motor neurone diseases Flashcards
characteristics of MNDs
Progressive degeneration of MNDs in CNS innervating skeletal muscles. Attributed with weakness and loss of muscle mass. Also inability to control movements.
Age of onset normally 40-60. Survival often short (approx 4 years). But up to 20 years. Can cause death due to respiratory weakness -> pneumonia,
Can lead to cognitive decline. 35% have mild cognitive deficits in planning, decision making and language (executive functions). Further 5-10% will show signs of frontotemporal dementia.
Brief overview of other MNDs (not ALS or MG)
In order of life expectancy
Progressive Bulbar Palsy (PBP) mainly affects facial, tongue and throat muscles. Causes slurring and difficulty swallowing. 6m - 3y life expectancy.
Progressive muscular atrophy (PMA) initially seen as weakness/clumsiness of hands. more than 5y life expectancy
Primary lateral sclerosis (PLS) is mainly lower limb weakness. can cause hand clumsiness and speech problems. Slow progression: 10-20y life expectancy
Kennedy’s disease is technically not an MND. Increases weakness and muscle wasting. Also causes hormonal changes. No life expectancy change.
Diagnostic tests for MNDs
Blood tests see increased creatine kinase (associated with muscle breakdown) and enzymes.
EMG to detect if muscle activity is normal
Nerve conduction tests to see speed which nerves carry signals
transcranial magnetic stimulation (TMS) measures upper motor neurone activity
MRIs to rule out other diseases with similar symptoms.
ALS symtpoms
Most common MND. affects all motoneurons, leading to weakness and wasting. Stiffness and cramps also occur. Initially tongue, hand and legs affected. Cognitive function and sensations unaffected. 2-5y life expectancy.
Stephen hawking is an example
ALS pathophysiology
Eyelids droop and speech becomes impaired from degeneration of cranial motoneurons.
Degradation of alpha-motoneurons leads to muscle wasting and weakness.
Ventral horn shrinks, seeing decreased levels of ChAT, increased [glutamate] and decreased motoneuron terminal sprouting.
Western pacific ALS
ALS-PDC. Includes symptoms of ALS, PD and dementia.
May have been due to ingestion of palm seeds which contained the neurotoxic beta-NMA. massively increased CSF [glutamate]
Autosomal dominant Causes of ALS
5-10% are familial.
dominant Mutations in chromosome 9 account for 25-40% of familial cases. This protein is highly expressed in motoneurons, influencing the production of RNA from the genes.
dominant Mutation to SOD1 gene in chromosome 21 causes 10-15% of familial. Converts superoxide to hydrogen peroxide and oxygen. In mutation, the SOD1 all aggregate. Excessive activity in MNDs
Rare mutation off senataxin gene in chromosome 9 can cause ALS. normal function is controlling RNA processing.
Recessive and atypical causes in gene mutations for ALS
Autosomal recessive mutation in ALS2 gene in chromosome 2 leads to formation of the short isoform of ALSIN, which is present in all motoneurons, and is associated with ALS in the short form. ALSIN has essential role in development of the axons and dendrites of motoneurons.
Atypical late-onset ALS caused by mutation of vesicle-associated membrane protein B gene in chromosome 20. leads to dysfunctionof IC membrane trafficking.
Causes of sporadic ALS
Glutamate imbalance (too high is toxic)
Dysfunction of ubiquilin2 (which repairs motoneuons)
Disorganised immune responses causes improper functioning of ubiquilin2 - leads to buildup of damaged proteins in the motoneurons.
Environmental toxin exposure increases risk. Double risk in military, who are exposed.
Pathology of degeneration in ALS
Increased glutamate activity causes high IC [Ca]. Can cause apoptosis
SOD1 mutations decrease zinc binding to increases apoptosis, and increase the intermediate filament peripherin. This increases disorganisation in neurofilaments.
mutations in neurofilament genes also lead to disorganisation. The disorganisation of neurofilaments can block axonal transport and lead to apoptosis.
Treatments
No cure.
Symptomatic treatments such as opiates, GABAB agonists (baclofen), riluzole (decreases glutamate release), and edaravone (scavenges free radicals - only clinical trial)
Opiates for pain, baclofen for anti spasticity, riluzole may reduce progression.
Myaesthenia gravis pathology
A chronic autoimmune disease, where antibodies are produced by B-cells for the nAChRs at the NMJ. Other form is antibodies for MuSK protein (an RTK) which develops the NMJ.
Loss of the nAChRs causes weakness in the ocular muscles. Also affects other muscles too.
Myaesthenia gravis diagnosis and treatment
Edrophonium an AChEI used to diagnose. In normal patient does little/nothing, but for myasthenia gravis largely increases muscle strength acutely.
Neostigmine and other AChEIs used as treatment.
Immunosuppressants such as corticosterone can be used to suppress antibody production.
Plasmapheresis (removing plasma and getting rid of antibodies) can be used to reduce the degradation of nAChRs.
Removal of the thymus gland (makes immune cells) can rebalance the immune system
