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Amyotrophic Lateral
Sclerosis
Authors: Vanessa Nowosad and Genevieve
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Citations in APA Format

Introduction & History

A) Introduction

Amyotrophic lateral sclerosis (also known as Lou Gehrigs

disease) is an adult-onset, neurodegenerative disease with an
unknown cure.

5 out of 100,000 people worldwide are affected by ALS. 10% of

cases of ALS are the result of a genetic defect, while the other
cases is are sporadic and the cause unknown.

Peak age onset is 58 to 63 years of age (Kiernarn et al., 2011).

It consists of death of motor neurons in the brain, brainstem

and spinal cord, which leads to the progressive failure of the
neuromuscular system and death within 2-3 years from
symptom onset (Ferraiuolo et al., 2011).

There has been evidence that ALS is neurovascular disease due

do the impairment of blood-brain and blood-spinal cord barriers
(BBB/BSCB) (Garbuzova-Davis et al., 2011).

B) History

Augustus Jacob Lockhart Clarke

(1817-1880) made a major
achievement by creating a
detailed typical signs and
symptoms of this disease
(Turner, Swash & Ebers, 2010).

The term amyotrophic lateral

sclerosis can be attributed to
Jean-Martin Charcot in 1874.

Over the past 150 years, since

Charcots original description,
little has been discovered about
the causes of ALS.

Cause of ALS

Mutations in the SOD1, TARDBP, and fused in sarcoma

gene (FUS) have been identified in familial ALS
(Kabashi et al., 2011).

Evidence suggests that ALS could initiate in skeletal

muscle rather than in motor neurons (Marcuzzo et al.,
2011).

Immunological causes are still being studied, but

current research proposes that ALS patients have
antibodies that recognize various neuronal structures
such as calcium receptors as foreign

Mechanisms

Increased intracellular [Ca2+], excitotoxicity mediated by glutamate,

and generation of superoxides (Pagani, Gonzalez, & Uchitel, 2011)

Glutamate-induced excitotoxicity results in the overactivation of

calcium dependent enzymatic pathways as well as the
generation of superoxides (Kiernan et al., 2011).

Oxidative stress plays a crucial role in the progression of motor

neuron loss observed in this disease (Tanaka et al., 2011).

Endoplasmic reticulum and mitochondrial stress from increased

[Ca2+] activates the unfolded protein response (Walker & Atkin,
2011).

It is suggested that these mechanisms are part of a series or

parallel events leading to neuronal death. An increase in [Ca 2+]
could enhance the generation of superoxides and the release of
glutamate and in turn increase [Ca2+] further (Pagani et al.,
2011).

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Calcium influx

IgG antibodies have

been found against
calcium (Ca2+)
channels (Gonzalez,
et al., 2011)

Antibodies recognize
channel as foreign,
binds, allows for
influx of calcium,
calcium enters into
mitochondria, causes
stress, and signals
apoptosis

+SOD1 mutations

SOD1, super oxide dismutase 1,

binds to cooper and zinc ions and
is responsible for destroying super
oxide radicals

Superoxides are produced by the

immune system to destroy foreign
cells
Misfolding of mutated SOD1
(Henkel et al., 2009)

Microglia cells secrete

inflammatory mediators in the
brain

Mutant SOD1 G93A is recognized by

microglia and is activated due to
binding of CD14 and TLR2 and TLR4
Activated phenotype (m1) promotes
Th1 responses, secretes
proinflammatory cytokines (TNF, IL1 and ROS superoxide), leading to
apoptosis of motor neuron cells
(Zhao et al., 2009)

Symptoms & Diagnosis

A) Symptoms

People with ALS lose muscle strength and coordination.

Symptoms include difficulty swallowing and breathing,
weak muscles, muscle cramps, muscle contractions,
paralysis, speech problems, and weight loss (PubMed
Health, 2010).

Cognitive abilities such as personality changes,

language and decision making, are impaired in 25-50%
of patients who receive neuropsychological tests
(Gordon, 2011).

+B) Diagnosis

There is no diagnostic test for

amyotrophic lateral sclerosis, so
physicians must rely on identifying
both upper and lower motor neuron
signs in limbs and other physical
evidence for the progression of the
disease (Kiernan et al., 2011).

Nerve conduction studies are

important for reducing
misdiagnosis of ALS, and
electromyography is essential for
the identification of lower motor
neuron loss this can help in the
early diagnosis of ALS (Kiernan et
al., 2011).

Current Treatments

Because there is no apparent cause in the majority of

ALS cases, there is only one available medication that
has been shown to modestly increase survival: riluzole
(Gordon, 2011).

Oral Baclofen and diazepam may be administered to

ALS patients to help control and reduce the intensity of
muscle spasms and rigidity (PubMed Health, 2010).

Symptomatic treatments such as physiotherapy,

speech therapy, and respiratory therapy help manage
the affects of the disease (Kiernan et al., 2011).

Clinical Research & Trials

Oxidative stress plays a large role in the progression of

motor neuron loss observed in ALS, so anti-oxidative
agents could be an important therapeutic means for
the ALS treatment antioxidant supplements (Tanaka,
et al., 2011).

Identification of biomarkers that influence the

occurrence and progression of ALS, including genes
other than SOD1, is a prominent area of research.

TDP-43 gene has more than 30 mutations in the C-terminus

(a binding domain for ribonucleoproteins) that have been
identified in both familial and sporadic ALS patients;
however, the mechanism is still unknown (Onodera et al.,
2011)

Conclusion & Future Studies

The underlying mechanisms that induce the generation of

autoantibodies that recognize calcium channels are still
not known.

The identification of more antigenic targets will provide a

way to determine the precise role of autoimmunity in this
disease.

Screening to identify the molecular targets for antibodies

from ALS patients is necessary design rational therapies
and to develop biochemical tests for early detection of
ALS.

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