PH2113 - Neurodegenerative Disease and Epilepsy 8 Flashcards
What is the mutation to the gene to cause Huntington’s disease?
The lengthened CAG repeat increases capacity of protein to aggregate in vitro producing insoluble polymers
- > 39 glutamines
Polymers may be pathogenic trigger
Aggregates may be protective
What are the effects of the mutant Huntingtin protein?
Alters endocytic and secretory pathways
Proteosomal function
Calcium handling and mitochondrial function
Reduced transport of growth factors
- needed to prevent apoptosis
Triggers
- apoptotic cascades
- free radical production
- causes oxidative stress
- glutamate toxicity
What drugs can be used to treat the symptoms of Huntington’s disease?
Mood disturbances
- anti-psychotic
Depression
- anti-depressants
Impulsiveness and aggression
- anti-epileptics
- valproate
Dystonia/myoclonus
- anti-spasticity
- anti-Parkinson’s
Chorea
- dopamine blocking agents
- dopamine can reduce the effect of the inhibitory indirect pathway
What is the IONIS trial?
UCL and Roche
- 46 patients
- HTT Rx
- anti-sense RNA drug
- up to 60% reduction in mutant HTT in CSF after 3 months
- corresponds to up to 85% reduction in brain mHTT
- may have long term benefit for Huntington’s disease patients
What is ALS also known as?
Motor Neurone Disease
Lou Gehrig’s Disease
What are the two types of motor neurones?
Upper motor neurones
- brain to spine
Lower motor neurones
- spine to muscles of the body
What is the most common variant of Motor Neurone Disease?
Amyotrophic Lateral Sclerosis (ALS)
- both types of neurones affected
What is Primary Lateral Sclerosis?
Motor Neurone Disease affecting only the upper motor neurones
What is Primary Muscular Atrophy?
Motor Neurone Disease affecting only the lower motor neurones
What are the characteristics of Motor Neurone Disease?
Progressive neurodegenerative disorder
Results in loss of cells
- motor cortex
- brain stem
- spinal cord
Lethal
- 2 - 5 years
Adult onset disease
- > 50 years
More common in men
- but not after menopause
Incidence is 2 per 100,000
- familial in 10%
- sporadic in 90%
What is the pathology of Motor Neurone Disease?
Shrinkage and loss of anterior horn cells in spinal cord
Aggregations
- spheroids
- neurofilament aggregations
- axons
- Bunina bodies
- granular inclusions
- cell bodies
- Hirano bodies
- ubiquitinated inclusions in lower motor neurones
Loss of myelinated fibres in corticospinal tracts
Loss of large pyramidal cells in the motor cortex
Muscle atrophy
What are the symptoms of Motor Neurone Disease?
Progressive muscle weakness
- arms
- hands
- legs
Hyperreflexia
- exaggerated reflex
Muscle fasciculations and cramps
- twitches
Slurred speech and dysphasia
Weakening and paralysis
- spreads to trunk of body
- speech
- swallowing
- chewing
- breathing
Most people remain mentally unimpaired despite physical deterioration
What are the environmental risk factors for Motor Neurone Disease?
Age
Family History
Pockets of high prevalence
- Guam
- 50x more
Heavy metal exposure
- doubtful
Viral/prion infection
- uncertain
Variable phenotypes
- suggest role of environment
Smoking
- post menopausal women
What genetic mutations might lead to Motor Neurone Disease?
Mutation superoxide dismutase SOD1 on chromosome 21
- associated 20% familial MND
~ 100 mutations now identified
Most autosomal dominant
- 50/50 chance of offspring having disease
High variation in onset and progression
- different to parents
What is Super-Oxide Dismutase 1?
SOD1
- metalloenzyme
- free radical scavenger
- converts superoxide free radicals into H2O2
- abundant in brain and other regions
- no clear reason for motor neurone vulnerability
Post mortem
- accumulation of mutant SOD1 enzyme
- would alter ability to handle Reactive Oxygen Species (ROS)
