What is Motor Neuron Disease?
Motor neuron diseases (MNDs) are a group of neurological disorders that affect nerve cells in the brain and the spinal column. Specifically, the diseases attack motor neurons, the nerve cells that control the movement of muscles throughout the body. MNDs cause the neurons to die slowly over time, and as they do, the patient loses the ability to control or use their muscles.
Types of Motor Neuron Disease
MNDs are classified according to their origin (inherited or not) and which motor neurons they affect. Some MNDs affect cells in the brain (upper motor neurons), and others affect cells in the brain stem and spinal cord (lower motor neurons).
- Amyotrophic lateral sclerosis (ALS) affects both upper and lower motor neurons. ALS is sometimes called Lou Gehrig’s Disease in recognition of the famous baseball player who developed the disease in the 1930s. ALS is usually fatal within 3-5 years after symptom onset.
- Primary Lateral Sclerosis (PLS) affects only the upper motor neurons but is otherwise similar to ALS. PLS is not usually fatal.
- Progressive Bulbar Palsy (PBP) affects lower motor neurons in the brain stem. PBP often progresses to ALS.
- Progressive Muscular Atrophy (PMA) affects lower motor neurons and may progress to ALS.
- Spinal Muscular Atrophy (SMA) is an inherited MND that affects the lower motor neurons.
- Kennedy’s Disease is an inherited MND that only affects males.
Symptoms of MNDs
Symptoms of MNDs and their progression vary depending on the type. Common symptoms include:
- Muscle weakness that expands and gets worse
- Muscle stiffness
- Muscle twitches
- Slurred speech
- Problems with coordination and balance
- Involuntary crying or laughing
- Loss of ability to walk
- Loss of ability to swallow or chew
- Difficulty breathing
The early signs of ALS are often so subtle that they go unnoticed, leading to the disease going undiagnosed for months. The earliest symptoms are typically muscle weakness, stiffness, cramping, and twitching; these initial symptoms tend to affect the hands, feet, and limbs. As the disease progresses, the symptoms will spread to other parts of the body and affect other motor functions, such as chewing, swallowing, speaking, and breathing.
What Causes Motor Neuron Disease?
The precise cause of MND has not yet been determined. Different forms of the disease may have distinct causes. One common characteristic of various forms of the disease is abnormal changes (called mutations) in specific genes in the patient’s cells. In some cases, these changes are passed on from affected parents to their children. In other cases, external environmental factors may trigger the gene mutations.
Scientists don’t yet know precisely which genes are involved in the development of MNDs, nor do they know with certainty how gene mutations lead to the development of the diseases.
- Some mutations seem to interfere with the communication between nerve cells and muscles.
- Other mutations may interfere with the nerve cells’ function and cause them to die.
- Still other mutations may cause toxic substances to accumulate in nerve cells, leading to damage and cell death.
Is Motor Neuron Disease Hereditary?
Some types of MNDs are inherited in an autosomal dominant pattern, meaning that children may develop the disorder if they inherit even one copy of the mutated gene from either of their parents. If a parent carries the disorder-causing mutation, they will have a 50 percent chance of having an affected child with each pregnancy.
MNDs are sometimes inherited in an autosomal recessive pattern. This means a child must inherit two copies of the gene mutation, one from each parent, to develop the disorder. People with only one copy of the mutated gene will not develop the MND but will be carriers who can pass the mutation on to their children. Two carrier parents have a 25 percent chance of having a child with the MND with each pregnancy. Therefore, half of their pregnancies will produce a carrier, and a quarter of them will produce a child with no mutated genes.
Kennedy’s disease is an X-linked disorder. This means that the chance of inheritance varies depending on the sex of the parent and the child. These cases affect males, and females are carriers who don’t develop symptoms of the disorder. Men with the condition will pass the gene mutation to all of their daughters, who will be carriers, but their sons will be unaffected. Female carriers of the mutation will have a carrier daughter 25% of the time, a non-carrier daughter 25% of the time, an affected son 25% of the time, and an unaffected son 25% of the time.
Of the two broad types of ALS, one has a definite connection to family history, while the other seems linked to non-inherited factors.
- Sporadic ALS. This is the most common type of ALS, affecting about 90% of patients with the disease. This form of the disease doesn’t seem to be linked to family history and is probably caused by a combination of gene mutations and external environmental factors. The most common age range for the onset of sporadic ALS is between the late 50s and early 60s.
- Familial ALS. This form of the disease affects approximately 10% of patients and is linked to genetic family history. In these cases, a mutation in a particular gene appears to substantially increase the risk of developing the disease. A person with the mutation has a 50% chance of passing it on to their child. In families where the mutation for ALS is present, multiple family members across generations are likely to have had ALS, or a related disease called frontotemporal dementia (FTD).
- Familial ALS often develops earlier than sporadic ALS, with initial onset occurring in the patient’s late 40s or early 50s. However, in rare cases, the disease can occur in teenagers or children.
How Is Motor Neuron Disease Detected?
Doctors often miss the earliest signs of MNDs, either failing to diagnose the disease entirely or mistaking the symptoms for another problem. The initial sign of an MND is muscle weakness, but the weakness is not always in the same part of the body. The symptoms may look like those of different, less severe problems such as a pinched nerve or carpal syndrome. Consequently, MNDs are difficult to spot early on, even for medical professionals. Early detection is even more unlikely because the disease is relatively uncommon, and most doctors don’t have experience diagnosing it.
Early signs of ALS and other MNDs include:
- Muscle weakness. There is usually no pain associated with the weakness, and the location of the weakness varies from patient to patient. Common areas for the weakness to begin are the hands, feet, arms, and legs. Patients might also have trouble speaking or swallowing early on.
- Muscle cramps
- Uncontrollable muscle twitches
- Falling or tripping
- Difficulty grasping or holding objects
- Fatigue in the extremities
- Slurred speech
- Difficulty swallowing
- Uncontrollable laughing, crying, or yawning
How Is Motor Neuron Disease Diagnosed?
When your doctor suspects that an MND might be the cause of early symptoms, they will conduct a variety of tests and exams. There is no single test or exam to detect ALS or other MNDs. Much of the diagnostic process is designed to rule out an MND by detecting other problems potentially causing symptoms rather than directly diagnosing the MND itself.
- Laboratory tests. Tests of your blood and urine will not necessarily confirm a diagnosis of MND, but the tests may be able to rule out other conditions that could be causing your symptoms.
- Electromyogram (EMG). This test uses electrodes to measure the electrical activity in your muscles as they work. The test can be used to detect abnormalities in muscle function that support a diagnosis of an MND.
- Imaging tests. Magnetic resonance imaging (MRI) scans can detect abnormalities in your brain, spinal column, or other parts of your body. These tests may be used to rule out an MND by revealing another condition that’s causing your symptoms.
- Spinal tap. This procedure removes and tests a small amount of the fluid that protects your brain and spinal column. The test can often detect viral infections or inflammation in the brain.
- Nerve conduction tests. These tests measure how well your nerves can communicate with your muscles. These tests may detect nerve damage or disorders other than an MND that could be causing symptoms.
- Muscle biopsy. In this test, a small amount of muscle tissue is removed and tested. The biopsy is typically used to detect other diseases and to rule out an MND.
How Is Motor Neuron Disease Treated?
There is no cure for MNDs, and no treatment can undo the damage that the disease does to the body’s nerve cells. Treatment plans, therefore, focus on slowing the progression of the disease, preventing complications associated with the disease, and easing discomfort caused by the disease’s symptoms.
- Drug treatments. Two drugs have been approved for use in the treatment of ALS, and both drugs have shown success in slowing the disease’s progression. Riluzole is an oral medication that may increase life expectancy by three to six months. Edaravone is administered intravenously; it may increase life expectancy, but studies have not yet shown how long.
- Other medications may be used to treat symptoms such as pain, depression, muscle cramps, fatigue, constipation, sleep disruptions, and uncontrollable crying or laughing.
- Physical therapy can help patients remain mobile and independent for a longer time as the disease progresses.
- Occupational therapy can help patients learn to remain independent as muscle function deteriorates.
- Speech therapy can help to maintain the ability to speak for as long as possible. Therapies can also help the patient learn how to use adaptive technologies to communicate as speech becomes more difficult.
- Breathing therapies can help to ease discomfort as breathing becomes more difficult.
How Does Motor Neuron Disease Progress?
The progression of MNDs varies depending on the type.
- PLS usually affects the legs first before spreading to other parts of the body. It progresses more slowly than ALS and typically isn’t fatal. However, many people with PLS eventually develop ALS.
- PMA usually begins in the hands before slowly spreading to the lower body. It may eventually progress to ALS.
- SMA more often affects muscles of the torso, upper legs, and arms than the hands or feet.
The muscle weakness characteristic of early ALS will eventually spread to other parts of the body, resulting in weakness and paralysis. As a result, the sufferer will have increased difficulty moving, speaking, swallowing, and breathing. Usually, patients will eventually be unable to stand, walk, or use their arms and legs, ultimately requiring mechanical assistance to breathe.
Although there is some evidence that a form of dementia is present in ALS cases, cognitive function does not usually decline as muscle deterioration progresses. The fact that the sufferer’s mental processes remain intact as their physical abilities decline often leads to depression and/or anxiety.
How Is Motor Neuron Disease Prevented?
The direct cause of MNDs is unknown, especially in sporadic MND cases where heredity doesn’t seem to play a role. However, research has identified some risk factors that may increase the risk of developing the disease. The risk factors include:
- Smoking. Some research has suggested a link between smoking and ALS, especially in post-menopausal women.
- Military service. Military veterans are twice as likely to develop ALS as those who have not served. The increased risk isn’t connected with any type of service, branch of service, combat experience, or location of service. Researchers have not yet been able to determine what aspect of service causes the increased risk.
- Exposure to toxins. Studies have suggested links between ALS and exposure to some toxins, including lead, but a definite link between the disease and any one toxin has not yet been established.
Motor Neuron Disease Caregiver Tips
A diagnosis of ALS is devastating both for the patient and for their loved ones and caregivers. Unfortunately, the disease is fatal, and coping with that outcome can make dealing with its symptoms and complications even more difficult.
- Make room for grief. Therapies and treatments can make the grieving process take a back seat to the daily routine. But giving the grieving process the time and space it deserves is essential to coping with the disease.
- Plan ahead. The progression of the disease will make communication and decision-making difficult in the years ahead. Make decisions about medical plans, end-of-life considerations, and financial issues now.
- Recognize the positive. ALS does not usually cause mental decline, and many sufferers have happy, joy-filled experiences for years following their diagnosis. Don’t let the physical symptoms rule out the possibilities.
- Get help. Find a support group for ALS caregivers to help you maintain your mental and physical health as you deal with caregiving demands.
Motor Neuron Disease Brain Science
Researchers are looking for the causes of ALS and other MNDs, for an understanding of how the disease affects the brain, and for effective treatments for the disease. Current studies include:
- Researchers suspect that a brain-cell protein called membralin might play a role in the development of ALS. Scientists don’t know precisely what membralin does in the brain’s nerve cells, but they have found evidence that a protein deficiency may cause ALS and other degenerative nerve diseases. Their studies suggest that gene therapies that increase levels of membralin may have potential as an ALS treatment.
- One clinical study is currently testing a drug that takes a new approach to treating ALS. The drug aims to improve muscle function rather than improve communication between nerves and muscles. The hope is that the drug will help muscles to work more efficiently to make up for the weakness caused by ALS nerve damage. The drug seems particularly effective at assisting the muscles that control breathing; patients may breathe better for longer.
Motor Neuron Disease Research
Title: HERV-K Suppression Using Antiretroviral Therapy in Volunteers With Amyotrophic Lateral Sclerosis (ALS)
Principal investigator: Avindra Nath, MD
National Institutes of Health Clinical Center
Objective: In this Phase I, proof-of-concept study, researchers aim to determine whether an antiretroviral regimen approved to treat human immunodeficiency virus (HIV) infection would also suppress levels of Human Endogenous Retrovirus-K (HERV-K) found to be activated in a subset of patients with amyotrophic lateral sclerosis (ALS). We propose to measure the blood levels of HERV-K by quantitative PCR before, during, and after treatment with an antiretroviral regimen. Researchers will evaluate the safety of the antiretroviral regimen for ALS participants and explore clinical and neurophysiological outcomes of ALS symptoms, quality of life, and pulmonary function.
Study Population: We will study a subset of ALS patients with a ratio of HERV-K:RPP30 greater than or equal to 13. About 30% of ALS patients may have detectable levels of HERV-K; about 20% of patients with ALS have a level >1000 copies/ml. To show whether the HERV-K could be suppressed, researchers will recruit from approximately 20% of patients with high levels so that the antiretroviral effect can be determined.
Design: This is an open-label study of a combination antiretroviral therapy for 24 weeks in 25 HIV-negative, HTLV-negative ALS patients with a high ratio of HERV-K:RPP30. The study duration for each participant will be up to 72 weeks. Participants will be followed regularly for safety, clinical, and neurophysiological outcomes.
Outcome Measures: The primary outcome measure will be the percent decline in HERV-K concentration measured by quantitative PCR. Percent decline for a patient is measured by: 100 x (screening visit – week 24 visit measurement) / screening visit. The safety of antiretrovirals in volunteers with ALS as measured by the frequency and type of AEs, the ability to remain on assigned treatment (tolerability), physical examinations, laboratory test results, vital signs, and weight/body mass index (BMI). Efficacy will be explored by measuring the change in mean scores of the ALS Functional Rating Scale-Revised (ALSFRS-R), the ALS Specific Quality of Life Inventory-Revised (ALSSQOL-R), the ALS Cognitive Behavioral Screen (ALS-CBS), vital capacity and maximal inspiratory pressure as measured by a handheld spirometer, electrical impedance myography (EIM), the change in neurofilament levels in the blood and/or CSF, and the change in uring p75ECD levels.
Title: Studies in Amyotrophic Lateral Sclerosis (ALS) and Other Neurodegenerative Motor Neuron Disorders
Principal investigator: Bjorn Oskarsson, MD
Mayo Clinic Florida
The purpose of this study is to collect, from patients with sporadic and familial ALS and their family members, clinical data and blood samples for extraction of DNA, RNA, preparation of lymphocytes, plasma, and serum to establish a repository for future investigations of genetic contributions to ALS pathogenesis. In addition, blood samples for DNA extraction also would be collected from control subjects with no personal or family history of ALS phenotypes.
Title: CNS10-NPC-GDNF Delivered to the Motor Cortex for ALS
Principal investigator: Richard Lewis, MD
Cedars-Sinai Medical Center
Los Angeles, CA
The investigator is examining the safety of transplanting cells engineered to produce a growth factor into the motor cortex (brain) of patients with Amyotrophic Lateral Sclerosis (ALS). The cells are called neural progenitor cells, which are a type of stem cell that can become several different types of cells in the nervous system. These cells have been derived to specifically become astrocytes, which is a type of neural cell. The growth factor is called glial cell line-derived neurotrophic factor, or GDNF. GDNF is a protein that promotes the survival of many types of neural cells. Therefore, the cells are called “CNS10-NPC-GDNF.” The investigational treatment has been tested in people by delivering it to the spinal cord. However, it has only been delivered to the motor cortex of animals. In this study, investigators want to learn if CNS10-NPC-GDNF cells are safe to transplant into the motor cortex (brain) of humans.