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Motor neurone disease

The motor neurone diseases (or motor neuron diseases) (MND) are a group of
neurological disorders that selectively affect motor neurones,[1] the cells that
control voluntary muscle activity including speaking, walking, breathing, swallowing
and general movement of the body.

Classification

Forms of motor neurone disease include:

• amyotrophic lateral sclerosis (ALS) (sometimes called Lou Gehrig's disease)

• primary lateral sclerosis (PLS)

• progressive muscular atrophy (PMA)

• bulbar

o pseudobulbar palsy - spastic

o progressive bulbar palsy - spastic and flaccid

Causes

About 90% of cases of MND are "sporadic", meaning that the patient has no family
history of ALS and the case appears to have occurred with no known cause. Genetic
factors are suspected to be important in determining an individual's susceptibility to
disease, and there is some weak evidence to suggest that onset can be "triggered"
by as yet unknown environmental factors (see 'Epidemiology' below).

Approximately 10% of cases are "familial MND", defined either by a family history of
MND or by testing positive for a known genetic mutation associated with the
disease. The following genes are known to be linked to ALS: Cu/Zn superoxide
dismutase SOD1, ALS2, NEFH (a small number of cases), senataxin (SETX) and
vesicle associated protein B (VAPB).

Of these, SOD1 mutations account for some 20% of familial MND cases. The SOD1
gene codes for the enzyme superoxide dismutase, a free radical scavenger that
reduces the oxidative stress of cells throughout the body. So far over 100 different
mutations in the SOD1 gene have been found, all of which cause some form of
ALS(ALSOD database). In North America, the most commonly occurring mutation is
known as A4V and occurs in up to 50% of SOD1 cases. In people of Scandinavian
extraction there is a relatively benign mutation called D90A which is associated with
a slow progression. In Japan, the H46R mutation is most common. G93A, the
mutation used to generate the first animal model (and by far the most widely
studied), is present only in a few families worldwide. Future research is
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concentrating on identifying new genetic mutations and the clinical syndrome

associated with them. Familial MND may also confer a higher risk of developing
cognitive changes such as frontotemporal dementia or executive dysfunction (see
'extra-motor change in MND' below).

It is thought that SOD1 mutations confer a toxic gain, rather than a loss, of function
to the enzyme. SOD1 mutations may increase the propensity for the enzyme to
form protein aggregates which are toxic to nerve cells.

Pathophysiology

Skeletal muscles are innervated by a group of neurones (lower motor neurones)

located in the ventral horns of the spinal cord which project out the ventral roots to
the muscle cells. These nerve cells are themselves innervated by the corticospinal
tract or upper motor neurones that project from the motor cortex of the brain. On
macroscopic pathology, there is a degeneration of the ventral horns of the spinal
cord, as well as atrophy of the ventral roots. In the brain, atrophy may be present in
the frontal and temporal lobes. On microscopic examination, neurones may show
spongiosis, the presence of astrocytes, and a number of inclusions including
characteristic "skein-like" inclusions, bunina bodies, and vacuolisation. Bunina
bodies were first described in 1962; they are markers of neuronal degeneration.

The availability of mouse models has led to extensive research into the causes of
SOD1-mutant linked familial ALS. The most commonly used mouse model is G93A,
[3] although many others have since been generated. At the gross physiological
level, the mouse models faithfully recapitulate the features of human ALS
(motorneuron death, muscle atrophy, respiratory failure).

Although there is no consensus as to the exact mechanism by which mutated SOD1

causes the disease (in either mice or patients), studies based largely on mouse
models suggest a role for excitotoxicity and more controversially, oxidative stress,
presumably secondary to mitochondrial dysfunction. Death by apoptosis has also
been suggested.

Signs and symptoms

Symptoms usually present themselves between the ages of 50-70, and include
progressive weakness, muscle wasting, and muscle fasciculations, spasticity or
stiffness in the arms and legs, and overactive tendon reflexes. Patients may present
with symptoms as diverse as a dragging foot, unilateral muscle wasting in the
hands, or slurred speech.

Neurological examination presents specific signs associated with upper and lower
motor neurone degeneration. Signs of upper motor neurone damage include
spasticity, brisk reflexes and the Babinski sign. Signs of lower motor neurone
damage include weakness and muscle atrophy.
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Note that every muscle group in the body requires both upper and lower motor
neurones to function. The signs described above can occur in any muscle group,
including the arms, legs, torso, and bulbar region.

The symptoms described above may resemble a number of other rare diseases,
known as "MND Mimic Disorders". These include, but are not limited to, multifocal
motor neuropathy, Kennedy's disease, hereditary spastic paraplegia, spinal
muscular atrophy and monomelic amyotrophy. A small subset of familial MND cases
occur in children, such as "juvenile ALS", Madras syndrome, and individuals who
have inherited the ALS2 gene. However, these are not typically referred to as MND,
but by their specific names.

Diagnosis

The diagnosis of MND is a clinical one, established by a neurologist on the basis of

history and neurological examination. There is no diagnostic test for MND.
Investigations such as blood tests, electromyography (EMG), magnetic resonance
imaging (MRI), and sometimes genetic testing are useful to rule out other disorders
that may mimic MND. However, the diagnosis of MND remains a clinical one. Having
excluded other diseases, a relatively rapid progression of symptoms is a strong
diagnostic factor. Although an individual's progression may sometimes "plateau", it
will not improve.

A set of diagnostic criteria called the El Escorial criteria[4][5] have been defined by
the World Federation of Neurologists for use in research, particularly as
inclusion/exclusion criteria for clinical trials. Owing to a lack of clinical diagnostic
criteria, some neurologists use the El Escorial criteria during the diagnostic process,
although strictly speaking this is functionality creep, and some have questioned the
appropriateness of the criteria in a clinical setting.[6]

Type UMN degeneration LMN degeneration

ALS yes yes

PLS yes no

PMA no yes

Progressive bulbar palsy no yes - bulbar region

Pseudobulbar palsy yes - bulbar region no

The "bulbar region" in the table above refers to the mouth, face, and throat.

It is possible that Transcranial magnetic stimulation can be used to diagnose MND