Familial ALS

Last updated March 13, 2023, by Marisa Wexler, MS
Fact-checked by Ines Martins, PhD

Amyotrophic lateral sclerosis (ALS), also called Lou Gehrig’s disease, is a progressive neurodegenerative disorder that runs in families in about 10% of cases. When more than one person in the same biological family is affected by the disease, it is referred to as familial ALS.

This differs from cases in which the disease occurs absent any family history, basically randomly, when it’s then classified as sporadic ALS.

Both types are marked by the progressive loss of motor neurons, the nerve cells responsible for controlling movement, and symptoms such as muscle weakness and atrophy.

Genetics of familial ALS

In about two-thirds of cases in which ALS runs in families, a specific disease-associated mutation has been identified. In the remainder of cases, the fact that ALS affects other family members implies genetics are playing a substantial role in influencing the disease’s development, but the specific mutation(s) remains unknown.

Mutations in more than 40 genes have been linked to familial ALS. Some mutations are associated with specific patterns of disease onset and progression, though these patterns can vary considerably even among individuals carrying the exact same mutation.

Not everyone who inherits an ALS-linked mutation will develop the disease during their lifetime — this depends on the specific mutation, as well as other factors like lifestyle habits and environmental exposures.

The most common ALS-associated genetic mutations affect the genes C9ORF72, SOD1, FUS, and TARDBP. Mutations in these four genes collectively account for the majority of familial ALS cases.

C9ORF72

The gene most commonly linked to ALS is C9ORF72, which is mutated in 30% to 50% of people with familial disease. The most common ALS-linked mutation in this gene is called a hexanucleotide repeat, where a sequence of six nucleotides (the building blocks of DNA) gets repeated an excessive number of times.

About half of people carrying a C9ORF72 mutation will develop symptoms of ALS by the time they are 58 years old, and virtually all people harboring this mutation will develop the disease by age 80. Psychiatric problems and involuntary muscle movements are common symptoms of ALS for people with this mutation.

SOD1

Mutations in the SOD1 gene account for 10% to 20% of familial ALS cases. Around half of people who carry mutations in this gene develop ALS symptoms by age 46, and 90% have symptoms by age 70. Most people with SOD1-related ALS do not experience cognitive issues or dementia.

Several specific mutations in SOD1 have been tied to ALS. The most common in North America, p.Ala4Val, is usually linked with rapid disease progression that leads to death within a year or two after symptom onset.

FUS

The FUS gene is mutated in about 5% of people with familial ALS, and mutations in this gene tend to be more common in Asian populations. Patients commonly develop cognitive impairment and dementia, and many experience Parkinson’s-like symptoms such as tremor or unusually slow movements.

The age of onset tends to be earlier in people with FUS mutations compared with those carrying SOD1 or C9ORF72 mutations. More than half of individuals carrying a FUS mutation will develop symptoms by the time they reach their 50s, and more than 90% will have symptoms by their 70s.

Two specific FUS mutations, known as p.Ser513Pro and p.Arg514Ser, tend to be associated with a later age of onset relative to other mutations in this gene. Another mutation, called p.Ser513Pro, is associated with slower ALS disease progression.

TARDBP

The TARDBP gene is mutated in 1% to 4% of people with familial ALS cases. This gene provides instructions for making a protein called TDP-43. Toxic clumps of TDP-43 protein inside of nerve cells are a common feature in ALS, even in people without mutations in the TARDBP gene.

The average age of ALS onset for people with TARDBP mutations is mid-50s. A specific TARDBP mutation called p.Gly298Ser has been associated with an earlier age at onset and faster disease progression.

Familial ALS inheritance pattern

For almost all genes, including C9ORF72, SOD1, FUS, and TARDB, every person inherits two copies — one from each biological parent.

The vast majority of ALS-linked mutations are inherited in an autosomal dominant manner, which means that having only one mutated gene copy is enough to cause the disease. This applies to all mutations in C9ORF72, FUS, and TARDB, as well as most mutations in SOD1 and most other ALS-related genes.

If individuals carrying one of the autosomal dominant ALS mutations have children, there is a 50% chance that each of their offspring will inherit the disease-causing mutation. However, many autosomal dominant ALS genes are incompletely penetrant — this means that, although one mutated gene is sufficient to cause the disease, not everyone carrying the mutation will actually develop the disease during their lifetime.

Rarer inheritance patterns

A few ALS-linked mutations are inherited in what’s called an autosomal recessive pattern. This means that the disease will only develop if both copies of the gene carry a disease-causing mutation. A SOD1 mutation called p.Asp90Ala is inherited in an autosomal recessive pattern, as are some rarer ALS-linked genes like ALS2 and SPG11.

People with only one copy of an autosomal recessive mutation are said to be carriers, because they themselves will not develop ALS but could pass the disease-linked mutation to any biological children. If two carriers have children, there is:

• a 25% chance the child will inherit two mutated copies of the gene and possibly develop the disease
• a 50% chance the child will inherit just one mutation and be a carrier like the parents
• a 25% chance the child will not inherit any mutated copies of the gene.

One rare mutation that causes familial ALS in the gene UBQLN2 is inherited in an X-linked manner. The UBQLN2 gene is located on the sex-determining X chromosome — women have two X chromosomes, while men have one X and one Y. Because women usually have a second healthy copy of the gene on the other X chromosome, which can compensate if one copy is mutated, X-linked inheritance predominantly affects men.

Familial vs. sporadic

Familial ALS is defined by the disease affecting multiple people within the same biological family. While specific disease-linked mutations aren’t always identified, the fact that the disease is diagnosed in genetically related people suggests genetics plays a key role in determining disease susceptibility. So, to some extent, the risk of disease is inherited through families.

Sporadic ALS refers to cases of the disease where there is no family history. Yet, about 10% of people with sporadic ALS are found to carry ALS-linked mutations that also have been seen in familial disease.

Clinical features are broadly comparable in familial or sporadic ALS, though individual experiences in either type of the disease can vary considerably from person to person. However, people with familial ALS tend to have more rapidly progressing disease and have an earlier age at symptom onset (mean age of 40-60) compared with those with sporadic disease (mean age 58-63).

Familial ALS symptoms

Common symptoms of familial ALS include:

• muscle weakness, stiffness, and atrophy (wasting)
• difficulty swallowing and speaking
• trouble breathing
• digestive problems such as constipation
• cognitive challenges and dementia
• uncontrolled bouts of crying or laughing, known as pseudobulbar affect
• anxiety and depression.

ALS is a progressive disease, meaning symptoms tend to start off fairly subtle, usually only affecting one part of the body, and then become more severe and spread to more regions of the body as time goes on. Symptoms of familial ALS are similar, overall, to the signs of ALS that typically characterize the sporadic form of the disease, though these symptoms do tend to occur earlier in familial cases.

There is no cure for familial ALS or any other form of the disease, but there are a number of treatments that can reduce symptoms and minimize disease complications.

Genetic testing

Genetic testing, usually performed on a sample of blood or a cheek swab, can be used to identify ALS-associated mutations. These tests are not required to diagnose familial ALS, but they may provide useful information, both for patients and their families.

A genetic counselor is a specialist who can work with patients and family members to understand the potential benefits and risks of genetic testing, and to interpret the results if testing is performed.

Individuals who already have been diagnosed with ALS may choose to undergo genetic testing  to learn more about the potential cause of the disease and the possible risk to family members. Additionally, some experimental therapies are being developed for people with specific ALS-linked mutations, and genetic testing can provide information about potential eligibility for clinical trials. Genetic testing of children or anyone younger than age 18 is generally not recommended because FALS is typically an adult-onset condition.

For people who have a family history of ALS but who do not have symptoms, genetic testing may provide information about the individual’s risk of developing the disease in the future or passing ALS-associated mutations along to any biological children.

Accessing genetic testing

Most health insurance companies will provide coverage for genetic testing if it’s ordered by a doctor. But because specific policies may vary, it’s always recommended that patients should talk to their insurance provider to understand what is or is not covered before getting tested.

A program called ALS Identified offers free genetic testing to adults in the U.S. and Puerto Rico who have been diagnosed with ALS or who have a family history of the disease. The program, sponsored by Biogen and run by the diagnostic company Invitae, tests for more than 20 ALS-associated genes. Optional testing also is offered for genes that are not definitively proven to be associated with ALS but may be in the future. Testing may be performed at home or in a doctor’s office, but must be ordered by a doctor.

ALS News Today is strictly a news and information website about the disease. It does not provide medical advice, diagnosis, or treatment. This content is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a medical condition. Never disregard professional medical advice or delay in seeking it because of something you have read on this website.