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Table of Contents > Genomics > Autosomal recessive disorders Print

Autosomal recessive disorders

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Related terms
Background
Methods
Research
Implications
Limitations
Safety
Future research
Author information
Bibliography

Related Terms
  • Amniocentesis, bleeding, chorionic villus sampling, DNA, DNA sequencing, Duchenne muscular dystrophy, Fabry disease, hemophilia, inherited genetic disease, muscle degeneration, PCR, polymerase chain reaction, recessive, sex chromosome, X chromosome.

Background
  • An X-linked recessive disorder is an inherited genetic disease caused by a mutation or error in the DNA (deoxyribonucleic acid) on the X chromosome. DNA is located in a compartment of the cell called the nucleus and is packaged in structures called chromosomes. In addition to DNA, chromosomes also contain proteins, such as histones, which help package the DNA in an orderly way. Human cells contain a total of 46 chromosomes (22 pairs of autosomes and one pair of sex chromosomes). Females have two copies of the X chromosome, while males have one X and one Y chromosome. Each chromosome contains hundreds of genes, each of which contain the instructions for making proteins in the body.
  • Individuals have two copies of most genes, one inherited from the father and one from the mother. In a recessive genetic disorder, both copies of a certain gene need to be defective for the condition to appear.
  • For an X-linked recessive disorder to affect a female, the X chromosomes from both parents must carry a certain genetic mutation. If a female receives one mutant and one normal X chromosome, the normal copy is usually able to compensate for the mutant copy. Because males have only one X chromosome, however, only one X-linked genetic mutation needs to be inherited for a male to be affected with an X-linked recessive disorder. Therefore, X-linked recessive disorders are more common in males than in females.
  • Duchenne muscular dystrophy (DMD) is a disease in which patients experience a progressive degeneration of muscle function. DMD is an X-linked recessive disorder caused by mutations in the gene that provides instructions for making dystrophin, a protein that helps maintain the structure and function of muscle cells. Patients with DMD experience a progressive degeneration of muscle function starting during infancy or early childhood. The loss of muscle function usually starts in the pelvis and the legs, but eventually spreads to all parts of the body. Patients with DMD first lose the ability to walk, and eventually lose the ability to move other parts of their body.
  • Because males inherit an X chromosome from their mother and a Y chromosome from their father, males can inherit an X-linked recessive disorder only from their mother. A male has a 100% chance of inheriting a mutant X chromosome and being at risk for developing a recessive X-linked disorder if his mother has a recessive X-linked disorder. However, if a mother is a carrier for an X-linked recessive disorder (meaning she has one mutant X chromosome and one normal X chromosome), then a male son has a 50% chance of inheriting a mutant X chromosome and being at risk for developing the disorder.
  • Because a female inherits one X chromosome from her mother and one X chromosome from her father, she would need to have a father who is affected with the X-linked recessive disorder to develop the disease. If a female has an affected father and an affected mother, there is a 100% chance she will inherit two mutant X chromosomes and be at risk for developing the disorder. If a female has an affected father and a mother who is a carrier for an X-linked recessive disorder, however, she will have a 50% risk of inheriting two mutant X chromosomes and of being at risk for developing the disease. If a female does not have an affected father and mother who is neither affected nor a carrier, she would be a carrier for the disease but would not develop the disease.
  • Many diseases are known to follow an X-linked recessive pattern of inheritance. Two examples of X-linked recessive diseases are hemophilia and Duchenne muscular dystrophy. Hemophilia is a bleeding disorder that affects the ability of blood to clot. It is an X-linked recessive disorder caused by mutations in genes that make clotting factor proteins. Blood clots normally form after injury to the skin and allow the skin to heal normally. In patients with hemophilia, blood clots don't form properly, which leads to bleeding that can range from mild to severe.

Methods
  • Classification: X-linked recessive disorders may be recognized based on their pattern of inheritance. X-linked recessive disorders affect males much more frequently than females and they cannot be transmitted from a father to a son. By examining families with a history of a disease and observing the pattern through which the disease is inherited, researchers or doctors may be able to classify a specific disease as an X-linked disorder.
  • Identification of mutation: The X chromosome contains hundreds of genes, and different X-linked disorders are caused by mutations in different genes. For some X-linked disorders, researchers have already identified the underlying genetic mutation on the X chromosome. To find a causative mutation for a particular X-linked disorder, researchers may perform a detailed comparison between X chromosomes from people with the disorder and those from healthy individuals. By looking for similar features in a DNA sequence (the order of chemical bases in DNA) that appear among the people with the disease but not among the healthy individuals, researchers may be able to determine which region of the X chromosome is mutated in the affected people and is likely responsible for causing the disease. Once a disease-causing mutation is identified, however, researchers may need to perform a variety of additional experiments in the laboratory to determine how that mutation causes a disease. Additional experiments may involve deactivating the gene in cells or in model organisms or identifying other proteins that interact with the protein made by the gene of interest.
  • Patient diagnosis: Once a causative mutation for an X-linked disease is identified, doctors may perform genetic testing to look for that mutation in patients to help diagnose a disease. Commonly, genetic testing is performed by removing a small amount of a patient's blood and extracting the DNA. To check for mutations in the DNA, a technique called polymerase chain reaction (PCR) may be used. PCR allows a researcher to generate many copies of a specific DNA sequence in order to study it. After DNA is amplified, or copied, using PCR, researchers may sequence the DNA to check for the mutation.
  • If there is a family history of disease, parents may also choose to perform prenatal genetic screening on a developing fetus. This testing may be performed through amniocentesis, in which the amniotic fluid surrounding the fetus is sampled through a needle inserted into the mother's abdomen. Chorionic villus sampling (CVS) is another type of prenatal diagnosis that can detect genetic problems in a fetus. Samples are taken from the chorionic villus, or placental tissue. Any prenatal test carries a risk of miscarriage, because these tests are invasive procedures that may disturb or damage the fetus. Consent is needed to perform prenatal testing.

Research
  • A number of inherited genetic diseases caused by recessive X-linked mutations have been identified. In some cases, researchers have been able to determine which gene on the X chromosome is mutated in a particular disease, and they have used this information to better understand how the mutation causes the disease.
  • Hemophilia: Hemophilia is an X-linked recessive disorder that affects the ability of blood to clot. Blood clots normally form after injury to the skin and are part of the normal healing process. In patients with hemophilia, blood clots don't form properly, which leads to bleeding that can range from mild to severe.
  • Hemophilia is caused by defects, or mutations, in genes that make proteins called clotting factors. These proteins function in coagulation, a step in the clotting process in which a protein net, made from a protein involved in blood clotting called fibrin, is formed around torn blood vessels to stop the bleeding. These clotting factors help cells in the blood called platelets stick together at the site of an injury.
  • Patients with hemophilia have mutations in two genes on the X chromosome, F8 and F9, which contain instructions for making clotting-factor proteins. Mutations in these genes may result in reduced levels of clotting factors or may completely eliminate clotting factor activity. In either case, blood clots do not form properly in patients with hemophilia.
  • Duchenne muscular dystrophy: Duchenne muscular dystrophy (DMD) is an X-linked recessive disorder that affects muscle function. Patients with DMD experience a progressive degeneration of muscle function starting in infancy or in early childhood. The loss of muscle function usually starts in the pelvis and the legs but eventually spreads to all parts of the body. Patients with DMD first lose the ability to walk and eventually lose the ability to move other parts of their bodies.
  • DMD is caused by a defect, or mutation, in the DMD gene, which provides the instructions for making a protein called dystrophin. The mutation prevents the full-length protein from being produced. Dystrophin normally helps maintain the structure and function of muscle cells, but in individuals with DMD, it is generally absent and therefore cannot carry out its normal function. Although the reasons are still not clearly understood, muscle cells lacking dystrophin eventually die causing muscles to atrophy, or wither.

Implications
  • Diagnose diseases: When a specific causative genetic mutation for an X-linked recessive disorder is known, genetic testing for that mutation can be used to diagnose the disease in patients. Genetic testing is most often used when patients have a family history of a disease or to confirm a diagnosis.
  • Fight diseases: The identification of mutations responsible for causing X-linked recessive disorders may help researchers fight disease. This is because mutations may cause certain genes to malfunction or be produced at reduced or increased levels. Identifying these abnormalities in gene function or levels may help researchers better understand how a disease is caused. This information may in turn help develop drugs to fight disease. For example, researchers have developed a drug to help treat Fabry disease, an X-linked recessive condition. Fabry disease is caused by defects in an enzyme called alpha galactosidase A, and researchers have developed a therapy in which patients are given an enzyme to help carry out the functions of the defective galactosidase A in patients.

Limitations
  • Not applicable.

Safety




Future research
  • Even if a disease is known to follow an X-linked recessive pattern, additional work may be needed to understand the disease. For example, researchers are still searching for the specific gene or genes that are mutated in some X-linked recessive disorders. Also, for X-linked recessive disorders in which the causative genetic mutation is known, researchers may need to perform additional experiments to better understand how that mutation actually causes a disease. When a specific causative genetic mutation has been identified, it may help researchers develop therapies or drugs that target a particular gene or treatments that replace the function of a defective gene.

Author information
  • This information has been edited and peer-reviewed by contributors to the Natural Standard Research Collaboration (www.naturalstandard.com).

Bibliography
  1. Ashton EJ, Yau SC, Deans ZC, et al. Simultaneous mutation scanning for gross deletions, duplications and point mutations in the DMD gene. Eur J Hum Genet. 2008 Jan;16(1):53-61.
  2. Casaña P, Cabrera N, Cid AR, et al. Severe and moderate hemophilia A: identification of 38 new genetic alterations. Haematologica. 2008 Apr 9.
  3. Castaldo G, D'Argenio V, Nardiello P, et al. Haemophilia A: molecular insights. Clin Chem Lab Med. 2007;45(4):450-61.
  4. Children's Hospital Boston. .
  5. Genetics Home Reference. .
  6. Maheshwari M, Vijaya R, Kabra M, et al. Prenatal diagnosis of Duchenne muscular dystrophy. Natl Med J India. 2000 May-Jun;13(3):129-31.
  7. National Library of Medicine. .
  8. Natural Standard: The Authority on Integrative Medicine. .
  9. Rossetti LC, Radic CP, Larripa IB, et al. Genotyping the hemophilia inversion hotspot by use of inverse PCR. Clin Chem. 2005 Jul;51(7):1154-8.

Copyright © 2011 Natural Standard (www.naturalstandard.com)


The information in this monograph is intended for informational purposes only, and is meant to help users better understand health concerns. Information is based on review of scientific research data, historical practice patterns, and clinical experience. This information should not be interpreted as specific medical advice. Users should consult with a qualified healthcare provider for specific questions regarding therapies, diagnosis and/or health conditions, prior to making therapeutic decisions.

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