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Motor Neuron Diseases
Introductory article
Article Contents
Michael Donaghy, University of Oxford, Oxford, UK
. Introduction
Motor neuron disease is an umbrella term referring to a group of diseases in which there is
death of the lower motor neurons and/or the upper motor neurons. Some of these diseases
are genetic, but most occur sporadically, that is unpredictably without any identified
environmental or genetic cause.
. Pathophysiology of ALS
. Frequency and Clinical Importance of ALS
. Major Clinical Features and Complications of ALS
. Prognosis and Management of ALS
. Pure Lower Motor Neuron Syndromes
. Pure Upper Motor Neuron Disorders
. Summary
Although many use the term ‘motor neuron disease’ to
refer to amyotrophic lateral sclerosis (ALS), the most
common and serious of these disorders occurring in adults,
there are a wide variety of different motor neuron diseases,
of varying severity, affecting all ages from infancy onwards
(Table 1). This death of motor neurons is a form of
neurodegenerative disease and results in paralysis of the
limb and swallowing muscles. This degenerative process
causes various disabilities, such as inability to walk, use the
arms, swallow or speak, and it may lead to death when the
breathing muscles become involved.
Table 1 Classification of the motor neuron diseases
Combined upper and lower motor neuron involvement
Amyotrophic lateral sclerosis
Sporadic (A, E)
Familial adult onset (A) [ad]
Familial juvenile onset (c) [ar]
Pure lower motor neuron involvement
Proximal hereditary motor neuronopathy
Acute infantile form (Werdnig–Hoffmann; I) [ar]
Chronic childhood form (Kugelberg–Welander; I, C)
Adult onset forms (A) [ar] [ad]
Hereditary bulbar palsy
With deafness (Brown–Violetta–Van Laere; C, A) [?]
Without deafness (Fazio–Londe; C) [ar]
X-linked bulbospinal neuronopathy (A, E) [slr]
Hexosaminidase deficiency (C, A) [ar]
Multifocal motor neuropathies (A, E)
Postpolio syndrome (E)
Postirradiation syndrome (A, E)
Monomelic, focal or segmental spinal muscular
atrophy (A)
Pure upper motor neuron involvement
Primary lateral sclerosis (A, E)
Hereditary spastic paraplegia (A, E) [ar]
Lathyrism (A)
Konzo (A)
There are two types of motor neurons, the lower and the
upper (Figure 1). Lower motor neuron cell bodies are located
in the anterior horn of the spinal cord and in the brainstem.
Their axons branch to innervate a group of muscle fibres
within the limbs, trunk, throat or face. The group of muscle
fibres innervated by a single lower motor neuron is known as
a motor unit. When a motor unit is diseased, as in a motor
neuron disease, it sometimes fires spontaneously without
any voluntary or reflex stimulus, and all the muscle fibres of
its motor unit contract simultaneously. This causes a visible
flickering in the muscle belly known as a fasciculation,
which can also be detected by electromyographic recording
from the muscle. When a lower motor neuron degenerates,
the muscle fibres of its motor unit atrophy due to loss of
activity and trophic influences. With loss of many of the
motor neurons innervating any particular muscle, the
muscle will visibly waste. Thus, the clinical features of
lower motor neuron loss are weakness, wasting and
fasciculations. The upper motor neuron cell bodies are
located in the cerebral cortex of the brain, principally in the
primary motor cortex. Their axons descend through the
brainstem and spinal cord in the pyramidal tracts. Many
terminate on neuronal circuits which influence how lower
motor neurons control movement. Some upper motor
neurons, known as Betz cells, synapse directly with the lower
motor neurons and are particularly responsible for controlling complex short latency movements such as individual
finger movements. In addition to paralysis, upper motor
neuron damage causes spastic stiffness of limb muscles,
brisk tendon reflexes, and a characteristic extension of the
great toe on stroking the sole of the foot, the so-called
Babinski response.
ALS causes degeneration both of the lower motor
neurons in the spinal cord and brainstem, which directly
control voluntary (striated) muscles, and of the upper
motor neurons in the motor areas of the cerebral cortex,
which direct and integrate the activity of these lower motor
neurons. By contrast the other forms of motor neuron
disease affect either the lower motor neurons or the upper
motor neurons but not both. This article focuses on ALS,
also known as Lou Gehrig disease.
ENCYCLOPEDIA OF LIFE SCIENCES © 2002, John Wiley & Sons, Ltd.
Motor Neuron Diseases
Upper motor neurons
Cerebral cortex
Cranial nerve motor nuclei
Medullary pyramid
The cause of sporadic ALS is unknown but nerve
terminals from affected regions show defective uptake of
the potentially toxic excitatory amino acid neurotransmitter, glutamate. This observation led to the development of
the antiglutamate agent, riluzole, the first treatment shown
to slow the progression of ALS. Twenty to 40% of
hereditary amyotrophic lateral sclerosis cases are associated with mutations in the gene for Cu/Zn superoxide
dismutase 1 on chromosome 21, which catalyses conversion of toxic superoxide anion free radicals to hydrogen
peroxide. The mechanism whereby this enzyme abnormality causes motor neuron disease is unknown; various
proposals include loss of the normal ability to detoxify free
radicals allowing them to accumulate intracellularly, the
possibility that the mutated enzyme protein agglomerates
intracellularly in deposits which damage the motor neuron
or that it affects the mitochondria, which are energy
sources within cells. Introduction of this mutant enzyme
transgenically into mice causes motor neuron degeneration, thereby providing the first good animal model of
motor neuron disease.
Pyramidal decussation
Spinal cord
Pyramidal tract
motor neurons
Figure 1 Schematic representation showing the course of the pyramidal
tract, the homuncular organization of the motor cortex in the precentral
gyrus, the concentration of the motor output within the internal capsule,
and the decussation of the pyramidal tract in the medulla oblongata. (From
Donaghy M (1997) Neurology, Oxford University Press.)
Pathophysiology of ALS
Pathological examination of the spinal cord and brain of
those who have died from amyotrophic lateral sclerosis
shows extensive loss of lower (alpha) motor neurons, and
also of the upper motor neurons from the motor cerebral
cortex. Many of the surviving motor neurons show
abnormalities indicating that they are in the earlier stages
of degeneration, particularly spheroids (round particles)
composed of disorganized elements of the normal intracellular cytoskeletal proteins in the proximal axon.
Although 90% of ALS cases occur sporadically, 10% are
inherited, usually on an autosomal dominant basis, that is
with a one in two chance of directly inheriting the disease
from an affected parent.
Frequency and Clinical Importance
of ALS
ALS occurs worldwide with an incidence of up to 2 cases
per 100 000 of the population; men are twice as frequently
affected as women. Particular geographical foci of an
increased incidence of ALS have been noted, such as the
Pacific island of Guam, where it is thought that dietary
factors are responsible.
Although relatively uncommon, ALS is a widely
dreaded disease because of its relentless progression which
eventually makes patients with normal mental function
prisoners within bodies that no longer move, and
ultimately leads to an undignified death. Caring for
patients with ALS causes great distress to relatives, usually
the spouse, and places a considerable burden upon
disability healthcare services.
Major Clinical Features and
Complications of ALS
The first symptom of ALS is usually either weakness of one
limb, difficulty with swallowing, or an alteration in the
quality of the voice. As the months go by, weakness and
wasting spread to other parts of the body, and progressively worsen. Many patients experience muscle cramping,
and inspection of the limb muscles shows involuntary
flickering movements of the muscles called fasciculations.
Clinical neurophysiological studies, undertaken for the
purposes of diagnosis, show that these fasciculations are
Motor Neuron Diseases
due to simultaneous contraction of the group of muscle
fibres within the motor unit innervated by a diseased motor
neuron. In most patients, that muscle region which was
first affected usually continues to be the worst affected.
Depending upon which muscle region is predominantly
weakened, patients ultimately become unable to walk, or
to use their arms and hands, or to swallow, or to speak.
Intellectual function remains normal, and there is no
involvement of skin sensation, or of the control of the
bladder or bowel. Interestingly, the striated muscles which
control eye movements are not affected. Patients with
advanced forms of ALS may become breathless because of
failure of breathing muscles, or may experience potentially
fatal choking attacks because the throat weakness allows
food and liquid to be inhaled rather than swallowed. Apart
from these respiratory complications of ALS, malnutrition
due to impaired swallowing is the other major complication affecting general health.
Prognosis and Management of ALS
Of those with onset in the swallowing muscles, only 5%
survive 5 years. Survival is rather better for those with limb
muscle onset, of whom 15% survive 5 years. Death usually
results from respiratory failure, often with associated
pneumonia or choking, and general malnutrition may
contribute. Malnutrition due to swallowing muscle
failure can be circumvented by placing percutaneous
feeding gastrostomy tubes through the abdominal
wall directly into the stomach, thereby bypassing the
throat. Walking aids, wheelchairs and devices to improve
hand function in those with weak arms can be of
assistance to affected individuals. Some patients with
distressing breathlessness due to breathing muscle failure
may be helped by continuous positive airways pressure at
night, in which a slightly positive air pressure is delivered
via a face mask. More definitive treatment of respiratory
failure with tracheostomy and formal endotracheal ventilation is rarely advised because it will simply prolong the
patient’s life whilst their limb, swallowing and speaking
muscles fail relentlessly. The pastoral care of patients with
ALS is all important, both in the manner in which one tells
the patient about the diagnosis early on, and in advising
him or her humanely about the best management in the
later stages.
Trials of drug therapy have aimed to slow the downhill
progress of the disease or improve survival. The antiglutamate drug riluzole improves survival at 18 months by
35%, although there seems to be no significant benefit in
terms of muscle function. This drug represents an
important advance in that it is the first effective intervention in the natural history of ALS. There is much activity
devoted to finding effective treatments to slow or halt
motor neuron degeneration, but thus far with little success.
Pure Lower Motor Neuron Syndromes
There are a wide range of pure lower motor neuron
syndromes, often known by the alternative name of spinal
muscular atrophy, which occur at all ages of life.
The commonest and most severe form is inherited,
occurs in infants and is known as Werdnig–Hoffmann
disease or spinal muscular atrophy (SMA) type 1. This
disorder is the second most common fatal autosomal
recessive disease of childhood and occurs once in every
20 000 births. Affected babies are weak from birth,
or soon after, can only suck weakly, and normally die
of respiratory failure within a year. Mutations in the
survival motor neuron gene (SMN) occur in 98% of
these patients but the mechanism whereby this genetic
mutation causes motor neuron abnormalities is not yet
known. Less severe forms of inherited spinal muscular
atrophy also occur in older children, adolescents and
adults and some of these too are associated with SMN gene
A distinctive inherited sex-linked form of spinal
muscular atrophy, only occurring in men, is called Xlinked bulbospinal neuronopathy or Kennedy syndrome.
This occurs at various ages of adulthood, with the most
serious weakness affecting the tongue and swallowing
muscles. The disease is due to an expanded CAG
trinucleotide repeat sequence within the androgen receptor
gene on the X-chromosome. The reason why this mutation
of a sex-hormone receptor causes motor neuron degeneration is not clear but may involve cellular damage induced
by deposition of the aberrant receptor protein. The
patients also show general evidence of inadequate testosterone influence, but this hormonal state is unlikely to be
directly responsible for the motor neuron disease.
Sporadic lower motor neuron syndromes also occur.
A small proportion of those who have suffered
paralysis due to acute poliomyelitis (polio) will develop
a slowly worsening weakness of the affected limb, more
than two decades later. Self-limited spinal muscular
atrophies occasionally occur, particularly in young
men, and often only affecting one arm. Multifocal
motor neuropathy is a condition resembling spinal
muscular atrophy in which diagnostic neurophysiological
tests show the problem to be one of focal blocking of the
passage of action potentials along motor nerve fibres,
rather than true degeneration of the motor axons. This
disorder often responds dramatically within a few days of
intravenous infusions with high dose human immunoglobulin.
Motor neuron diseases occasionally occur in association
with benign or malignant tumours. Lower motor neuron
syndromes are well recognized in association with proliferations of lymph node tissue, both in the form of
malignant lymphomas and with the production of monoclonal immunoglobulins by benign lymphocyte proliferations.
Motor Neuron Diseases
Pure Upper Motor Neuron Disorders
These are the rarest forms of motor neuron disease. A
sporadic condition known as primary lateral sclerosis
causes stiffness and weakness of the limbs, voice or
swallowing muscles due to degeneration of the upper
motor neurons. A similar picture can occur, although
usually earlier in adult life with less progressive deterioration, in an autosomal dominantly inherited condition
known as hereditary spastic paraplegia. It is of interest to
note that pure upper motor neuron degenerations have
occurred following dietary consumption of Lathyrus
sativus, the chickling pea vetch, during famine conditions,
causing the disease neurolathyrism which mainly occurs in
India, and following consumption of dietary cyanide
derived from the flour of cassava root, during famine
causing konzo in Central Africa.
Various sporadic and inherited degenerations affect the
lower and upper motor neurons to cause paralysis of limb,
swallowing and breathing muscles. This selective motor
neuron degeneration appears to be a common endpoint of
diverse pathophysiological processes ranging from altered
glutamate handling, to abnormalities of free radical
detoxifying enzymes, mutations in genes affecting neuronal survival during early development, and in the gene for
the androgen receptor. Although an antiglutamate drug
has been shown to improve the natural history of one form
of motor neuron disease, the fatal amyotrophic lateral
sclerosis of adults, it seems likely that a wider range of
therapies will have to be developed specific to the different
abnormalities of cell biology causing these diverse motor
neuron syndromes. This is an important challenge to
modern pharmacological medicine given the disabling,
distressing, and often fatal nature of these disorders.
Further Reading
Amato AA, Prior TW, Barohn RJ et al. (1993) Kennedy’s disease: a
clinico-pathologic correlation with mutations in the androgen
receptor gene. Neurology 43: 791–794.
Dalakas MC, Elder G, Hallett M et al. (1986) A long-term follow-up
study of patients with post-poliomyelitis neuromuscular symptoms.
New England Journal of Medicine 314: 959–963.
Donaghy M (1995) Motor neuron diseases in adults. In: Kennard C (ed.)
Recent Advances in Clinical Neurology 8, pp. 73–88. Edinburgh, UK:
Churchill Livingstone.
Donaghy M (1999) Classification and clinical features of motor neurone
diseases and motor neuropathies in adults. Journal of Neurology 246:
Gordon PH, Rowland LP, Younger DS et al. (1997) Lymphoproliferative disorders and motor neurone disease. Neurology 48: 1671–1678.
Gurney ME, Pu H, Chiu AY et al. (1994) Motor neuron degeneration in
mice that express a human Cn, Zn superoxide dismutase mutation.
Science 164: 1772–1775.
Lefebvre S, Burglen L, Frezal J et al. (1998) The role of the SMN gene in
proximal spinal muscular atrophy. Human Molecular Genetics 7:
Pringle CE, Hudson AJ, Munoz DG et al. (1992) Primary lateral
sclerosis. Clinical features, neuropathology and diagnostic criteria.
Brain 115: 495–520.
Rosen DR, Siddique T, Patterson D et al. (1993) Mutations in Cu/Zn
superoxide dismutase gene are associated with familial amyotrophic
lateral sclerosis. Nature 362: 59–62.
Rothstein JD, Martin LJ and Kuncl RW (1992) Decreased glutamate
transport by the brain and spinal cord in amyotrophic lateral sclerosis.
New England Journal of Medicine 326: 1464–1468.