13 - Amyotrophic Lateral Sclerosis (ALS) Flashcards
DONT NEED TO KNOW: Groups of genes associated with ALS
When are Babinski signs common in people?
Alcoholics and ALS patients
True or false? Head trauma can be linked to ALS, Parkinson’s and Alzheimer’s?
True
When is loss of child implicated in the development in sporadic ALS?
When it is accidental (eg. not due to cancer etc.)
True or false? Drinking reduces chance of ALS
True
What is amyotrophic lateral sclerosis?
Amyotrophic lateral sclerosis (ALS) – also referred to as motor neurone disease (MND) in most Commonwealth countries, and as Lou Gehrig’s disease in the United States – is a debilitating disease with varied etiology characterized by rapidly progressive weakness, muscle atrophy and fasciculations, muscle spasticity, difficulty speaking (dysarthria), difficulty swallowing (dysphagia), and difficulty breathing (dyspnea). ALS is the most common of the five motor neuron diseases.
What are the signs and symptoms of ALS?
- The disorder causes muscle weakness and atrophy throughout the body due to the degeneration of the upper and lower motor neurons.
- Unable to function, the muscles weaken and exhibit atrophy. Individuals affected by the disorder may ultimately lose the ability to initiate and control all voluntary movement, although bladder and bowel sphincters and the muscles responsible for eye movement are usually, but not always, spared until the terminal stages of the disease.
- Cognitive function is generally spared for most patients, although some (about 5%) also have frontotemporal dementia.
- A higher proportion of patients (30–50%) also have more subtle cognitive changes which may go unnoticed, but are revealed by detailed neuropsychological testing.
- Sensory nerves and the autonomic nervous system are generally unaffected, meaning the majority of people with ALS will maintain hearing, sight, touch, smell, and taste.
Describe the pathophysiology of ALS (3)
- The defining feature of ALS is the death of both upper and lower motor neurons in the motor cortex of the brain, the brain stem, and the spinal cord.
- Prior to their destruction, motor neurons develop proteinaceous inclusions in their cell bodies and axons. This may be partly due to defects in protein degradation.
- These inclusions often contain ubiquitin, and generally incorporate one of the ALS-associated proteins: SOD1, TAR DNA binding protein (TDP-43), or FUS
What are the three ALS-associated proteins?
- SOD1
- TAR DNA binding protein (TDP-43)
- FUS
These are associated with ubiquitin to form inclusions commonly observed in ALS affected motor neurons.
What does sclerosis mean?
Scarring or hardening
What is FTD?
Frontotemporal dementia (FTD) is a neurodegenerative disease characterized by severe frontotemporal lobar degeneration. Distinguished from Alzheimer’s disease and Lewy body dementia based on the fact that it does not manifest with amyloid plaques, neurofibrillary tangles, or Lewy bodies.
Second only to Alzheimer’s disease (AD) in prevalence, FTD accounts for 20% of pre-senile dementia cases. Symptoms can begin to appear on average around 45 to 65 years of age, regardless of gender. The most common symptoms include significant changes in social and personal behavior, as well as a general blunting of emotions. Currently, there is no cure to FTD, but there are treatment options available that help alleviate the symptoms.
GGGGCC expansions of C9orf72 gene can cause ALS and FTD
What is FUS?
RNA-binding protein FUS (Fused in Sarcoma) is a protein that in humans is encoded by the FUS gene
The disease entities which are now considered subtypes of FTLD-FUS are atypical frontotemporal lobar degeneration with ubiquitinated inclusions (aFTLD-U), NIFID (otherwise known as neurofilament inclusion body disease) and basophilic inclusion body disease (BIBD), which together with ALS-FUS comprise the FUS-opathies
Recount the abstract of the study that generated pluripotent stem cells (iPS) from an ALS patient. (5)
- The generation of pluripotent stem cells from an individual patient would enable the large-scale production of the cell types affected by that patient’s disease.
- These cells could in turn be used for disease modeling, drug discovery, and eventually autologous cell replacement therapies.
- Although recent studies have demonstrated the reprogramming of human fibroblasts to a pluripotent state, it remains unclear whether these induced pluripotent stem (iPS) cells can be produced directly from elderly patients with chronic disease.
- We have generated iPS cells from an 82-year-old woman diagnosed with a familial form of amyotrophic lateral sclerosis (ALS).
- These patient-specific iPS cells possess properties of embryonic stem cells and were successfully directed to differentiate into motor neurons, the cell type destroyed in ALS.
What are two alternative names for ALS?
- Lou Gehrig’s disease
- Charcot’s disease
What are the two forms of ALS?
- Idiopathic (sporadic)
- Heritable (familial)
What is the incidence of sporadic ALS?
1.5-5/100,000 (1 in 1000 deaths)
What percent of ALS can run in families?
10%
ALS can more often be diagnosed in what gender?
Men, by about 1.5x
What is the common age of onset of ALS?
55-65 years
What causes most ALS patients to die?
- Respiratory failure
- Pneumonia
Only 25% survive more than 5 years post-diagnosis
What are often the first symptoms of ALS? (2)
Difficulty in swallowing (causing weight loss) and breathing
True or false? ALS doesn’t affect senses and bladder/bowel functions
True
What does ALS selectively affect?
Motor neurons
Degeneration in the motor cortex: overactive tendon reflexes, Hoffmann signs, Babinski signs, clonus
Degeneration in the brain stem/spinal cord: muscle atrophy, weakness and fasciculation
