Motor neurone disease
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Motor neurone disease (MND) is a term used to cover a number of illnesses of the motor neurone: amyotrophic lateral sclerosis (ALS), progressive muscular atrophy (PMA), progressive bulbar palsy (PBP) and progressive lateral sclerosis (PLS). MND is the term used internationally while ALS is often used in the United States (where it is also known as Lou Gehrig's disease, after a famous patient) to cover all forms of MND. It was first described by Jean-Martin Charcot, a French neurologist, in 1869 and in France the disease is therefore known as Maladie de Charcot (Charcot's disease).
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Signs and symptoms
The onset of symptoms is usually between 40-70 years of age (average 55). The disorder is characterized by the progressive loss of voluntary muscle contraction due to the destruction of nerve cells in the brain and the spinal cord that are responsible for the stimulation of the voluntary muscles.
While the initial symptoms are subtle, the disease causes progressive physical disability. Mental functioning and physical sensation is spared, although many patients exhibit depression as their symptoms worsen.
Diagnosis
The diagnosis is established on both clinical grounds and an electromyography (EMG) examination, which is obligatory to demonstrate the diffuse loss of nervous stimulation of muscles of extremities, face and abdomen.
Clinically, upper motor neuron damage signs (such as spasticity, lively reflexes and Babinski signs) can be found, while the lower motor neurones demonstrate weakness and muscle atrophy. Weakness of bulbar musculature can also be seen (difficulty breathing, swallowing, coughing or speaking).
Neuroimaging examinations are usually performed to rule out alternative causes, such as a mass lesion of upper parts of spinal cord.
Causes
Most cases of MND are "sporadic", although there is a suggestion that the onset is triggered by a viral infection. At least 4 genes are known to be linked to ALS: SOD1, ALS2, NEFH and VAPB. Only ~10% of cases are identified as genetic/hereditary; the causes for the remaining 90% are unknown.
The SOD1 gene codes for the enzyme superoxide dismutase that reduces the oxidative stress of the nerve cells. So far over 100 different mutations in the SOD1 gene have been found, all of which cause some form of ALS.
Similar findings led the researchers to assume that the nerve cell death was caused by an excess of free radicals in the cell. This hypothesis is one of many others developed to describe the etiology of ALS/MND and is waiting to be reliably proven.
Pathophysiology
Skeletal muscles are stimulated by a group of neurons (lower motor neurons) located on the frontal portion of the spinal cord projecting to the muscle cells and these nerve cells are stimulated by a group of nerve cells (upper motor neurons) that project from a specific region called the motor area, located on the frontal lobe. The latter projection is called the corticospinal tract. In MNS, the nerve cells of both pathways shrink and die. On macroscopic pathology, there is a degeneration of the ventral horns of the spinal cord, as well as atrophy of the ventral roots (shrunken in appearance). Similarly, a degeneration of the motor neurons in the brainstem is seen. Neuronal loss and astrogliosis develops as well. Degeneration of the corticospinal tracts, as well as of the neurons in the motor strip of the cerebral cortex is known.
There is a role in excitotoxicity and oxidative stress, presumably secondary to mitochondrial dysfunction. In animal models, death by apoptosis has also been identified (tranlocation of Bax to mitochondria, and translocation of cytochrome c to cytosol).
Epidemiology
MND has three major subgroups called primary lateral sclerosis (PLS, only the upper motor neurons are affected), progressive muscular atrophy (PMA, only the lower motor neurons are affected) and ALS (both are affected). PLS and PMA each account for about 5% of cases, with the majority of diagnoses being ALS.
The incidence of MND is approximately 1-5 out of 100,000 people, and men have a 20% higher rate of incidence than women. Approximately 5600 cases are diagnosed in the U.S. every year.
Prognosis
The disease usually has a grave prognosis and 50% of patients die within the first 3 years, 20% will live 5 years or more, only 10% survive for 10 years or more. There are documented cases of people living 35 years or more after diagnosis; Stephen Hawking has lived for more than 42 years since his (1963) diagnosis. The rarer subgroups of MND have better prognoses than ALS; people with PMA are more likely to be "long survivors" i.e. > 5 years, whilst people with PLS effectively have a normal lifespan. In ALS and PMA, mortality is typically caused by respiratory weakness or complications arising from prolonged paralysis.
Treatment
Treatment is essentially supportive and symptomatic. Many patients require modifications to their living environment as they become progressively physically impaired. Riluzole, an inhibitor of glutamate, may delay the progression of ALS in selected patients. Meanwhile, some experimental drugs are used in trial setting; many of these are intended to interfere with oxidative stress of the cells (a suspected mechanism); success has so far been limited.
Some current promising research towards a cure has focused on gene therapy and the use of stem cells, though the ethical and legal difficulties surrounding the harvesting of stem cells have slowed progress, particularly in the United States.
Etymology
Amyotrophic comes from the Greek language. A- means "no", myo refers to "muscle", and trophic means "nourishment"; amyotrophic therefore means "no muscle nourishment," which describes the characteristic atrophication of the sufferer's disused muscle tissue. Lateral identifies the areas in a person's spinal cord where portions of the nerve cells that are affected are located. As this area degenerates it leads to scarring or hardening ("sclerosis") in the region.
History and prominent patients
Lou Gehrig brought national and international attention to the disease in 1939 when he abruptly retired from baseball after being diagnosed with ALS/MND. Former guitar virtuoso Jason Becker, theoretical physicist Stephen Hawking and ex-Celtic football player Jimmy Johnstone also suffer from the disease.
Founder of care homes Leonard Cheshire VC, Rangers footballer Sam English, Hall of Fame pitcher Jim "Catfish" Hunter, Blues singer and guitarist Leadbelly, Jazz giant Charles Mingus, Hollywood actor David Niven, legendary Leeds United manager Don Revie, American soap opera veteran Michael Zaslow and Chinese Chairman Mao Zedong died from the disease.
References
- Some information gathered from Dr. M Norenberg, Oct 26th, 2004: University of Miami.
- Crossing the Finishing Line – Last Thoughts of Leonard Cheshire VC, ed. Reginald C. Fuller (London 1998).
External links
- ALS Association (http://www.alsa.org/)
- ALS Online Database (http://www.alsod.org)
- ALS/MND Alliance (http://www.alsmndalliance.org/index.shtml)
- MND Association (http://www.mndassociation.org/full-site/home.shtml)
- The Hereditary Motor Neurone Disease Foundation (http://hereditarymnd.org.au/index.html) - Australian group seeking to find a cure for familial Motor Neurone Disease.de:Amyotrophe Lateralsklerose