SETX Gene

Amyotrophic lateral sclerosis (ALS) is a progressive disease that affects motor neurons, which are specialized nerve cells that control muscle movement. These nerve cells are found in the spinal cord and the brain. In ALS, motor neurons die (atrophy) over time, leading to muscle weakness, a loss of muscle mass, and an inability to control movement.

There are many different types of ALS; these types are distinguished by their signs and symptoms and their genetic cause or lack of clear genetic association. Most people with ALS have a form of the condition that is described as sporadic, which means it occurs in people with no apparent history of the disorder in their family. People with sporadic ALS usually first develop features of the condition in their late fifties or early sixties. A small proportion of people with ALS, estimated at 5 to 10 percent, have a family history of ALS or a related condition called frontotemporal dementia (FTD), which is a progressive brain disorder that affects personality, behavior, and language. The signs and symptoms of familial ALS typically first appear in one's late forties or early fifties. Rarely, people with familial ALS develop symptoms in childhood or their teenage years. These individuals have a rare form of the disorder known as juvenile ALS.

The first signs and symptoms of ALS may be so subtle that they are overlooked. The earliest symptoms include muscle twitching, cramping, stiffness, or weakness. Affected individuals may develop slurred speech (dysarthria) and, later, difficulty chewing or swallowing (dysphagia). Many people with ALS experience malnutrition because of reduced food intake due to dysphagia and an increase in their body's energy demands (metabolism) due to prolonged illness. Muscles become weaker as the disease progresses, and arms and legs begin to look thinner as muscle tissue atrophies. Individuals with ALS eventually lose muscle strength and the ability to walk. Affected individuals eventually become wheelchair-dependent and increasingly require help with personal care and other activities of daily living. Over time, muscle weakness causes affected individuals to lose the use of their hands and arms. 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 the signs and symptoms of ALS first appear; however, disease progression varies widely among affected individuals.

Approximately 20 percent of individuals with ALS also develop FTD. Changes in personality and behavior may make it difficult for affected individuals to interact with others in a socially appropriate manner. Communication skills worsen as the disease progresses. It is unclear how the development of ALS and FTD are related. Individuals who develop both conditions are diagnosed as having ALS-FTD.

A rare form of ALS that often runs in families is known as ALS-parkinsonism-dementia complex (ALS-PDC). This disorder is characterized by the signs and symptoms of ALS, in addition to a pattern of movement abnormalities known as parkinsonism, and a progressive loss of intellectual function (dementia). Signs of parkinsonism include unusually slow movements (bradykinesia), stiffness, and tremors. Affected members of the same family can have different combinations of signs and symptoms.

Ataxia with oculomotor apraxia is a condition characterized by problems with movement that worsen over time. The hallmark of this condition is poor coordination and balance (ataxia), which is often the first symptom. Most affected people also have oculomotor apraxia, which makes it difficult to move their eyes side-to-side. People with oculomotor apraxia have to turn their head to see things in their side (peripheral) vision.

There are several types of ataxia with oculomotor apraxia, the most common of which are types 1, 2, and 4. The types are very similar but are caused by mutations in different genes.

Type 1 begins around age 4. In addition to ataxia and oculomotor apraxia, affected individuals can have involuntary jerking movements (chorea) or muscle twitches (myoclonus); these movement problems tend to disappear over time. Individuals with this type may also develop muscle wasting in their hands and feet, which further impairs movement. As in all forms of ataxia with oculomotor apraxia, nearly all people with type 1 develop nerve abnormalities (neuropathy). Neuropathy impairs reflexes and leads to limb weakness and an inability to sense vibrations. Many individuals with ataxia with oculomotor apraxia require wheelchair assistance, typically 10 to 15 years after the start of movement problems.

People with some types of ataxia with oculomotor apraxia may have characteristic blood abnormalities. Individuals with type 1 tend to have reduced amounts of a protein called albumin, which transports molecules in the blood. The shortage of albumin likely results in elevated levels of cholesterol circulating in the bloodstream. Increased cholesterol levels raise a person's risk of developing heart disease.

Ataxia with oculomotor apraxia type 2 usually begins around age 15. As in type 1, affected individuals may have chorea or myoclonus, although these movement problems persist throughout life in type 2. Neuropathy is also common in this type.

A key feature of ataxia with oculomotor apraxia type 2 is high amounts of a protein called alpha-fetoprotein (AFP) in the blood. (Raised levels of this protein are normally seen in the bloodstream of pregnant women.) Individuals with type 2 may also have high amounts of a protein called creatine phosphokinase (CPK) in their blood. This protein is normally found primarily in muscle tissue. The effect of abnormally high levels of AFP or CPK in people with ataxia with oculomotor apraxia type 2 is unknown. Although individuals with type 2 usually have normal albumin levels, cholesterol may be elevated.

Ataxia with oculomotor apraxia type 4 begins around age 4. In addition to ataxia and oculomotor apraxia, individuals with this type typically develop dystonia, which is involuntary, sustained muscle tensing that causes unusual positioning of body parts. Dystonia can be the first feature of the condition, and it tends to disappear gradually over time. Muscle wasting in the hands and feet and neuropathy are also common in individuals with type 4.

In ataxia with oculomotor apraxia type 4, albumin levels can be low, and cholesterol or AFP can be elevated. However, the amounts of these molecules are normal in many affected individuals.

Intelligence is usually not affected by ataxia with oculomotor apraxia, but some people with the condition have intellectual disability.

Amyotrophic lateral sclerosis (ALS) is a progressive disease that affects motor neurons, which are specialized nerve cells that control muscle movement. These nerve cells are found in the spinal cord and the brain. In ALS, motor neurons die (atrophy) over time, leading to muscle weakness, a loss of muscle mass, and an inability to control movement.

There are many different types of ALS; these types are distinguished by their signs and symptoms and their genetic cause or lack of clear genetic association. Most people with ALS have a form of the condition that is described as sporadic, which means it occurs in people with no apparent history of the disorder in their family. People with sporadic ALS usually first develop features of the condition in their late fifties or early sixties. A small proportion of people with ALS, estimated at 5 to 10 percent, have a family history of ALS or a related condition called frontotemporal dementia (FTD), which is a progressive brain disorder that affects personality, behavior, and language. The signs and symptoms of familial ALS typically first appear in one's late forties or early fifties. Rarely, people with familial ALS develop symptoms in childhood or their teenage years. These individuals have a rare form of the disorder known as juvenile ALS.

The first signs and symptoms of ALS may be so subtle that they are overlooked. The earliest symptoms include muscle twitching, cramping, stiffness, or weakness. Affected individuals may develop slurred speech (dysarthria) and, later, difficulty chewing or swallowing (dysphagia). Many people with ALS experience malnutrition because of reduced food intake due to dysphagia and an increase in their body's energy demands (metabolism) due to prolonged illness. Muscles become weaker as the disease progresses, and arms and legs begin to look thinner as muscle tissue atrophies. Individuals with ALS eventually lose muscle strength and the ability to walk. Affected individuals eventually become wheelchair-dependent and increasingly require help with personal care and other activities of daily living. Over time, muscle weakness causes affected individuals to lose the use of their hands and arms. 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 the signs and symptoms of ALS first appear; however, disease progression varies widely among affected individuals.

Approximately 20 percent of individuals with ALS also develop FTD. Changes in personality and behavior may make it difficult for affected individuals to interact with others in a socially appropriate manner. Communication skills worsen as the disease progresses. It is unclear how the development of ALS and FTD are related. Individuals who develop both conditions are diagnosed as having ALS-FTD.

A rare form of ALS that often runs in families is known as ALS-parkinsonism-dementia complex (ALS-PDC). This disorder is characterized by the signs and symptoms of ALS, in addition to a pattern of movement abnormalities known as parkinsonism, and a progressive loss of intellectual function (dementia). Signs of parkinsonism include unusually slow movements (bradykinesia), stiffness, and tremors. Affected members of the same family can have different combinations of signs and symptoms.