Amyotrophic lateral sclerosis (ALS) is a member of a group of diseases called motor neuron diseases. There are many diseases in this group. They all affect nerve cells that control voluntary functions such as walking, talking, swallowing, and even breathing. ALS is also called Lou Gehrig's disease after a famous American baseball player who was afflicted with it. It is called motor neurone disease in many other countries. In French, it is called maladie de Charcot, after Dr. Jean-Martin Charcot, who, in 1869, discovered connections between the manifestations of the disorder and underlying neurological problems.

All motor neuron diseases are progressive, which means that they get worse with time. Other diseases in this group include progressive bulbar palsy, spinal muscle atrophy, primary lateral sclerosis, and post-polio syndrome. A larger list of MNDs is available from the National Institutes of Health.

Clinical information

Motor neurons have important roles in muscle strength and in controlling the movement of muscles. Motor neurons in ALS patients die as time passes, which creates problems with walking, talking, swallowing, and ultimately, breathing. In addition to losing control of their muscles, ALS patients also become weak. Most cases of ALS are sporadic, which means that they occur with no known cause. People with ALS do not have a distinctive facial appearance, but they do share a common set of physical problems that include the following:

Common problems in ALS

•  Weakness
•  Unsteady gait
•  Muscle atrophy or wasting
•  Increased deep tendon reflexes
•  Problems that get worse with time
•  A persistent dry cough, in the absence of disease
•  Increased jaw jerk reflex (see video links at right)
•  Fasciculations (muscle twitches; see video links at right)
•  Abnormal electryomyogram (EMG; tests nerve impulses in muscles)
•  Dysarthria (difficulty speaking due to nerve damage; see video link)
•  Diminished appetite and/or trouble swallowing (weight loss may also occur)
•  Pseudobulbar affect (unconrollable crying, laughing, or other emotional episodes)

A hallmark feature of ALS is the loss of fine and gross motor skills. Problems devvelop in new areas and get worse as time passes. For example, a person may initially notice that when walking, one or both legs give out without warning. This problem will progress to a point where the person can no longer stand alone. Patients will also develop problems eating and drinking, and will have difficulty caring for themselves.

Although ALS has been described as a disease that spares the mind, the unfortunate facts are that cognitive abilities are affected in roughly a third of patients. Patients may become forgetful, for example. They may also find that their ability to concentrate is not as good as it once was. Dementia may also occur.

ALS is often fatal within 3-5 years of diagnosis, but a minority of patients can live for 7 or even 10 years. Additionally, in a very small number of patients, the condition stabilizes. In some, this state lasts for years. In others, it may last for decades. Notable ALS patients who have lived with the disease for 20 years or more include Steven Hawking and former Van Halen guitarist Jason Becker.

Types of ALS and causes of ALS

There are a number of forms of ALS. The most common one is the sporadic type, or SALS. As noted above, sporadic means that the cause of SALS is unknown. A large variety of possible causes have been studied, but outside of cases on Guam (see below), there is not a lot of evidence for definitive connections. A list of possible causes include oxidative stress, immune system abnormalities, viruses that had been dormant and were reactivated, toxins, and glutamate toxicity. Glutamate is a substance that aids in cells-to-cell communication in the nervous system. There is some evidence showing that glutatmate in ALS patients accumulates between nerve cells, which cause problems. The only FDA-approved drug for ALS (Rilutek) is aimed at reducing glutamate levels.

Another form of ALS is familial ALS, or FALS. Familial ALS is passed down in families and is caused by mutations in one of a number of genes, including SOD1, C9ORF72, NEK1, TDP43, FUS, UBQLN2, and others. The course of FALS is generally the same as SALS, but the average age of onset can be ~10 years earlier. FALS caused by mutations in SOD1 may sometimes progress faster than SALS. Given that recent studies have found new associations between genes and ALS, many apparently sporadic cases may turn out to have genetic causes. Researchers continue to seek new genes associated with ALS.

Juvenile ALS (JALS) begins in people who are age 25 or younger. JALS can be caused by mutations in a gene called ALS2. ALS2-JALS is an autosomal recessive disease. This term means that the syndrome occurs when both parents carry a mutated copy of a gene, and both pass it to a child. Other genes are associated with JALS. They include SETX, SIGMAR1, and FUS. JALS is generally a relatively mild form of ALS, and patients can live into their 60s or beyond.

Other forms of ALS occur in some areas of the Pacific (Guam, West Papua, and Japan, for example). The official name for these diseases is amyotrophic lateral sclerosis-parkinsonism-dementia complex (ALS-PDC), as many patients have medical problems associated with both ALS and Parkinson's disease. The local people on Guam call the condition lytico-bodig. Lytico-bodig has not appeared in a person from Guam in many years, and it appears to have been caused by the consumption of now-extinct flying fox bats on Guam. The bats appeared to have had high levels of a neurotoxin called beta-methylamino-L-alanine (BMAA; 1). Although the connection between BMAA and lytico-bodig has not been definitively proven, the evidence for a connection is very strong.

Interested readers may wish to consult a thorough review of ALS (2).

The cause of ALS is not known in a large majority of SALS cases. This means that diagnosis is clinical, or based on signs and symptoms. Unfortunately, in its early stages, ALS resembles other diseases, making early diagnosis difficult and often a matter of ruling out other conditions. Certain tests, including imaging of the nervous system (see photos below) and electromyography (EMG) are helpful. It is important to note that experts in the field do not appear to have reached a consensus on imaging abnormalities that are definitive for ALS (3). Other tests that can help with diagnosis include tests of nerve conduction velocity, myelograms of the cervical spine, blood/ urine studies, and spinal taps. For a complete list of tests that should be used in the diagnosis of potential ALS cases, see the list compiled by the Mayo Clinic. In addition, the ALS Association lists criteria for diagnosis. A revised set of criteria for diagnosis was created in 2010; interested readers may wish to consult publications describing them in detail (4, 5).

A minority of cases may be definitively diagnosed via molecular methods such as gene sequencing. The familial form of ALS is one example. FALS has different causes, not all of which are known. One cause is a mutation in the gene SOD1. SOD1-FALS is an autosomal dominant disorder. This term means that it is caused by a mutation in a gene not located on an X or Y chromosome, and that it can be passed on by only one parent (who would most likely also develop ALS). Mutations in SOD1 account for 10-20% of FALS cases.

Another gene associated with ALS is called C9ORF72. According to the ALS Association, mutations in this gene account for 25-40% of FALS cases and 4-6% of SALS cases (meaning that some cases of SALS are actually genetic). Mutations in C9ORF72 are also associated with a condition called frontotemporal dementia (FTD). Like SOD1-FALS, C9ORF72-ALS appears to be passed in an autosomal dominant manner.

Other genes that have been associated with ALS include ALS2, ANG, FUS, SETX, SIGMAR1, TARDBP, and VAPB (see Genetics Home Reference article linked to at right or the ALS Association's website for more information.

The US National Institutes of Health maintains a list of centers that can look for mutations in the genes listed above (see link at right). If you are not a doctor and suspect that you or someone in your family has ALS, check with your family physician, who will compare signs and symptoms with those known to occur in ALS. Your doctor can obtain a sample from you and send it to a testing center.

Differential Diagnosis

The differential diagnosis of ALS includes a number of the other disorders in the motor neuron disease group. For example, primary lateral sclerosis (PLS) is very similar to ALS and has been considered to be a variant form of ALS. Like ALS, PLS is a very rare disorder that causes progressive loss of upper motor neurons, and muscle weakness in the extremities. Unlike ALS, PLS does not cause muscle atrophy. Also unlike ALS, PLS spares lower motor neurons, progresses slowly, and does not typically reduce life expectancy. Mutations in the gene ALS2 can cause PLS. Note that ALS2 is also associated with juvenile ALS, a relatively mild form of this disease.

Spinal muscular atrophy (SMA) is another motor neuron disease. SMA attacks lower motor neurons and spares upper motor neurons (6). The result is weakness and atrophy of skeletal muscles. Weakness is often more severe in the trunk and the muscles of the upper arms and legs, and less severe in the hands and feet. Most cases of SMA are caused by mutations in the gene SMN1. There are 5 forms of SMA; type 1 generally presents before the age of 6 months. Patients have hypotonia (floppiness), fasciculations, absent tendon reflexes, and feeding difficulties. Most have trouble breathing and die of respiratory failure, usually occurs by age 2. Type 2 generally presents bewteen 6 and 18 months; typically, children cannot walk unaided and may have trouble breathing. Most patients die by young adulthood or well sooner. Type 3 presents between the ages of 2 and 17. Patients have abnormal gaits and may have trouble running or standing up from a chair. The lower limbs are most typically affected, but tremors may be present in the hands. These patients typically have a normal life expectancy. Other subtypes of SMA are described in reference 6.

Hereditary spastic paraplegia (HSP) is a progressive disorder involving lower limb weakness and spasticity. Patients may also have overactive bladder difficulties (feelings of urgency, with or without incontinence). In the complicated form of HSP, patients may have seizures, dementia, and other neurological signs. The complicated form is life-threatening.

Other conditions in the differential diagnosis of ALS are described in the GeneReviews document linked to at the right.

Clinical research in ALS is an active area, and there are likely to be a relatively large number of clinical trials running, recruiting, or recently completed at any given time. The link at the right will provide a list of clinical trials for ALS.

There is currently only one drug approved by the FDA for the treatingALS. This drug is Rilutek (riluzole). Rilutek is not highly effective and extends life by only an estimated 2-3 months. However, it may be more effective when given in the early stages of the disease.

References

1. 1. Cox PA et al (2003). Biomagnification of cyanobacterial neurotoxins and neurodegenerative disease among the Chamorro people of Guam. PNAS 100(23):13380-13383. Full text on PubMed.
2. 2. Wijesekera LK & Leigh PN (2009) Amyotrophic lateral sclerosis. Orphanet J Rare Dis 4:3. Full text on PubMed.
3. 3. Bede P & Hardiman O (2014) Lessons of ALS imaging: pitfalls and future directions - a critical review. Neuroimage Clin 4:436-443. Full text on PubMed.
4. 4. de Carvalho M et al (2008) Electrodiagnostic criteria for diagnosis of ALS. Clin Neurophysiol 119(3):497-503. Abstract on PubMed.
5. 5. Costa J et al. (2012) Awaji criteria for the diagnosis of amyotrophic lateral sclerosis: a systematic review. Arch Neurol 69(11):1410-1416. Abstract on PubMed.
6. 6. La Spada A (1999) Spinal and bulbar muscular atrophy. Updated January 26, 2017. GeneReviews [Internet] Pagon RA et al., editors. Seattle (WA): University of Washington, Seattle; 1993-2021. Full text.
7. 7. Li A (2010) Amyotrophic Lateral Sclerosis (ALS). This information is freely available.
8. 8. Okumiya K et al. (2014) Amyotrophic lateral sclerosis and parkinsonism in Papua, Indonesia: 2001-2012 survey results. BMJ Open 4(4):e004353. Full text on PubMed.
9. 9. Gaillard F (2003). Radiopedia entry on ALS. This information is freely available.