Familial Amyotrophic Lateral Sclerosis

Familial amyotrophic lateral sclerosis (fALS) is an inherited form of ALS that runs in families, accounting for about 5-10% of all ALS cases. Unlike the more common sporadic form, fALS is caused by genetic mutations passed down from parents to children, often striking at a younger age and offering new hope for targeted gene therapies.

Table of contents

• What is Familial ALS?
• How Common is Familial ALS?
• Genetic Causes of Familial ALS
• How Familial ALS is Inherited
• Differences Between Familial and Sporadic ALS
• Symptoms of Familial ALS
• Diagnosis and Genetic Testing
• Treatment and Gene Therapy Advances
• What it Means for Family Members

What is Familial ALS?

Familial amyotrophic lateral sclerosis is a genetic form of ALS where mutations passed through families cause motor neuron degeneration, which means the death of nerve cells that control voluntary muscle movements^[1]. A person with familial ALS typically has at least one immediate family member who also developed the disease^[5].

Like all forms of ALS, familial ALS is a progressive disease that affects the large motor neurons in the brain and spinal cord. These nerve cells are responsible for controlling muscle movement throughout the body. When these motor neurons die, the brain can no longer start and control muscle movement, leading to progressive paralysis and eventual death from respiratory failure^[1].

How Common is Familial ALS?

Familial ALS accounts for approximately 5-10% of all ALS cases^[2][3]. The remaining 90-95% are sporadic cases, which occur in people with no apparent family history of the disorder. However, the distinction between familial and sporadic ALS is becoming less clear, as genetic factors are increasingly recognized even in cases without obvious family history^[2].

The frequency of specific genetic mutations varies significantly by geographic region and ethnic background. For example, mutations in the SOD1 gene are more common in Japan, while the C9orf72 mutation is more frequent in Europe and the United States but rare in Japan^[10]. This means that the target mutations for potential gene therapy vary by ethnicity.

Genetic Causes of Familial ALS

More than 10 genes have been linked to familial ALS since the first gene was discovered in 1993^[1]. The most common genes associated with familial ALS include SOD1, C9orf72, FUS, and TARDBP^[3][4].

The SOD1 gene was the first gene linked to ALS in 1993. This discovery came from genetic analysis of ALS families, including the historic Farr family of Vermont, whose disease was first recognized by Sir William Osler in 1880^[1]. Mutations in SOD1 account for 13-20% of familial ALS cases^[6]. The gene produces a protein called superoxide dismutase 1, and mutations result in a toxic, misfolded form of the protein that accumulates in motor neurons^[6].

The C9orf72 gene mutation represents the most common genetic cause of familial ALS, accounting for 30-40% of familial cases^[3]. However, its frequency is much lower in Japan compared to Europe and the United States^[10].

About 70% of familial cases and 5-10% of sporadic cases involve gene changes. More than 40 genes have been identified as related to ALS^[4][7].

How Familial ALS is Inherited

The most common inheritance pattern in familial ALS is autosomal dominant, which means that only one copy of the mutated gene from one parent is enough to cause the disease^[5][6]. When a parent has an autosomal dominant form of familial ALS, each child has a 50% chance of inheriting the mutation.

However, not all familial ALS follows this pattern. Other inheritance patterns can occur in familial ALS, though autosomal dominant is the most common^[5]. The disease can affect multiple generations within a family, and understanding the inheritance pattern is important for family planning and genetic counseling.

Differences Between Familial and Sporadic ALS

While familial and sporadic ALS share core symptoms and disease progression, several key differences exist between them. The most notable difference is the age of onset. Familial ALS typically develops earlier, with symptoms appearing in people’s late forties or early fifties, compared to late fifties or early sixties for sporadic cases^[3][5]. In rare cases, familial ALS can develop even earlier, in childhood or teenage years, known as juvenile ALS^[3].

Disease progression can vary significantly in familial ALS. Some mutations, like SOD1 A4V, cause rapid decline within months, while others progress more slowly over years^[5]. Sporadic ALS generally follows a more predictable 3-5 year progression pattern, though about 10% of patients with ALS live for 10 years or more^[1][14].

Genetic testing can identify specific mutations in familial cases, particularly in the SOD1, C9orf72, FUS, and TARDBP genes, while sporadic ALS rarely shows these inherited variants^[5]. Understanding these distinctions helps healthcare providers offer targeted care and genetic counseling for families affected by ALS.

Symptoms of Familial ALS

The symptoms of familial ALS are similar to those of sporadic ALS. Early symptoms may be subtle and easily overlooked. The earliest signs include muscle twitching, cramping, stiffness, or weakness^[3][4]. People may develop slurred speech (called dysarthria) and difficulty chewing or swallowing (called dysphagia)^[3][4].

As the disease progresses, muscles become weaker and arms and legs begin to look thinner as muscle tissue atrophies (wastes away)^[3][4]. Affected individuals eventually lose muscle strength and the ability to walk, becoming wheelchair-dependent and increasingly requiring help with personal care and daily activities^[3].

Breathing becomes difficult because the muscles of the respiratory system weaken. Most people with ALS die from respiratory failure within 2 to 10 years after symptoms first appear^[3]. However, the speed at which symptoms progress varies widely among affected individuals.

Approximately 20% of individuals with ALS also develop frontotemporal dementia (FTD), a progressive brain disorder that affects personality, behavior, and language^[3]. This combination is diagnosed as ALS-FTD.

Diagnosis and Genetic Testing

Diagnosing familial ALS can be challenging early on because it shares symptoms with other diseases. Tests used to help diagnose ALS include electromyogram (EMG), which records electrical activity of muscles, nerve conduction studies that measure nerves’ ability to send impulses, and MRI scans that can reveal spinal cord problems or rule out other conditions^[11].

Blood and urine tests help eliminate other possible causes of symptoms. Serum neurofilament light levels, measured from blood samples, are generally high in people with ALS and can help make a diagnosis early in the disease^[11]. A spinal tap may be performed to rule out other conditions.

For familial ALS, genetic testing plays a vital role. Several types of genetic tests are available that can identify mutations in genes known to cause ALS^[5]. Genetic counseling is essential for families affected by ALS. Counselors can help interpret test results, explain inheritance patterns, and discuss the implications for family members^[5][8].

Anyone who has lost a family member to ALS should consider genetic testing and counseling to determine if they are a candidate for preventive treatments or clinical trials^[8].

Treatment and Gene Therapy Advances

Although there is no cure for ALS, treatments are constantly improving, and the right combination may slow disease progression and improve quality of life^[4][7]. The past two decades have seen significant advances in understanding disease mechanisms and developing rational therapies^[1].

A major breakthrough came in April 2023 when the FDA approved tofersen (marketed as Qalsody) for the treatment of ALS caused by SOD1 mutations^[6][8]. Tofersen is an antisense oligonucleotide (ASO), a type of precision therapy designed to modify the expression of a specific gene. It binds to SOD1 messenger RNA and prevents translation into protein, thereby reducing the overall level of SOD1 protein, including the toxic mutated form^[6].

Over 30 years of research funded by the National Institutes of Health provided pivotal discoveries crucial for the development of tofersen^[6]. Clinical experience suggests that tofersen slows disease progression and improves quality of life, with people living more independently and longer on the drug^[8]. However, not everyone responds the same way, depending on the specific mutation and nature of their disease.

A new clinical trial called ATLAS is now enrolling people who have SOD1 mutations but do not show any signs of disease. Researchers believe the drug may be most effective in these pre-symptomatic carriers^[8]. Currently, tofersen is only available to pre-symptomatic individuals through this clinical trial.

The development of gene therapy based on disease-modifying genes and early intervention is expected to become an important therapeutic strategy in ALS^[10]. The success of tofersen has triggered a paradigm shift in developing ALS therapies and expanded the freedom of target choice for gene therapy^[10].

What it Means for Family Members

When one person in a family has familial ALS, it affects the entire circle of friends and family^[13]. Understanding the inheritance pattern is crucial for family members. With autosomal dominant inheritance, each child of an affected parent has a 50% chance of inheriting the mutation^[5].

Family members who may have inherited a mutation should consider genetic testing and counseling. This is especially important now that targeted treatments like tofersen are available for certain mutations, and clinical trials are testing preventive treatments in people who have mutations but no symptoms yet^[8].

Genetic counseling helps family members understand their risk, make informed decisions about testing, and learn about available options for managing that risk^[5]. Counselors can also provide emotional support and connect families with resources and support groups.

For family members who become caregivers, the role can be both rewarding and challenging. Caregivers help with daily tasks, attend medical appointments, provide emotional support, and assist with decision-making about care^[15]. It’s important for caregivers to also take care of themselves and seek support when needed^[13][15].