ALS Genetic disorder

Amyotrophic Lateral Sclerosis (ALS)

Kim MatiasNoel RabajanteRommuel RebatisSylene Reyes

Background history

Jean- Marie Charcot (1825-1893) noted the first reports of the characteristics of ALS in 1874, and named the fatal syndrome based on what he found. He was a noted French neurologist who has been called “the Father of Neurology”, and explained how the central nervous system works.

Background history

ALS is also known as Lou Gehrig's Disease, after the famous baseball player who died of the disease in 1941.


• A progressive neurodegenerative disease that affects nerve cells in the brain and the spinal cord.

Normal vs. ALS

• Normally the muscle tissue is supplied by the nerves. It all happens in the muscle fiber and produce an action potential, allowing the muscle to contract.

• In ALS the motor nerve cells in the anterior horns of the spinal cord and in the motor nuclei of the brain stem are lost affecting the innervation of the muscle.


A-myo-trophic comes from the Greek language. "A" means no or negative. "Myo" refers to muscle, and "Trophic" means nourishment

"No muscle nourishment."

Early symptoms of ALS often include:•increasing muscle weakness, especially involving the arms and legs, speech, swallowing or breathing. •When muscles no longer receive the messages from the motor neurons that they require to function, the muscles begin to atrophy (become smaller). Limbs begin to look "thinner" as muscle tissue atrophies.

• As motor neurons degenerate, they can no longer send impulses to the muscle fibers that normally result in muscle movement.


Genotypic Apperance

In humans, the SOD1 gene is located on chromosome 21 at location: 21q22.11. The 9,310 base pair gene has 5 exons and encodes a short 153 amino acid protein.


Phenotypic Appearance

A CNTF-null allele modulates the age of onset of the dominantly transmitted disease amyotrophic lateral sclerosis (ALS). Mutations in both SOD1 and CNTF lead to early-onset ALS (age 25) and death within 11 months (the third-generation male in the diagram). The third-generation female with a SOD1 mutation but no CNTF mutation did not present with the disorder until the age of 54

CNTF gene• The protein encoded is a polypeptide

hormone and nerve growth factor.

• The protein is a potent survival factor for neurons and oligodendrocytes and may be relevant in reducing tissue destruction during inflammatory attacks.

Type of mutation• Sporadic - the most common form of ALS in the

United States - 90 to 95% of all cases. It is not inherited from parents, but arises via a mutation and can pass it to their children.

• Familial - occurring more than once in a family lineage (genetic dominant inheritance) accounts for a very small number of cases in the United States - 5 to 10% of all cases.

• Guamanian - an extremely high incidence of ALS was observed in Guam and the Trust Territories of the Pacific in the 1950's.


• About 5—10% of ALS is familial, with a Mendelian pattern of inheritance. A defect on chromosome 21, which codes for superoxide dismutase, is associated with approximately 20% of familial cases of ALS, or about 2% of ALS cases overall.


Type of mutation

What is superoxide dismutase?

are enzymes that catalyze the dis-mutation of superoxide (O2

−) into oxygen and hydrogen peroxide. Thus, they are an important anti-oxidant defense in nearly all cells exposed to oxygen.

Cause of mutationThe most common ALS-causing

mutation is a mutant SOD1 gene.


Researchers have hypothesized the ff:• mutant SOD1 takes on a toxic gain-of-function

form, causing a wide range of cellular defects including mitochondrial dysfunctions, oxidative stress, calcium misregulation, aggregation of aberrantly processed proteins, endoplasmic reticulum (ER) stress, axonal transport disruption, neurotransmitter misregulation, programmed cell death and inflammation.

• While genetic mutations in SOD1 cause familial ALS, defects in normal post-translational modifications can cause sporadic ALS in patients with wild-type SOD1 genes .


Mutation Rate

• Affects 1.89 per 100,000 a year and prevalence average of 5.2 per 100,000

• male/female ratio 1.5:1• Approximately 2/3 of patients with typical ALS have a spinal

form of the disease.• Most common motor neuron disorder in adults.


Symptoms• Common symptom:

fasciculations (a small, involuntary muscle twitch).

• muscle weakness affecting an arm or a leg

• nasal speech (difficulty in swallowing or speaking)

• will not be able to stand or walk• problems with memory or

decision-making• difficulty in breathing


DiagnosisALS is difficult to diagnose because it has similar symptoms of other neuromuscular disorders. It is through clinical examination and many diagnostic tests that a diagnosis for ALS can be established. Some of the procedures include

• spinal tap • x-rays, including magnetic • resonance imaging (MRI) • myelogram of cervical spine

Treatment• No cure • riluzole (Rilutek)• Physical therapy and

special equipment • Speech therapist• Nutritional support• use of nocturnal

ventilatory assistance• mechanical ventilation

(respirators)• Social workers and home

care and hospice nurses


Research Being Done

• The National Institute of Neurological Disorders and Stroke

• studies in animals• development of innovative cell culture

systems• develop biomarkers for ALS• testing of drug-like compounds, gene therapy

approaches, antibodies and cell-based therapies


Ice Bucket Challenge

•sometimes called the ALS Ice Bucket Challenge

•an activity involving dumping a bucket of ice water on someone's head to promote awareness of the disease amyotrophic lateral sclerosis (ALS) and encourage donations to research.

References• http://www.powershow.com/view/dafc-NzVjN/

Amyotrophic_Lateral_Sclerosis_powerpoint_ppt_presentation

• http://www.alsa.org/about-als/what-is-als.html

• Turner, B. and Talbot, K. (2008) Transgenics, toxicity and therapeutics in rodent models of mutant SOD1-mediated familial ALS. Progress in Neurobiology 85 (1): 94-134.

• Faes, L. and Geert, C. (2011) Mitochondrial dysfunction in family amyotrophic lateral sclerosis. J Bioenerg Biomembr 43: 587-92.

• Bosco et al. (2010) Wild-type and mutant SOD1 share an aberrant conformation and a common pathogenic pathway in ALS. Nature Neuroscience 13: 1396-1403.

• Furukawa, Y. and O'Halloran, T. (2005) Amyotrophic lateral sclerosis mutations have the greatest effect on the Apo- and reduced form of SOD1, leading to unfolding and aggregation. J Biol Chem 280 (17): 17266-74.

• Zinman, L. and Cudkowicz, M. (2011) Emerging targets and treatments in amyotrophic lateral sclerosis. The Lancet Neurology 10 (5): 491-90.

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ALS Genetic disorder