B3: KING - ALS and Trinucleotide Repeat Disorders Flashcards
Basics - What is ALS
Amylotrophic Lateral Sclerosis
MND affecting both UMNs and LMNs.
Sensory changes not involved
Onset may be Limb or Bulbar initially
Oculomotor (eyes) neurons and Onufs nucleus spared
Most common form of MND
Peak onset 58-63 years
Invariably fatal (usually 2-5 years from diagnosis) neurological condition -> usually from respiratory failure
What are the key pathological mechanisms of ASL
- Excitotoxicity of neurons and glial cells: excitory action of glutamate and related excitory amino acids is transformed into a neuropathological process that can kill of CNS neurons. (too much = toxic)
- Ubiquinated protein aggregates (ubiquenation indicates defective protein folding due to RNA disturbances). Misfolding can arise from mutations, defective RNA processing, endoplasmic reticulum stress (e.g. from icnreased Ca++ uptake), oxidative stress
- Glial Cell Activation (astrocytes and microglia) -> harmful in ALS (but in general can be protective or harmful). This has been linked to SOD1 gene mutations in both glial cells and neurons -> presence of this mutation in both is necessary for disease
- Neurofilament accumulations (in cell body and axons) and Axonal Transport Defects. Neurofilament accumulations may be a cause of consequence of disrupted axonal transport. Mutations in kinesin (anterograde transport) and dynesin (retrograde transport) have been associated with ALS.
Treatment options for ALS?
Only Riluzone shown therapeutic use
What is Ubiquenation?
Ubiquetin is a protein that tags other proteins for degradation
What are the UMN signs of ALS?
Weakness
Spacticity
Incresed Tone
Hyperactive Reflexes
Babinski’s Sign (plantar reflec, indicitive of brain/SC damage)
Clonus (involuntary muscular contractions)
Loss of voluntary movement
What are the LMN Signs of ALS?
Weakness/paralysis Decreased reflexes Decreased tone Fasiculations (muscle twitching) Severe muscular atrophy
Describe Bulbar onset of ALS
Often affects tongue: slurred speech (dysarthria), dysphagia
Usually rapidly progressing
Describe Lims (spinal) onset of ALS
Usually first presents as asymmetrical weakness of one of the limbs
E.g. flail arm syndrome, split hand syndrome
Diagnostic requirements of ALS
No distinctive diagnostic tests - is clinical
Presence of of all three:
1. Evidence of UMN degeneration (by clinical, electrophysiological or neuropathologic examination)
2. Evidence of LMN degeneration (by clinical examination)
3. Progressive spread of symptoms within one region or to other regions
PLUS absence of:
- Electrophysiological or pathological evidence for another disease which might explain the UMN and LMN degeneration
- Neuroimaging evidence of other disease processes that might explain the signs/symptoms
Epidemiology of ALS
90% cases sporadic; 10% familial
Definite risk factors:
Age (40-60)
Males more often- 1:1.4
Suspected risk factors: Military service Elite athletes Toxin exposures Electric shock
What specific mutations have been identified as causes of Familial ALS?
- SOD1 (antioxidant enzyme expressed in all cells in body)
- TDP-43 (may also be associated with sporadic disease)
- FUS: involved in RNA processing; responsible for 5% of familial cases
- C9ORF72 mutations: accounts for 43% of familial ASL; mechanism of pathogenesis unknown
General pathological features of ASL
Loss of UMNs and LMNs Loss of Inhibitory Neurons Extensive Gliosis (activation of glial cells) Proteinacious accumulations Muscle Wasting
Pathology of UMN in ALS
Loss of Betz Cells - large layer 5 pyramidal neurons of the Motor Cortex
Some loss of inhibitory neurons
Corticospinal tract (CST) degeneration
**Suggests that the axons of the UMNs are degenerating
Pathology of LMN ALS
Loss of LMNs
Bunina bodies: nique marker for ALS
Ubiquinated (hyaline) inclusions
Axonal pathological spheroids within the axon
Muscle pathology in ALS
Atrophy
Mixed grouping of atrophied fibre types
Collateral sprouting of nerve fibres
Dying back of NMJs
Describe genetics of Huntington’s Disease
HD is a trinucleotide repeat disorder.
All humans have two copies of the Huntington’s gene HTT, located on Ch 4, which encodes for the huntingtin protein (Htt).
Part of HTT involves a trinucleotide repeat sequence (CAGCAG, etc.). This repeat sequence varies in length between individuals and can change with subsequent generations, or with mutations, etc.
When it reaches a certain length, it produces a mutant variant of the protein huntingtin: mHtt. This is the disease-causing protein.
Mutated HTT is dominant - one copy of HTT will cause disease.
What is the risk of Huntington’s Disease, based on number of CAG repeats?
10-35: will not be affected
> 40: will definitely be affected
36-39: usually affected, but risk high in offspring as repeats often increase with subsequent generations
*Note that higher numbers of CAG-repeats are also associated with younger age of onset. I.e. juvenile huntington’s usually have 50-60 repeats
Describe epidemiology of Huntingon’s
Average age of onset 30-50, (but can theoretically occur at any age) with a course of ~15-20 years before death
Juvenile Huntington’s typically presents at ~20yo and is faster-progressing
General incidence = 7/100,000
Tasmanian incidence = 14/100,000 (founder effect)
Neurologically, Huntington’s Disease involves…
Progressive degeneration of the frontal lobes and striatum -> atrophy of the striatum
Also affects basal ganglia
Symptoms/Signs of Huntington’s Disease:
Chorea: sudden/uncontrollable movements
Loss of, or exaggerated facial expression, slowed speech, chewing or swallowing
Features of demenia, abnormal behaviour, personality changes, psychiatric features (e.g. of OCD, anxiety, depression)
What is Spinocerebellar Ataxia (SCA)
A group of ~60 conditions. Involving Ataxia (loss of co-ordination) - but cognition unaffected.
Involves progressive degeneration of the SC and Cerebellum (cerebellar atrophy can be seen)
Around 30 different genes involved - mostly autosomal dominant.
Onset in childhood or adulthood. (all this varies with condition)
Nearly all SCAs involve expansion of CAG (glutamine) - i.e. most are polyglutamine disorders
General signs/symptoms of SCAs:
Decreased co-ordination of gait, hands, eye movement, speech.
Symptoms vary depending on the gene involved.
Risk factors for SCAs:
PolQ expansions in ataxin
What is Friedreich’s Ataxia?
One of the most common forms of SCA
Genetic features of Friedreich’s Ataxia
Abnormal GAA repeats (>100( in an intron of the frataxin gene (Ch9)
Results in silencing of the Frataxin Gene -> leading to defective iron metabolism and oxidative damage to mitochondria
Neurological feautres of FA?
Degeneration and Strophy of spinal tracts and myelinated peripheral motor nerves
Epidemiology of FA
1/50,000 -> most common inherited form of SCA
Onset of symptoms betwee 5-15
Eventually wheelchair-bound
Major cause of death is due to cardiacdefects (remember affects mitochondria) -> usually in late 30-40s
Symptoms of FA
Loss of co-ordination Initial difficulties walking Speech difficulties Vision impaiements Diminished tendon reflexes Scoliosis Foot deformities Cardiac defects (major cause of death in late 30-40s) Diabetes
