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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.
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.
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.
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.
Symptoms of the following disorders can be similar to those of hereditary nonspherocytic hemolytic anemia. Comparisons may be useful for a differential diagnosis:
Hereditary spherocytic hemolytic anemia (HSHA) is a rare inherited blood disorder characterized by the presence of sphere-shaped red blood cells. These cells have difficulty circulating through the spleen resulting in the premature destruction of red blood cells. The symptoms of hereditary spherocytic hemolytic anemia may be present at birth or not be apparent for years, and in many people the disease may be so mild that it is not diagnosed. Symptoms may include fatigue and/or a yellow (jaundice) appearance to the skin. Generally the spleen is enlarged resulting in abdominal discomfort. An infection is the most common trigger of an anemic crisis. Trauma or pregnancy may also cause an anemic crisis. The patient may experience fever, headache, loss of appetite, vomiting, leg sores, and/or general weakness. (For more information on this disorder, choose "Hereditary spherocytic hemolytic anemia" as your search term in the Rare Disease Database.)
Thalassemia major is a rare blood disorder characterized by a marked increase in F hemoglobin and a decrease in the production of certain oxygen carrying proteins in red blood cells. The symptoms of this disorder typically occur very suddenly in infancy or early childhood. These may include generalized weakness (malaise), an upset stomach (dyspepsia), and/or heart palpitations. Children may have a yellow appearance to their skin (jaundice), leg ulcers, and/or an abnormally enlarged liver (hepatomegaly) or spleen (splenomegaly). (For more information on this disorder, choose "thalassemia major" as your search term in the Rare Disease Database.)
Thalassemia minor is a relatively mild form of anemia that is typically present at birth. It is inherited as an autosomal recessive genetic trait. Constant fatigue may be the only symptom of this disorder. However, if anemia becomes severe, the spleen may become slightly enlarged (splenomegaly) and there may be a pale color to the skin. Occasionally a child with Thalassemia minor may complain of pain in the left upper side of the abdomen. This disorder may be aggravated by stress, infections, malnutrition, and/or pregnancy. (For more information on this disorder, choose "Thalassemia Minor" as your search term in the Rare Disease Database.)
Other types of anemias include: aplastic anemia, megaloblastic anemia, warm antibody hemolytic anemia, cold antibody hemolytic anemia, acquired autoimmune hemolytic anemia, pernicious anemia, folic acid deficiency anemia, Blackfan-Diamond anemia, sickle cell anemia, and Fanconi's anemia. (For information on other types of anemias, use the name of the specific anemia as your search term in the Rare Disease Database.)
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.
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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.
Report last updated: 2007/07/23 00:00:00 GMT+0