Anemia, Hereditary Nonspherocytic Hemolytic

Anemia, Hereditary Nonspherocytic Hemolytic

National Organization for Rare Disorders, Inc.

Important

It is possible that the main title of the report Anemia, Hereditary Nonspherocytic Hemolytic is not the name you expected. Please check the synonyms listing to find the alternate name(s) and disorder subdivision(s) covered by this report.

Synonyms

  • HNHA
  • NSA
  • NSHA
  • Congenital Nonspherocytic Hemolytic Anemia

Disorder Subdivisions

  • None

General Discussion

Hereditary nonspherocytic hemolytic anemia is a term used to describe a group of rare, genetically transmitted blood disorders characterized by the premature destruction of red blood cells (erythrocytes or RBCs). If the red blood cells cannot be replaced faster than they destroy themselves, anemia is the result.



In these disorders, the outside membrane of the cell is weakened, causing it to have an irregular, non-spherical shape and to burst (hemolyze) easily. These disorders are caused by, among other things, defects in the chemical processes involved in the breakdown of sugar molecules (glycolysis). Red blood cells depend on this process for energy and if an enzyme is defective in any one of the stages, the red blood cell cannot function properly and hemolysis, or the breakdown of the membrane that holds the cell together, takes place. The more common of the enzyme deficiencies that lead to HNSHA involve glucose-6-phosphate dehydrogenase (G6PD) deficiency, pyruvate kinase deficiency and hexokinase deficiency. There may be as many as 16 red blood cell enzyme abnormalities that may cause hereditary nonspherocytic hemolytic anemia. In addition, HNSHA may arise as the result of immune disorders, toxic chemicals and drugs, antiviral agents (eg, ribavirin), physical damage, and infections.

Symptoms

The symptoms of hereditary nonspherocytic hemolytic anemia may include moderate anemia (which may cause tiredness), recurrent yellow appearance to the skin (jaundice), and an abnormally large spleen (splenomegaly) and/or liver (hepatomegaly). These symptoms usually occur in childhood, but some infants are jaundiced at birth.



When the red blood cells (erythrocytes) of a newborn contain irregularly shaped bits of abnormal hemoglobin (Heinz bodies), a diagnosis of nonspherocytic hemolytic anemia can be made. In some cases of this disorder, a definite decrease in the amount of hemoglobin in red blood cells may occur.

Causes

When hereditary nonspherocytic hemolytic anemia is associated with defects in the membrane of red blood cells, or defects in a chemical step in the synthesis of hemoglobin from its component parts (porphyrin), or in the breakdown of sugars, the disorder is inherited as an autosomal recessive genetic trait.



Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated "p" and a long arm designated "q". Chromosomes are further sub-divided into many bands that are numbered. For example, the gene that is defective in the case of NHSA due to pyruvate kinase deficiency is located at "gene map locus 1q21." The notation refers to band 21 on the long arm of chromosome 1. The numbered bands specify the location of the thousands of genes that are present on each chromosome.



Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother.



Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.



All individuals carry a few abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.



Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy regardless of the sex of the resulting child.



X-linked recessive genetic disorders are conditions caused by an abnormal gene on the X chromosome. Females have two X chromosomes but one of the X chromosomes is "turned off" and all of the genes on that chromosome are inactivated. Females who have a disease gene present on one of their X chromosomes are carriers for that disorder. Carrier females usually do not display symptoms of the disorder because it is usually the X chromosome with the abnormal gene that is "turned off". A male has one X chromosome and if he inherits an X chromosome that contains a disease gene, he will develop the disease. Males with X-linked disorders pass the disease gene to all of their daughters, who will be carriers. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male offspring. Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease, and a 25% chance to have an unaffected son.



X-linked dominant disorders are caused by an abnormal gene on the X chromosome, but in these rare conditions, females with an abnormal gene are affected with the disease. Males with an abnormal gene are more severely affected than females, and many of these males do not survive. Hereditary NSHA that is associated with glucose-6 phosphate dehydrogenase deficiency is inherited as a X-linked dominant genetic trait with incomplete penetrance. Incomplete penetrance means that some individuals who inherit the gene for a dominant disorder will not be affected or be only mildly affected with the disorder.



Heterozygote is the term used to describe a person who has two different genes for a particular trait, one inherited form each parent. A person heterogygous for a genetic disease caused by a dominant gene will be affected with the disease. An individual heterozygous for a genetic disorder produced by a recessive gene will not usually be affected by the disease, or will have a milder form of it.



Some people exhibit a genetic predisposition towards HSNA, which means that a person may carry a gene for a disease but it may not be expressed unless something in the environment triggers the disease.



In the case of HSNA that occurs with glucose- 6-phosphate dehydrogenase deficiency, such diverse articles as fava beans, drugs such as some sulfonamides, antimalarial drugs, and phenacetin, can bring on hemolytic crises.

Affected Populations

Hereditary nonspherocytic hemolytic anemia is a rare blood disorder that affects more males than females. Males are more likely to have severe symptoms of this disorder, whereas females have milder symptoms or no symptoms.

Standard Therapies

Blood transfusions may occasionally be necessary for the treatment of hereditary nonspherocytic hemolytic anemia. Any drug that may cause the destruction of red blood cells (hemolytic precipitating agent) should be avoided. If an environmental trigger is identified, it should be avoided at almost any cost. If the need for transfusions becomes chronic, then iron chelation therapy (i.e., deferoxamine) may be necessary in some cases. While surgical removal of the spleen (splenectomy) is beneficial in the treatment of HSHA, it is of no benefit for people with HNSHA.



Genetic counseling will be of benefit for people with hereditary nonspherocytic hemolytic anemia and their families.

Investigational Therapies

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.



For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:



Tollfree: (800) 411-1222

TTY: (866) 411-1010

Email: prpl@cc.nih.gov



For information about clinical trials sponsored by private sources, contact:

www.centerwatch.com

References

TEXTBOOKS

Paglia DE. Enxymopathies. In: Hoffman R, Benz Jr EJ, Shattil SJ et al. Eds. Hematology: Basic Principles and Practice. 2nd ed. Churchill-Livingstone, Inc. New York, NY; 1995:656-664.



Hirono A, Kanno H, Miwa S, et al. Pyruvate Kinase Deficiency and Other Enzymopathies of the Erythrocyte. In: Scriver CR, Beaudet AL, Sly WS, et al. Eds. The Metabolic Molecular Basis of Inherited Disease. 8th ed. McGraw-Hill Companies. New York, NY; 2001:4637-52.



REVIEW ARTICLES

Schneider AS. Triosephosphate isomerase deficiency: historical perspectives and molecular aspects. Baillieres Best Pract Res Clin Haematol. 2000:13:119-40.



Vives i Corrons JL. Chronic non-spherocytic haemolytic anaemia due to congenital pyrimidine 5' nucleotidase deficiency: 25 years later. Baillieres Best Pract Res Clin Haematol. 2000:13:103-18.



Kugler W. Lakomek M. Glucose-6-phosphate isomerase deficiency. Baillieres Best Pract Res Clin Haematol. 2000:13:89-101.



Kanno H. Hexokinase: gene structure and mutations. Baillieres Best Pract Res Clin Haematol. 2000:13:83-88.



Zanella A, Bianchi P. Red cell pyruvate kinase deficiency: from genetics to clinical manifestations. Baillieres Best Pract Res Clin Haematol. 2000:13:57-81.



JOURNAL ARTICLES

Hilgard P, Gerken G. Liver cirrhosis as a consequence of iron overload caused by hereditary nonspherocytic hemolytic anemia. World J Gastroenterol. 2005;11:1241-44.



Hamilton JW, Jones FG, McMullin MF. Glucose-6-phospahate dehydrogenase Guadalajara:a case of chronic nonspherocytic hemolytic anemia responding to splenectomy and the role of splenectomy in this disorder. Hematology. 2004;9:307-09.



Valentini G, Chiarelli LR, Foran R, et al. Structure and function of human erythrocyte pyruvate kinase. Molecular basis of nonspherocytic hemolytic anemia. J Biol Chem. 2002;277:23807-814.



FROM THE INTERNET

McKusick VA, ed. Online Mendelian Inheritance In Man (OMIM). The Johns Hopkins University. Glucose-6-phosphate Dehydrogenase. Entry Number; 305900: Last Edit Date; 2/7/2005.



McKusick VA, ed. Online Mendelian Inheritance In Man (OMIM). The Johns Hopkins University. Pyruvate Kinase Deficiency of Erythrocyte. Entry Number; 266200: Last Edit Date; 1/21/2005.



McKusick VA, ed. Online Mendelian Inheritance IN Man (OMIM). The Johns Hopkins University. Hexokinase Deficiency Hemolytic Anemia. Entry Number; 235700: Last Edit Date; 11/1/1995.



McKusick VA, ed. Online Mendelian Inheritance In Man (OMIM). The Johns Hopkins University. Glucose-6-phosphate Isomerase. Entry Number; 172400: Last Edit Date; 1/7/2002.

Resources

March of Dimes Birth Defects Foundation

1275 Mamaroneck Avenue

White Plains, NY 10605

Tel: (914)997-4488

Fax: (914)997-4763

Tel: (888)663-4637

Email: Askus@marchofdimes.com

Internet: http://www.marchofdimes.com



NIH/National Heart, Lung and Blood Institute

P.O. Box 30105

Bethesda, MD 20892-0105

Tel: (301)592-8573

Fax: (301)251-1223

Email: nhlbiinfo@rover.nhlbi.nih.gov

Internet: http://www.nhlbi.nih.gov/



Genetic and Rare Diseases (GARD) Information Center

PO Box 8126

Gaithersburg, MD 20898-8126

Tel: (301)251-4925

Fax: (301)251-4911

Tel: (888)205-2311

TDD: (888)205-3223

Internet: http://rarediseases.info.nih.gov/GARD/



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