Types of ALS

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that can be classified into different types based on factors like genetics, family history, and early symptoms.

Across all types, ALS is marked by the loss of motor neurons, the nerve cells that control muscle movements, leading to muscle weakness and atrophy (wasting) that affects a person’s ability to walk, speak, breathe, and swallow.

Clinicians typically use two main methods to classify the disease, focusing either on family history or on which muscles are affected first. Other, less common classifications are also sometimes used.

While the disease type can help inform symptom progression, prognosis, and treatment options after an ALS diagnosis, the disease ultimately affects everyone differently. There can be a lot of disease progression variability, even among individuals with the same types of ALS.

Classification by family history

While the causes of ALS remain incompletely understood, genetics plays a sizable role in influencing an individual’s risk of developing the disorder.

Because ALS-associated genetic mutations can be passed from parents to their biological children, the disease can run in families. If more than one person in a family has ALS, these patients are said to have familial ALS. Cases without a clear family history of the disease are referred to as sporadic ALS.

Importantly, genetics plays a role in both familial and sporadic ALS. The distinction is based solely on whether the affected individual has biological family members who have or have had the disease. The term genetic ALS is sometimes used to refer to cases of ALS, either sporadic or familial, in which the patient harbors a known ALS-associated genetic mutation.

Familial ALS

Familial ALS accounts for about 5%-10% of ALS cases. Importantly, while children who inherit an ALS-associated mutation from their parents are at a higher risk of developing ALS, this does not guarantee that ALS will develop.

Mutations associated with familial ALS are usually inherited in an autosomal dominant manner, meaning that a person with an ALS mutation has a 50% chance of passing it to a biological child. For a child who inherits the mutation, the specific gene affected, as well as environmental and lifestyle factors, can influence whether symptoms develop.

The disease-driving mutation is known in about two-thirds of familial ALS cases. The most commonly affected genes in familial ALS are C9ORF72 (25%-40%) and SOD1 (10%-20%), while TARDBP and FUS each account for around 3%-5% of cases.

In the remaining cases, the fact that the disease runs in families suggests a genetic contribution, but specific disease-associated mutations have not been identified.

Familial and sporadic ALS have the same symptoms, although signs of the disease tend to emerge at a younger age in the familial form.

Sporadic ALS

The vast majority of people with ALS, about 90%-95% of all patients, do not have any family members with the disease, and thus are classified as having sporadic ALS.

In these patients, lifestyle and environmental factors are believed to play an important role in disease development. Yet, about 10% of patients with sporadic ALS have a known ALS-associated mutation. The most common mutations in these patients, found in about 5% to 10% of cases, are in the C9ORF72 gene, while SOD1 mutations are present in 1% to 2% of sporadic ALS patients.

No genetic change or environmental factor appears to cause sporadic ALS on its own. Rather, it’s thought that several risk factors, each increasing a person’s susceptibility, interact to drive motor neuron degeneration.

Classification by clinical onset

Muscle weakness, in some form, is typically the first symptom of ALS. The early signs of the disease are usually mild and affect only one part of the body before spreading to affect other body parts as the disease progresses. Depending on which muscles are affected first, ALS may be classified as limb-onset or bulbar-onset.

Limb-onset ALS

Limb-onset ALS is a form of the disease in which initial symptoms affect the muscles in the arms and hands, or the legs and feet. This type is observed in about two-thirds of ALS patients, and is sometimes referred to as spinal ALS .

When the upper limbs are first affected, the earliest symptom is usually weakness in the dominant hand, which can manifest as difficulty with writing or holding objects. In the lower limbs, initial ALS symptoms often affect the calves, leading to balance issues and difficulty walking.

Bulbar-onset ALS

In about a quarter to one-third of patients, ALS first affects the bulbar muscles in the head and neck. These muscles coordinate mouth and throat movements, and this form of the condition is known as bulbar-onset ALS.

The most common initial symptoms in bulbar-onset ALS are speech difficulties, such as trouble articulating words, slurred speech, or a hoarse voice, and trouble swallowing. Any person experiencing speech or swallowing problems should seek immediate medical care.

Bulbar-onset ALS is more often diagnosed in women and in older people. It also tends to progress more rapidly than limb-onset ALS, and is thus associated with a shorter survival time, although this can vary.

Other types of ALS

In addition to the main ALS types, other rare classifications may be used. These include juvenile ALS, when disease onset happens early in life, and ALS-PDC, an ALS-related disorder seen mainly in regions of the Pacific.

Juvenile ALS

In most people, ALS develops in middle or late adulthood. Juvenile ALS, meanwhile, refers to disease that develops in patients younger than 25, ranging from early childhood to early adulthood. This form of ALS is extremely rare, affecting fewer than 1,000 people in the U.S.

In general, juvenile ALS symptoms can overlap with those of adult-onset ALS, although disease presentation and progression vary considerably. While the condition typically progresses more slowly than adult-onset ALS, some cases are extremely aggressive and lead to death in a few years.

While disease-causing mutations are identified in around 10% of all adult-onset ALS cases, juvenile ALS has a greater genetic contribution, with about 40% of patients having a known gene mutation. The most commonly affected genes include FUS, SETX, and ALS2, although several others have also been implicated. The specific genetic mutation is believed to impact the age of onset, symptoms, and disease progression.

ALS-parkinsonism-dementia complex 1 (ALS-PDC)

ALS-parkinsonism-dementia complex 1, called ALS-PDC for short, is a rare, ALS-related neurodegenerative disorder. It is characterized by:

• symptoms of classic forms of ALS, such as muscle weakness and atrophy
• symptoms of Parkinson’s disease, such as slowed movements, rigidity, and tremors
• dementia, or cognitive problems that substantially impair daily life

ALS-PDC is sometimes called Guam disease because it was first recognized on the Pacific island of Guam. Beyond Guam, ALS-PDC is mostly isolated to other Pacific regions, namely the Kii Peninsula of Honshu Island in Japan, and Papua, Indonesia.

The exact cause of ALS-PDC is not known. Current research suggests it may result from exposure to toxins found in the seeds of cycad plants, coupled with underlying genetic vulnerability. In recent decades, the incidence of ALS-PDC has decreased substantially, tied to reduced consumption of cycad seeds.

Although it is geographically isolated and very rare, ALS-PDC remains important to ALS research, providing insight into the role of environmental factors in causing motor neuron diseases.