Amyotrophic Lateral Sclerosis (ALS)

Stephen Hawking

Prof. Prakash Babu

Department of Biotechnology & Bioinformatics
University of Hyderabad
Stephen William Hawking (born 8 January 1942) is an English theoretical physicist
and cosmologist, whose scientific books and public appearances have made him an
academic celebrity.

He is an Honorary Fellow of the Royal Society of Arts , a lifetime member of the

Pontifical Academy of Sciences
In 2009 was awarded the Presidential Medal of freedom, the highest civilian
award in the United States.

Hawking was the Lucasian Professor of Mathematics at the University of

Cambridge for thirty years, taking up the post in 1979 and retiring on 1 October
2009
Amyotrophic Lateral Sclerosis (ALS)

Prof. Prakash Babu

Department of Biotechnology & Bioinformatics
University of Hyderabad
 Also know as Lou Gehrig's Disease
Named after the New York Yankees
baseball star who played first base
and was diagnosed with the disease
in 1939 and died in 1941 but due to
popular belief this disease had been
discovered almost 100 years earlier

ALS is also known as Lou Gehrig's Disease, after the famous

baseball player who died of the disease in 1941
Characteristics

Disease of the motor system

Progressive muscle atrophy

Fatal (2 5 years) d/t respiratory failure

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Characteristics

Most commonly diagnosed in 40 - 70s

Affects men more often than women

The disease has no racial, socioeconomic, or ethnic

boundaries

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Symptoms
Early signs and symptoms of ALS include:
Difficulty walking or doing your normal daily activities
Tripping and falling
Weakness in your leg, feet or ankles
Hand weakness or clumsiness
Slurred speech or trouble swallowing
Muscle cramps and twitching in your arms, shoulders and
tongue
Difficulty holding your head up or keeping good posture
Signs and Symptoms

Difficulty swallowing (dyphagia)

Slurred speech (dysarthria)
Fatigue
Fasciculations of tongue (twitching) while at rest
Usually the first muscles affected are those in the arms
and legs
(Walking or climbing stairs may be difficult, may drop things, fall, experience
muscle cramps. The arms and legs may feel especially tired. If the hands are
affected, may have difficulty picking up small objects or turning keys)

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 ALS often starts in the hands, feet or limbs, and then spreads to
other parts of your body. As the disease advances and nerve
cells are destroyed, your muscles progressively weaken. This
eventually affects chewing, swallowing, speaking and
breathing.

ALS doesn't usually affect your bowel or bladder control, your

senses or your thinking ability. It's possible to remain actively
involved with your family and friends.
Upper motor neurons normally send signals to lower
motor neurons, which send signals to muscles. In ALS,
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upper and lower motor neurons are lost.
Whats in a Name ?

Amyotrophy refers to the atrophy (progressive muscle wasting)

Lateral sclerosis refers to demyelination followed by hardening

of the spinal column from buildup of scar tissue (sclerosis =
scar)

As the disease progresses, it will move up the affected leg or arm

until eventually all muscle groups become involved. This spread
into all muscle groups is the defining characteristic of ALS

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Probable Causes of ALS cont
Autoimmune responses. Sometimes, a
person's immune system begins attacking
some of his or her body's own normal
cells, and scientists have speculated that
such antibodies may trigger the process
that results in ALS.
Thus ALS is not contagious.
 NEUROLATHYRISM

Oral daily consumption of the chikling pea vetch

(lathyrus sativus)
Exitotoxic B-N oxaylamino-l-alanine (BOAA)
Spastic paraparesis
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Why ?... Etiology..

Mitochondrial dysfunction?
Genetic defect (chromosome 21) suggests the disease is inherited and
accounts for 5 to 10%

Environmental factors, since the disease tends to cluster in

geographical pockets?
(Extremely high incidence of ALS has been observed in Guam and the Trust
Territories of the Pacific )

Free radical damage?

Glutamate excitotoxicity? (Apoptosis / Programmed Cell Death)

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Diagnostics
EMG / NCV studies

- NCV is administered before EMG and measures the speed

at which nerves transmit electrical signals
- EMG measures nerve impulses within the muscles

Muscle Biopsy

Tests to rule out other neurological disorders

- MRI may be used to rule out spinal cord diseases

- Blood tests may be done to detect the presence of heavy
metals such as lead, abnormal proteins or hormone
levels associated with other neurological diseases
- Lumbar puncture to analyze the cerebrospinal fluid for
genetic abnormalities (e.g., viral, autoimmune,
neurotoxic)

Electromyography (EMG) Nerve Conduction Velocity (NCV) 16

Late Stage

As disease progresses and more muscle groups are affected, the person
becomes progressively incapacitated

When respiratory muscles weaken, the client will require a ventilator

Percutaneous Endoscopic Gastrostomy (PEG) or feeding tube

ALS patients often experience fear, anxiety, & depression

** Ability to think or reason remain intact !

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Collaborative Goals

Focus on maintaining quality of life

Control symptoms

Prevent complications

Provide adaptive devices to increase mobility and self-

care

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Collaborative Team

Physical therapy helps to relieve cramping and muscular pain. Passive

stretching helps to avoid permanent contraction of muscles
(contractures) that may cause joint problems

Dietician ensures diet of high-energy foods that are easy to swallow

Splints, braces, and wheelchairs are used to help with mobility

Occupational and Speech therapy as their motor control gradually

deteriorates

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Risk factors
Established risk factors for ALS include:
Heredity. Five to 10 percent of the people with ALS inherited it
(familial ALS). In most people with familial ALS, their children
have a 50-50 chance of developing the disease.
Age. ALS risk increases with age, and is most common between
the ages of 40 and 60.
Sex. Before the age of 65, slightly more men than women
develop ALS. This sex difference disappears after age 70.
Genetics. Some studies examining the entire human genome
(genomewide association studies) found many similarities in the
genetic variations of people with familial ALS and some
people with non-inherited ALS. These genetic variations might
make people more susceptible to ALS.
Environmental factors may trigger ALS

Smoking. Smoking is the only likely environmental risk factor

for ALS. The risk seems to be greatest for women, particularly
after menopause.
Environmental toxin exposure. Some evidence suggests that
exposure to lead or other substances in the workplace or at
home may be linked to ALS. Much study has been done, but no
single agent or chemical has been consistently associated with
ALS.
Military service. Recent studies indicate that people who have
served in the military are at higher risk of ALS. It's unclear
exactly what about military service may trigger the
development of ALS. It may include exposure to certain metals
or chemicals, traumatic injuries, viral infections, and intense
exertion.
 Complications

As the disease progresses, people with ALS experience complications, which may include:
Breathing problems
Over time, ALS paralyzes the muscles you use to breathe.
Some people with advanced ALS choose to have a tracheostomy a surgically created
hole at the front of the neck leading to the windpipe (trachea) for full-time use of a
respirator that inflates and deflates their lungs.
The most common cause of death for people with ALS is respiratory failure. On average,
death occurs within three to five years after symptoms begin.
Speaking problems
Most people with ALS will develop trouble speaking over time. This usually starts as
occasional, mild slurring of words, but progresses to become more severe. Speech eventually
becomes more difficult for others to understand, and people with ALS often rely on other
communication technologies to communicate.
Eating problems
People with ALS can develop malnutrition and dehydration from damage to the muscles that
control swallowing. They are also at higher risk of getting food, liquids or saliva into the
lungs, which can cause pneumonia. A feeding tube can reduce these risks and ensure proper
hydration and nutrition.
Dementia
Some people with ALS experience problems with memory and making decisions, and some
PATHOLOGY OF ALS
Gross Pathology
Motor neuron
degeneration and death
with gliosis
Gliosis of the CST
Atrophy of ventral
nerve roots
Microscopic Pathology

Intracellular inclusions
- Bunina bodies
- Ubiquinated inclusions (not tau)
PATHOGENIC MECHANISMS
OF ALS
Proposed Pathogenic Mechanisms in ALS

Oxidative Stress
Excitotoxicity
Abnormal Protein Precipitation and/or Aggregation
Cytoskeletal defects
Axonal transport
Neuroinflammation
Abnormalities in hypoxia-regulated genes
Apoptosis
Oxidative Stress

Motor neuron damage as a result of oxidative stress

Not necessarily linked to gene mutation
i.e. SOD1
Post-mortem studies have shown evidence of
increased oxidative by-products
Linked to other mechanisms
Excitotoxicity
Glutamate mediated
Possible mechanisms of disease include:
Production of free radicals
Increased intracellular calcium
Excitatory amino acid transporter 2 (EAAT2) plays a
critical role in the maintenance of low extracellular
glutamate levels.
Decreased EAAT2 functions has been described in
some ALS post-mortem studies
More on Excitoxocity

Goodall and Morrison Expert Reviews in Molecular Medicine. Vol. 8(11) 24 May 2006.
Abnormal Protein Precipitation and/or Aggregation

Abnormal protein aggregates, including Bunina

bodies, ubiquitinated inclusions and neurofilament rich
hyaline inclusions are pathological hallmarks of ALS
Unknown cause and effect relationship
SOD1 mutants can misfold and coprecipitate with
other molecules as well
Cytoskeletal defects

Neurofilament proteins are the

most abundant structural protein
in motor neurons, and
aggregates of neurofilament
proteins motor neurons are
commonly seen in ALS
Can be found as part of
inclusions
Overexpression of peripherin
or alpha-internexin in mice can
cause motor neuron disease
Axonal transport

Axonal transport of materials is essential for neuronal function

and survival
Dynactin is a protein involved in fast retrograde transport
in the axon
Mutations in this gene have been associated with motor
neuron disease
Neuroinflammation

Microglia have been

found to be activated
in parts of CNS
affected by ALS
COX-2 Receptors and
downstream
prostaglandins are
elevated in ALS brains
Apoptosis

Represents eneergy-dependent programmed cell death

In human ALS spinal cord tissue, increases in caspase-1
and -9 activation have been detected
Very unclear how much this plays a role in the
pathogenesis of the disease
Goodall and Morrison. Expert Reviews in Molecular
Medicine. Vol. 8(11) 24 May 2006.
Why Motor Neurons?
Extreme size of cells
High metabolic activity
Sensitivity to mitochondrial dysfunction
Elevated neurofilament content
Reduced capacity to buffer calcium
Medication
Riluzole (Rilutek) is one of the few drugs
effective against ALS and may prevent
progression and prolong life for a few
months or so

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Depression

Very common

Antidepressant medication and

counseling can help patients and their
families cope

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Family related issues

While it may be emotionally difficult, it is important for clients and

caregivers to make informed, carefully considered decisions regarding the
future while the patient is capable of making his or her contribution to
a planned course of action
Patients and their family members should discuss and consider issues such
as legal concerns, home care, assisted care, and institutionalization

Draw up wills and other important documents as early as possible to avoid

legal problems later on, when the patient may be unable to represent his or
her own interests

Legal assistance may be necessary if the patient encounters discrimination over

insurance or employment.

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 Prognosis

Fifty percent of patients die within 3 years of diagnosis

20% live 5 years

10% live 10 years

Hospice care can provide comfort and dignity to patients

and their loved ones

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Conclusions
We do not understand ALS
Familial ALS is caused by genetic mutations and is rare
Sporadic ALS is caused by a combination of:
Genetic susceptibility
Environmental triggers
Motor neuron specific cellular damage
Key Points to Remember
1. Main cause of familial ALS is SOD1 mutations with are gain
of function
2. Bunina bodies are inclusions found in ALS motor neurons
3. Excitoxicity and oxidative damage are likely major
contributors to motor neuron death in ALS
References
Valdmanis, P.N. and Rouleau, G.A. Genetics of
familial amyotrophic lateral sclerosis. Neurology.
2008;70:144-152.
Goodall, E.F. and Morrison, K.E. Amyotrophic
lateral sclerosis: proposed mechanisms and pathways
to treatment. Expert Reviews in Molecular Medicine.
Vol. 8; Issue 11; 24 May 2006.
Mitchell, J.D. and Barasio, G.D. Amyoptrophic
Lateral Sclerosis. Lancet 2007; 369: 2031-41.