What is pyruvate kinase deficiency?

Pyruvate Kinase Deficiency is an inherited disease characterized by the rapid breakdown of red blood cells due to a deficiency of a key enzyme called pyruvate kinase. This enzyme is the most common enzyme deficiency affecting the glycolytic pathway used by red blood cells to generate energy. Lacking energy, red blood cells break down and die. The spleen destroys the broken red blood cells, further eliminating them from circulation.

Red blood cells are responsible for circulating oxygen in the body, so when red blood cells break down faster than the body can replace them, this causes a condition called hemolytic anemia. Healthy red blood cells live approximately 120 days (about 4 months), whereas the red blood cells of people affected with PK deficiency last roughly a few weeks.

What causes Pyruvate Kinase Deficiency (PK deficiency)?

The PKLR gene is active in the liver and red blood cells, where it provides instructions for producing the enzyme pyruvate kinase, which helps break down glucose to energy cells can use, called ATP. People with PK deficiency have at least two pathogenic variants, one on each copy, of the PKLR gene on chromosome 1. More than 300 unique mutations in the PKLR gene have been reported; most are very rare. About 25% of patients diagnosed with PK deficiency appear to have a previously unrecorded mutation; however, a few mutations are recorded more frequently. The heterogeneity of these causative mutations is thought to contribute to the variability in patient symptoms.

What are the symptoms of PK deficiency?

The symptoms of PK deficiency are variable but manifest primarily as chronic anemia.

fatigue
tiredness
shortness of breath
lethargy
headache
brain fog
problems with concentration
bone pain

While anemia decreases people’s quality of life, the serious, long-term impacts of iron overload are life-threatening. Monitoring for iron overload is indicated in PK deficiency at all ages. Too much iron in the body is toxic and can be stored:

in the heart leading to arrythmia
in the liver, leading to cirrhosis, enlargement, or liver cancer
in the endocrine organs, leading to hormone-related problems like diabetes, thyroid disease, and delayed puberty
in the joints leading to arthritis

Other symptoms of PK deficiency include:

pale skin
jaundice of the skin and eyes
gallstones
enlarged spleen
leg ulcers
osteopenia or osteoporosis
poor appetite
pulmonary hypertension
thrombosis

How is PK deficiency diagnosed?

The rarity of PK deficiency and wide variability of symptoms can make it difficult to diagnose, resulting in misdiagnosis and underdiagnosis. Without the right diagnosis, people with PK deficiency can’t get the care they need.

PK deficiency can be diagnosed through laboratory testing by demonstrating a decrease in PK enzyme activity in a blood sample. It can also be detected by genetic testing by identifying one or more changes in the PKLR gene. It is recommended to confirm the diagnosis of PK deficiency initially made with PK enzyme activity methods using PKLR genetic testing. Enzyme activity testing is recommended for confirmation in people diagnosed with PKD by gene testing without two known disease-causing mutations. This happens sometimes in non-genetic instances of PK deficiency (or “secondary PK deficiency”) or when changes in the PKLR gene are not found on testing.

How is PK deficiency treated?