Pruebas genéticas para la ELA
ALS is directly hereditary only in a small percentage of families. About 90% of patients with adult-onset ALS have no family history of ALS and present as an isolated case in their family. This is called sporadic ALS (SALS), and although there is likely a genetic predisposition involved, SALS is not directly inherited. Rarely, a person may initially appear to be affected with sporadic disease, but only because the family history isn't known or is limited. This can happen when an individual is adopted or if the individual's parents died at a young age. The remaining 10% of people with ALS have a family member with ALS, and this is referred to as familial ALS (FALS).
Currently the best tool to distinguish between SALS and FALS is the family history. A neurologist or genetic counselor will ask whether anyone else has ever been diagnosed with ALS, and if anyone else in the family had progressive walking or speech problems. If so, they will likely ask additional questions to see if the health problems were related to ALS or another cause. They will also inquire about the ages that family members passed away to see if any close relatives passed away at a young age, meaning that a long health history is not available. It's very common to have limited information on one's family, but most families can still be reassured as the majority of instances of ALS are not hereditary. Older relatives are often good sources of family history information, and medical records can often be obtained with the help of a hospital's medical release form.
To answer this question, it's helpful to review some basic information on genetics. Every cell in the human body contains genes. Genes have many functions, and act as an 'instruction manual' for our cells. Some genes contribute to traits like eye and hair color while other genes are responsible for making proteins that determine how our bodies circulate blood or send nerve signals to muscles. When a gene is disrupted by a change in its sequence called a mutation, the gene cannot function correctly.
Genes are packaged in chromosomes, and chromosomes are present in pairs. Our genes, therefore, are also present in pairs. For each chromosome pair, one is inherited from the mother and one is inherited from the father. We have 23 pairs of chromosomes, giving us a total of 46 chromosomes. The first 22 pairs are the autosomes, and both males and females share them in common. Only the 23rd pair differs between males and females - these are the sex chromosomes, and females typically have two Xs and males have an X and a Y.
There are several inheritance patterns, but the most common inheritance pattern for FALS is called autosomal dominant. Autosomal means that it is equally likely that a female or male would inherit the gene mutation for FALS because the gene is located on an autosome - a chromosome that both males and females share in common. Dominant refers to the fact that a person only needs one gene to have a mutation in a gene for FALS to have an increased risk for ALS. Someone who has FALS would have one copy of the gene with a mutation and one copy of the gene without a mutation. Therefore, a child born to someone who has FALS has a 50% chance to inherit the FALS gene mutation and conversely, a 50% chance to not inherit the FALS gene mutation. This 1 in 2, or 50% chance, comes from the fact that parents randomly pass on only one member of their gene pair, so that either the gene with the mutation will be passed on or the gene without the mutation will be passed on. Even though parents often feel responsible for their children's health, they have no control over which gene they pass on, just as their parent had no control which gene they passed onto their child. It is also important to remember that inheriting the gene for FALS in no way guarantees that a person will develop symptoms of ALS. Also, if a child does not inherit the gene mutation for ALS, they cannot pass it onto their children.
Yes, although genetic testing is limited. About 50% of families with FALS will have a mutation found in one of the genes known to be associated with ALS. The remaining 50% of families with FALS will have normal genetic testing results - presumably because they have mutations in genes we have not identified yet and therefore cannot test.
The most common genes currently known to be associated with FALS include SOD1, TDP-43, FUS and the more recently discovered C9ORF72 and UBQLN2. A neurologist familiar with FALS and a genetic counselor may decide to test affected family members for one or several of these genes based on that individual's neurological exam and specific family history.
Prenatal genetic testing technology for FALS mutations exist when there is a known mutation within the family. Patients and their families should discuss questions and concerns with their neurologist and genetic counselor for more information about this complex and personal matter.
For families that do not have a change in any of the currently known FALS genes, a normal genetic test is not informative. Unaffected family members cannot pursue presymptomatic testing to determine whether or not they carry the FALS mutation, because it is unidentified in their family. Although researchers are diligently looking for other genes, at this time there is no genetic testing to offer these families. Participation in ongoing research studies to identify new genetic factors is a way for families to help researchers identify more genes. For these reasons, the determination that an individual has FALS is typically based on family history rather than a genetic test.
No. Since the vast majority of patients do not have the hereditary type of ALS, a diagnosis of ALS is not determined by a genetic test. Instead, a neurologist makes the diagnosis after a review of a person's symptoms, a neurological exam, and results on nerve and muscle function tests. Clinically, FALS and SALS are basically identical.
Genetic testing is appropriate for anyone who has symptoms of ALS in addition to a family history of ALS, such as a parent, grandparent, aunt, uncle or sibling. Additionally, if one's family history is unknown or a parent passed away at a young age, testing may also be appropriate. However, only about 5% of all patients with ALS will have a genetic change. Those patients with ALS without a family history can also be offered genetic testing but it is extremely important that it is offered in the context of genetic counseling or discussion with a neurologist about the implication of finding a mutation, as a mutation would mean that what was thought to be SALS is actually FALS. This is a rare situation.
A positive test means that the genetic cause of FALS has been identified. A positive test does not change medical treatment at this time. Researchers have developed mouse models with similar genetic change so that they can better understand how changes in FALS genes can lead to the symptoms of ALS. Currently, new therapies are being tried on this animal model to slow or halt the progression of ALS. Although still in the distant future, gene therapy to correct the genetic change is also being researched. A positive test may or may not provide prognostic information, as particular mutations may affect the course of the disease. Even though the inheritance may already be established by the family history, an individual may feel furthered burdened by learning they carry a genetic change as concerns for children resurface. Others prefer to have this knowledge and may feel comforted that there is much research aimed specifically at ALS caused by changes in the FALS genes.
A negative test for an affected family member means only that the genetic cause of ALS has not been identified. However, this does not rule out familial ALS since there are still other unidentified genes that cause ALS in half of FALS families.
This situation is called presymptomatic testing. The decision to have presymptomatic genetic testing is highly personalized and often individuals in the same family will disagree whether to pursue it. However, in order for the test to be meaningful, a genetic change in a FALS gene needs to first be found in a family member affected with ALS. When a genetic change is not identified in a symptomatic person, presymptomatic genetic testing is not available for other family members, because the ALS is being caused by an unidentified gene, and therefore we cannot test for it.
Benefits of presymptomatic genetic testing in ALS are limited by the absence of preventative treatment and the inability to predict the age at which someone who is a gene carrier will get ALS or even that a gene carrier will definitely get ALS. Since both a negative or positive presymptomatic test result in a family with a known mutation can have a great emotional impact, genetic and psychological counseling is required before undergoing such testing. Individuals often consider how the information that they did or did not inherit the predisposing gene would affect their lives, who they would tell about the results, and how relationships may change depending on the results.
Individuals who learn they do not carry the family's genetic change often feel great relief, although they can sometimes wonder why they escaped while another family member did not. They may regret past decisions made based on the presumed at risk status, or find it hard to let go of that part of their identity. Learning that one does carry a predisposing gene is usually more difficult and that person may need ongoing professional support. Ambiguity is not entirely erased as the question may change from 'Do I carry the gene?' to 'When or will I get symptoms?' Commitment to friends and family may be strengthened. A genetic counselor can further discuss the issues involved in presymptomatic testing including insurance and employment discrimination concerns.
A blood sample is taken and sent to a specialized lab where the genetic material, or DNA, is removed. Special laboratory techniques allow the genes of interest to be replicated and then tested. One form of testing is running the sample on a gel to generate a series of bands. If a genetic change is present, the bands will be in a different location compared to a control sample, which is known not to have a genetic change in the gene. This method is called single strand conformation polymorphism - SSCP for short. Another method called sequencing may also be used to either initially test or confirm results. Sequencing is able to view the DNA on a finer scale by displaying the actual letters of the 'instruction book' so that changes can be seen.
This varies depending on the genes being tested and the laboratory doing the testing. On average, the test usually takes about two to three months. The cost varies as well, from about $300-500 up to $4,000 for a panel (multiple gene tests done at one time).