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Paroxysmal nocturnal hemoglobinuria

Reviewed May 2007

What is paroxysmal nocturnal hemoglobinuria?

Paroxysmal nocturnal hemoglobinuria is an acquired disorder that leads to the premature death and impaired production of blood cells. The disorder affects red blood cells (erythrocytes), which carry oxygen; white blood cells (leukocytes), which protect the body from infection; and platelets (thrombocytes), which are involved in blood clotting. Paroxysmal nocturnal hemoglobinuria affects both sexes equally, and can occur at any age, although it is most often diagnosed in young adulthood.

People with paroxysmal nocturnal hemoglobinuria have sudden, recurring episodes of symptoms (paroxysmal symptoms), which may be triggered by stresses on the body, such as infections or physical exertion. During these episodes, red blood cells are prematurely destroyed (hemolysis). Affected individuals may pass dark-colored urine due to the presence of hemoglobin, the oxygen-carrying protein in blood. The abnormal presence of hemoglobin in the urine is called hemoglobinuria. In many, but not all cases, hemoglobinuria is most noticeable in the morning, upon passing urine that has accumulated in the bladder during the night (nocturnal).

The premature destruction of red blood cells results in a deficiency of these cells in the blood (hemolytic anemia), which can cause signs and symptoms such as fatigue, weakness, abnormally pale skin (pallor), shortness of breath, and an increased heart rate. People with paroxysmal nocturnal hemoglobinuria may also be prone to infections due to a deficiency of white blood cells.

Abnormal platelets associated with paroxysmal nocturnal hemoglobinuria can cause problems in the blood clotting process. As a result, people with this disorder may experience abnormal blood clotting (thrombosis), especially in large abdominal veins; or, less often, episodes of severe bleeding (hemorrhage).

Individuals with paroxysmal nocturnal hemoglobinuria are at increased risk of developing cancer in blood-forming cells (leukemia).

In some cases, people who have been treated for another blood disease called aplastic anemia may develop paroxysmal nocturnal hemoglobinuria.

How common is paroxysmal nocturnal hemoglobinuria?

Paroxysmal nocturnal hemoglobinuria is a rare disorder, estimated to affect between 1 and 5 per million people.

What genes are related to paroxysmal nocturnal hemoglobinuria?

Mutations in the PIGA gene cause paroxysmal nocturnal hemoglobinuria.

The PIGA gene provides instructions for making a protein called phosphatidylinositol glycan class A. This protein takes part in a series of steps that produce a molecule called GPI anchor. GPI anchor attaches many different proteins to the cell membrane, thereby ensuring that these proteins are available when needed at the surface of the cell.

Some gene mutations are acquired during a person's lifetime and are present only in certain cells. These changes, which are called somatic mutations, are not inherited. In people with paroxysmal nocturnal hemoglobinuria, somatic mutations of the PIGA gene occur in blood-forming cells called hematopoietic stem cells, which are found mainly in the bone marrow. These mutations result in the production of abnormal blood cells. As the abnormal hematopoietic stem cells multiply, increasing numbers of abnormal blood cells are formed, alongside normal blood cells produced by normal hematopoietic stem cells.

The premature destruction of red blood cells seen in paroxysmal nocturnal hemoglobinuria is caused by a component of the immune system called complement. Complement consists of a group of proteins that work together to destroy foreign invaders such as bacteria and viruses. To protect the individual's own cells from being destroyed, this process is tightly controlled by complement-regulating proteins. Complement-regulating proteins normally protect red blood cells from destruction by complement. In people with paroxysmal nocturnal hemoglobinuria, however, abnormal red blood cells are missing two important complement-regulating proteins that need the GPI anchor protein to attach them to the cell membrane. These red blood cells are prematurely destroyed, leading to hemolytic anemia.

Research suggests that certain abnormal white blood cells that are also part of the immune system may mistakenly attack normal blood-forming cells, in a malfunction called an autoimmune process. In addition, abnormal hematopoietic stem cells in people with paroxysmal nocturnal hemoglobinuria may be less susceptible than normal cells to a process called apoptosis, which causes cells to self-destruct when they are damaged or unneeded. These features of the disorder may increase the proportion of abnormal blood cells in the body. The proportion of abnormal blood cells affects the severity of the signs and symptoms of paroxysmal nocturnal hemoglobinuria, including the risk of hemoglobinuria and thrombosis.

Related Gene(s)

Changes in this gene are associated with paroxysmal nocturnal hemoglobinuria.

  • PIGA

How do people inherit paroxysmal nocturnal hemoglobinuria?

This condition is acquired, rather than inherited. It results from new mutations in the PIGA gene, and generally occurs in people with no previous history of the disorder in their family. The condition is not passed down to children of affected individuals.

Where can I find information about diagnosis or management of paroxysmal nocturnal hemoglobinuria?

These resources address the diagnosis or management of paroxysmal nocturnal hemoglobinuria and may include treatment providers.

  • Duke University School of Medicine: Hemostasis & Thrombosis Center (http://htc.medicine.duke.edu/)
  • Genetic Testing Registry: Paroxysmal nocturnal hemoglobinuria (http://www.ncbi.nlm.nih.gov/gtr/conditions/C0024790)
  • MedlinePlus Encyclopedia: Paroxysmal nocturnal hemoglobinuria (PNH) (http://www.nlm.nih.gov/medlineplus/ency/article/000534.htm)
  • Memorial Sloan-Kettering Cancer Center (http://www.mskcc.org/cancer-care/adult/rare-blood-disorders/diagnosis-treatment-other-rare-blood-disorders)

You might also find information on the diagnosis or management of paroxysmal nocturnal hemoglobinuria in Educational resources (http://www.ghr.nlm.nih.gov/condition/paroxysmal-nocturnal-hemoglobinuria/show/Educational+resources) and Patient support (http://www.ghr.nlm.nih.gov/condition/paroxysmal-nocturnal-hemoglobinuria/show/Patient+support).

General information about the diagnosis (http://ghr.nlm.nih.gov/handbook/consult/diagnosis) and management (http://ghr.nlm.nih.gov/handbook/consult/treatment) of genetic conditions is available in the Handbook. Read more about genetic testing (http://ghr.nlm.nih.gov/handbook/testing), particularly the difference between clinical tests and research tests (http://ghr.nlm.nih.gov/handbook/testing/researchtesting).

To locate a healthcare provider, see How can I find a genetics professional in my area? (http://ghr.nlm.nih.gov/handbook/consult/findingprofessional) in the Handbook.

Where can I find additional information about paroxysmal nocturnal hemoglobinuria?

You may find the following resources about paroxysmal nocturnal hemoglobinuria helpful. These materials are written for the general public.

You may also be interested in these resources, which are designed for healthcare professionals and researchers.

What other names do people use for paroxysmal nocturnal hemoglobinuria?

  • Hemoglobinuria, Paroxysmal
  • Marchiafava-Micheli Syndrome

For more information about naming genetic conditions, see the Genetics Home Reference Condition Naming Guidelines (http://ghr.nlm.nih.gov/ConditionNameGuide) and How are genetic conditions and genes named? (http://ghr.nlm.nih.gov/handbook/mutationsanddisorders/naming) in the Handbook.

What if I still have specific questions about paroxysmal nocturnal hemoglobinuria?

Ask the Genetic and Rare Diseases Information Center (http://rarediseases.info.nih.gov/GARD/).

What glossary definitions help with understanding paroxysmal nocturnal hemoglobinuria?

anemia ; aplastic anemia ; apoptosis ; autoimmune ; bacteria ; blood clotting ; bone marrow ; cancer ; cell ; cell membrane ; class ; clotting ; deficiency ; gene ; glycan ; hematopoietic ; hemoglobin ; hemoglobinuria ; hemolysis ; hemolytic anemia ; hemorrhage ; immune system ; infection ; inherited ; leukemia ; molecule ; nocturnal ; oxygen ; pallor ; platelets ; protein ; stem cells ; syndrome ; thrombocytes ; thrombosis ; veins ; white blood cells

You may find definitions for these and many other terms in the Genetics Home Reference Glossary (http://www.ghr.nlm.nih.gov/glossary).

References

  • Brodsky RA, Hu R. PIG-A mutations in paroxysmal nocturnal hemoglobinuria and in normal hematopoiesis. Leuk Lymphoma. 2006 Jul;47(7):1215-21. Review. (http://www.ncbi.nlm.nih.gov/pubmed/16923549?dopt=Abstract)
  • Grünewald M, Grünewald A, Schmid A, Schöpflin C, Schauer S, Griesshammer M, Koksch M. The platelet function defect of paroxysmal nocturnal haemoglobinuria. Platelets. 2004 May;15(3):145-54. (http://www.ncbi.nlm.nih.gov/pubmed/15203716?dopt=Abstract)
  • Inoue N, Izui-Sarumaru T, Murakami Y, Endo Y, Nishimura J, Kurokawa K, Kuwayama M, Shime H, Machii T, Kanakura Y, Meyers G, Wittwer C, Chen Z, Babcock W, Frei-Lahr D, Parker CJ, Kinoshita T. Molecular basis of clonal expansion of hematopoiesis in 2 patients with paroxysmal nocturnal hemoglobinuria (PNH). Blood. 2006 Dec 15;108(13):4232-6. Epub 2006 Aug 29. (http://www.ncbi.nlm.nih.gov/pubmed/16940417?dopt=Abstract)
  • Luzzatto L, Gianfaldoni G. Recent advances in biological and clinical aspects of paroxysmal nocturnal hemoglobinuria. Int J Hematol. 2006 Aug;84(2):104-12. Review. (http://www.ncbi.nlm.nih.gov/pubmed/16926130?dopt=Abstract)
  • Luzzatto L. Paroxysmal nocturnal hemoglobinuria: an acquired X-linked genetic disease with somatic-cell mosaicism. Curr Opin Genet Dev. 2006 Jun;16(3):317-22. Epub 2006 May 2. Review. (http://www.ncbi.nlm.nih.gov/pubmed/16650759?dopt=Abstract)
  • Mortazavi Y, Merk B, McIntosh J, Marsh JC, Schrezenmeier H, Rutherford TR; BIOMED II Pathophysiology and Treatment of Aplastic Anaemia Study Group. The spectrum of PIG-A gene mutations in aplastic anemia/paroxysmal nocturnal hemoglobinuria (AA/PNH): a high incidence of multiple mutations and evidence of a mutational hot spot. Blood. 2003 Apr 1;101(7):2833-41. Epub 2002 Nov 7. (http://www.ncbi.nlm.nih.gov/pubmed/12424196?dopt=Abstract)
  • OMIM: PHOSPHATIDYLINOSITOL GLYCAN, CLASS A (http://omim.org/entry/311770)
  • Rosti V. The molecular basis of paroxysmal nocturnal hemoglobinuria. Haematologica. 2000 Jan;85(1):82-7. Review. (http://www.ncbi.nlm.nih.gov/pubmed/10629597?dopt=Abstract)
  • Shichishima T, Noji H. Heterogeneity in the molecular pathogenesis of paroxysmal nocturnal hemoglobinuria (PNH) syndromes and expansion mechanism of a PNH clone. Int J Hematol. 2006 Aug;84(2):97-103. Review. (http://www.ncbi.nlm.nih.gov/pubmed/16926129?dopt=Abstract)
  • Tiu R, Maciejewski J. Immune pathogenesis of paroxysmal nocturnal hemoglobinuria. Int J Hematol. 2006 Aug;84(2):113-7. Review. (http://www.ncbi.nlm.nih.gov/pubmed/16926131?dopt=Abstract)

 

The resources on this site should not be used as a substitute for professional medical care or advice. Users seeking information about a personal genetic disease, syndrome, or condition should consult with a qualified healthcare professional. See How can I find a genetics professional in my area? (http://ghr.nlm.nih.gov/handbook/consult/findingprofessional) in the Handbook.

 
Reviewed: May 2007
Published: August 25, 2014