Genetic Testing for ALS

ALS is directly hereditary in 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).

The ALS Association has made significant investments into identifying the underlying genetic causes of the disease. This support led to the landmark discoveries of the SOD1 gene mutations in 1993 and C9orf72 in 2011, the most common gene associated with ALS.

Since then, multiple large, global "big data" initiatives supported by the Association, such as the New York Genome Center and Project MinE, have undertaken large sequencing and gene identification efforts, leading to the discovery of additional genes that are thought to cause or increase the risk of developing ALS.

Of the more than 40 genes that have been identified, four - C9orf72, SOD1, TARDBP and FUS - account for the disease in up to 70% of people with familial ALS, at least in European populations. Below you will find more information about these four genes, as well as a list of other genes that have been linked to ALS.

C9ORF72
Mutations in this gene are the most common genetic cause of ALS, accounting for between 25% and 40% of familial ALS cases (depending on the population) as well as approximately 6% of sporadic ALS cases. This gene also causes approximately 25% of another neurodegenerative disease, called frontotemporal dementia (FTD). Some people with the mutation only develop ALS, some people only develop FTD, and some people develop both diseases. How the same gene mutation can cause two diseases is not yet fully understood (although other genetic factors may play a role), and it is not yet possible to predict which will develop, or whether both will develop, in a person carrying the mutation.

The healthy function of the C9orf72 gene is still being studied, so its name refers to the position of the gene "open reading frame" on chromosome 9. The mutation in the C9orf72 gene that causes ALS is a hexanucleotide repeat expansion, meaning a six-letter repeated segment (GGGGCC) within the gene is expanded. The healthy version of the gene has about six of these hexanucleotide repeat units, while the disease-causing mutation has hundreds to thousands of them. Researchers are actively trying to understand all the effects of the C9orf72 expansion in hopes of designing treatments to mitigate them.

SOD1
Mutations in the SOD1 gene are the second-most common cause of familial ALS, found in about 10-20% of cases, as well as 1-2% of sporadic ALS cases. Researchers have identified more than 150 different mutations in the SOD1 gene linked to ALS. Each of these mutations influences the disease in different ways, most notably how quickly the disease progresses. In North America, the most common SOD1 mutation is called A4V, which is a shorthand way to say that the mutation changes the fourth amino acid in the protein from an alanine to a valine. The A4V mutation often causes rapid disease progression, although there are exceptions.

Healthy SOD1 proteins attach to copper and zinc molecules to break down toxic byproducts produced during normal cell processes. These byproducts must be broken down regularly so they don't damage cells. SOD1 mutations are thought to cause the protein to misfold and clump up (aggregate) within motor neurons and astrocytes, the types of cells involved in ALS development and progression. These clumps (aggregates) may interfere with healthy cell functions or may cause other necessary proteins to misfold and lose their function. Researchers are looking for ways to prevent this aggregation.

TARDBP
The TARDBP gene contains instructions for making a protein called transactive response DNA binding protein 43 kDa (TDP-43). This protein plays an important role in keeping cells healthy. It attaches (binds) to DNA in the nucleus and regulates an activity called transcription, which is the first step cells use to create proteins from the instructions found in genes. TDP-43 is also involved in processing mRNA. By cutting and rearranging mRNA molecules in different ways, the TDP-43 protein controls the production of different versions of certain proteins.

Mutations in the TARDBP gene, which have been linked to about 4% of familial ALS and about 1% of sporadic ALS cases, cause TDP-43 to mislocalize in motor neurons, away from the nucleus where it is normally found and into the cytoplasm (the material surrounding the nucleus). In the cytoplasm, it aggregates into clumps that can be seen under the microscope. These clumps not only interfere with the important normal function of TDP-43 but also block other normal cellular processes. As more and more clumps form, they become toxic and eventually kill the cell.

Interestingly, clumps of abnormal TDP-43 can be found in almost all cases of ALS, even those without a TARDBP mutation, suggesting that TDP-43 may play a pivotal role in many forms of ALS.

FUS
The FUS gene provides instructions for making a protein called fused in sarcoma (FUS) that is found within the cell nucleus in most tissues. Like TDP-43, the FUS protein is involved in many steps of protein production. In fact, FUS and TDP-43 may interact as part of their normal function.

Mutations in the FUS gene are responsible for about 5% of familial ALS and about 1% of sporadic ALS cases. These mutations cause the FUS protein to mislocalize away from the nucleus and into the cytoplasm where they can aggregate into clumps and cause neuron dysfunction. Researchers are looking for ways to prevent this aggregation as a potential ALS treatment.

Other ALS-Linked Genes 
With the accelerating advancement of technology, an ever-increasing number of new ALS-linked genes are being discovered each year. Below is a list of many (although not all) of the genes researchers have identified. The certainty that any specific gene is linked to ALS varies depending on the techniques used to identify the gene, the number of other studies that support its link to ALS, and whether the mutation's biological effects are known. Genetic risk factors may also be different for different ethnic populations.

ACSL5
ALS2
ANG
ANXA11
ATXN2
ATXN3
C21orf2
CAV1
CCNF
CHCHD10
CHMP2B
CHRNA3
DAO

DCTN1
DNAJC7
ELP3
ERBB4
EWSR1
FIG4
GLE1
GLT8D1
hnRNPA1
hnRNPA2B1
KANK1
KIF5A
LGALSL

MATR3
MOBP
NEFH
NEK1
NIPA1
OPTN
PARK9
PFN1
PON1,2,3
PRPH
SARM1
SCFD1
SETX

SIGMAR1
SPG11
SPTLC1
SQSTM1
TAF15
TBK1
TIA1
TUBA4A
UBQLN2
VAPB
VCP
WDR7