This is the second part of our series about the condition based on our patient booklet “Fast Facts for Patients and Supporters: Pyruvate Kinase Deficiency”, which is freely available online. This article details what causes pyruvate kinase deficiency and how it is diagnosed.
Causes of PKD
The production of pyruvate kinase is controlled by a gene called PKLR, which is found on the long (q) arm of chromosome 1 at position 22 (1q22).
How Is Pyruvate Kinase Deficiency Inherited?
Everyone inherits two copies of the PKLR gene, one from each of their parents. To inherit PK deficiency you have to receive two non-working copies of the PKLR gene. This is called an autosomal recessive genetic disease.
People who inherit only one non-working copy of the PKLR gene (from one parent) do not have symptoms of hemolysis or anemia but are known as carriers of PK deficiency.
The PKLR gene provides instructions to produce two types of pyruvate kinase, one found in red blood cells and one found in liver cells. The liver is able to compensate for non-working PKLR genes whereas the red blood cells are not.
PKLR Gene Mutations
Over 300 different mutations of the PKLR gene have been identified. Most people inherit a different PKLR mutation from each of their parents.
Many PKLR gene mutations are very rare, occurring only once; approximately 25% of people diagnosed with PK deficiency have a newly described genetic mutation.
If I Have Pyruvate Kinase Deficiency, Will My Children Have It too?
If your partner does not have or does not carry PK deficiency, your child will not have PK deficiency but will carry one non-working PKLR gene (inherited from you). So your child will be a carrier of the disease, but will not develop the disease.
PK deficiency is uncommon, so it is very unlikely that your partner will carry a non-working PKLR gene. However, if you have a child with someone who is from an area where PK deficiency is more common (for example, in the Amish community), then your partner could consider a genetic screening test to better understand the likelihood of having a child with PK deficiency.
Who Is Most at Risk of Inheriting Pyruvate Kinase Deficiency?
PK deficiency is equally common in men and women.
People with PK deficiency are from all over the world. Although most mutations are rare, some specific amino acid changes are found more commonly in particular populations such as the Amish community, the Romany population and in some Mediterranean countries. The frequency of PK deficiency is highest in the Amish community in Pennsylvania, USA, because of the founder effect. The founder effect is when a group of people has common ancestors and therefore less genetic variation. In the Amish community, PK deficiency can be traced to a single immigrant couple.
It is thought that carriers of PK deficiency may be more resistant to malaria infection and, therefore, carriers are more likely to be found in regions where malaria is common.
In studies looking at the most common PKLR mutations in white populations, PK deficiency has been estimated to affect 1 in 20 000 people. However, in clinical practice, PK deficiency appears to be even more rare than this estimate suggests. Doctors and researchers have been trying to understand why this is the case. It may be that PK deficiency is under-diagnosed (particularly in people with mild findings). In addition, many patients may be misdiagnosed with an alternative type of hemolytic anemia.
Diagnosis of PKD
PK deficiency is present from birth. However, some individuals are not diagnosed until late childhood or adulthood.
Signs and Symptoms
As discussed, in PK deficiency red blood cells break apart more easily (hemolysis), causing hemolytic anemia. As a result, you may look pale, feel tired and/or lack energy for exercise.
You may also have yellowing of the whites of your eyes (scleral icterus), yellowing of your skin (facial jaundice) and/or dark urine.
Some people with PK deficiency have a lot of symptoms; others have none, with PK deficiency being diagnosed on routine laboratory tests.
Blood Tests for Hemolytic Anemia
First, your doctor will take a blood sample to send for laboratory testing to see if you have hemolytic anemia.
Tests for Pyruvate Kinase Deficiency
Enzyme Activity Test
For the specific diagnosis of PK deficiency, you will need a further blood test to measure pyruvate kinase enzyme activity. Your doctor will take a blood sample to send to a specialized laboratory to ensure the accuracy of the test.
Most people with PK deficiency have 5–25% of the normal enzyme activity. Occasionally, even though you have PK deficiency, your test may show that you have a normal level of PK enzyme activity. If this is the case, your PK enzyme activity will be compared to that of other red blood cell enzymes (such as hexokinase or glucose-6-phosphate dehydrogenase), which will be higher in comparison.
Analysis of the PKLR gene is also used to screen for, or confirm, PK deficiency. Genetic testing is useful:
- if you receive frequent blood transfusions, as the transfused blood will make the enzyme activity test difficult to interpret
- to confirm the diagnosis if you have low or low-normal pyruvate kinase enzyme activity and a high suspicion for PK deficiency
- to test your parents, to confirm you inherited one non-working PKLR gene from each parent
- before the birth of a child, if you already have a child with PK deficiency.
Please check out the first post of our series here:
Information based on Fast Facts for Patients and Supporters: Pyruvate Kinase Deficiency (Karger, 2019).