serious illness as delay of prompt treatment can even cause kidney failure, seizures, mental confusion, coma and eventually, death.
Why is it such a cause of worry? Despite the fact that there are anti-malarial drugs available for consumption, there is currently no known malarial vaccine. This is due to the fact that the malaria parasite is able to constantly make changes to its surface and thereby evade the body's immune system which in turn makes it a challenge to produce a vaccine to these ever-changing surfaces.
However, studies show that PKD actually exerts a shield-like effect over malaria affected individuals. This is something amazing in itself as it is a natural defence against a serious illness.
To find out how exactly PKD reduces the effects of malaria, do refer to the scientific article on our blog.
References:
>> The New York Times, 2012. Pyruvate Kinase Deficiency. [online] Available at: <http://health.nytimes.com/health/guides/disease/pyruvate-kinase-deficiency/overview.html> [Accessed 12 December 2012].
>> Medscape Reference, 2011. Pyruvate Kinase Deficiency. [online] Available at: <http://emedicine.medscape.com/article/125096-overview> [Accessed 12 December 2012].
>> St. Edward’s University, 2012. Pyruvate Kinase Deficiency and Hemolytic Anemia. [online] Available at: <http://www.cs.stedwards.edu/chem/Chemistry/CHEM44/alarid/pyrkin.html#biochemistry> [Accessed 12 December 2012].
>> PubMed Health, 2012. Pyruvate Kinase Deficiency. [online] Available at: <http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0002177/> [Accessed 12 December 2012].
>> Homerton University Hospital, 2012. Pyruvate Kinase. [online] Available at: <http://www.homerton.nhs.uk/our-services/pathology/guide-to-laboratory-tests-and-directory/haematology-tests/pyruvate-kinase/> [Accessed 12 December 2012].
>> Office of Rare Diseases Research, 2011. Pyruvate Kinase Deficiency. [online] Available at: <http://rarediseases.info.nih.gov/GARD/QnASelected.aspx?diseaseID=7514> [Accessed 12 December 2012].
>> Patient.co.uk, 2011. Pyruvate Kinase Deficiency. [online] Available at: <http://www.patient.co.uk/doctor/Pyruvate-Kinase-Deficiency.htm> [Accessed 12 December 2012].
>> Centers for Disease Control and Prevention, 2012. Malaria. [online] Available at: <http://www.cdc.gov/malaria/about/faqs.html> [Accessed 20 January 2013]
Images obtained from:
>> http://ghr.nlm.nih.gov/dynamicImages/chromomap/PKLR.jpeg
>> http://www.vetmed.vt.edu/education/Curriculum/VM8304/vet%20pathology/CASES/CELLINJURY2/ SPHEROCYTOSIS.JPG
>> http://cdn.c.photoshelter.com/img-get/I0000AIEUK4DZsL8/s/600/600/85636DS.jpg
>> http://chemistry.berea.edu/~biochemistry/2010/cd/paper.html20_files/image002.jpg
