Myasthenia gravis, Lems, and botulism Flashcards
Breifly explain 3 mechanisms by which Ach auto-antibodies could cause NMJ dysfunction
This is seen in myasthenic syndromes. here are 4 mechanisms.
In Myasthenia Gravis
- IG1 antibodies specific to the ACHR receptor bind froming cross links between the variable arms of the antibody. This drives the internalisation of the receptor, driving a defficiency of the in ACHR and the the ability of the motor end plate to respond in NMJ fucntion.
- The binding of antibodies to the morot end plate ate ACHR receptors can induced the recruitment of subunits of the complement cascade. This is a degredation cascade that will punch holes/channels in the muscle fibres of the motor end plate. As this is made up of many cells they can repair damge, but repair is cocommitant with inflamation which widens the synaptic cleft and reduces the folds in the motor end plate. Hence the efficacy of signalling the NMJ is reduced.
- Alternative forms of MG result from the tragetting of Muscle specific Kinase (MuSK) or Lipoprotein related protein 4 (LRP4). These are part of a postsynaptic complex whos downstream siganlling is important to the clustering ACHRs. In this case the binding of antibodies simoly acts as a hinderence to protein interactions and signalling.
Lamber-Eaton Myasthenic syndrome
- In this case antibodies taget the pre-synatpic process of the NMJ. They target P/Q type calcium channels binding to cause their internalisation. Hence this inhbits the role of calcium entry in motivating SNARE protein mediation of ACH release. This is commonly asscoiated with a overlap of antibodies targetting cancer cells, hence the srong link to small cell lung cancer (50%)
What is myastenia gravis?
Myasthenia gravis is an autoimune disease charcaterised by the dysfunction of he NMJ.
Fatigable weakness of reproximal limbs, bulbar function and respiratory systems is common.
outline the normal functional mechanisms of the NMJ.
The NMJ acts via ACH release confering movement.
- The depolarisation of the pre-synaptic node results in the activation of voltage gated calium channles and the subsquent influx of calcium down the concentration gradient.
- cacium ion entry acts on caclium sensitive SNARE proteins that mediate the fusion of cystoplasmic vesicles to the cell membrane to drive the exocytosis of stored ACH into the synaptic cleft.
- Ach will diffuse down its conc grad across the synaptic cleft and bind to nicotinic ACH receptors.
- These ACH receptors are found on the corners of several folds in the motor end plate and their activation drive sodium entr and depolarisation. This is turn will recruit voltage gated Na channels in the pits of folds to pottentiate depolarisation in the AP firing.
- The system is turned off via Acetylcholinesterase which breaks ACH down to ACETYL and CHOLINE.
- Acetyl diffuse away whilst Choline is taken back up into the pre-synaptic terminal via co-transport with sodium down a conc grad.
It is the function of these Nicotinic ACH receptors that is drisrupted in MG.
Within the NMJ they are key proteins needed for efficient function.
- A protein known as Agrin binds to the post-synaptic comples that consists of MuSK and LRP4.
- This complex will autophosphoryalte itself and several other targets involving: Postynaptic protein downstream kinase 7 (DOK7), Rapsyn, and the delta subunit of ACHRS.
- This downstream action mediates the clustering of ACHRs at the NMJ. hence it is critical to their function.
- Familial forms of MG hav reported muattions in some of these components and in rarer autoimmune forms these components are targetted.
What is the structure of the ACHR?
ACHR
- 2 alpha subunits, which is where ACH binds, 1 per unit.
- 1 beta
- 1 delta (weird F)
- 1 gamma
in image alpha, gamma, alpha,theta and beta
Which receptor function is lossed in MG?
Nicotinic ACHR
Which proteins controll the clustering of ACHRs? What forms of MG have these been asscoiated with?
Within the NMJ they are key proteins needed for efficient function.
- A protein known as Agrin binds to the post-synaptic comples that consists of MuSK and LRP4.
- This complex will autophosphoryalte itself and several other targets involving: Postynaptic protein downstream kinase 7 (DOK7), Rapsyn, and the delta subunit of ACHRS.
- This downstream action mediates the clustering of ACHRs at the NMJ. hence it is critical to their function.
- congenital forms of MG hav reported muattions in some of these components and in rarer autoimmune forms these components are targetted.
Outline the epidemiology in gender in MG?
This effects around 1 in 17.
- If occuring in younger individuals it tends o have a higher risk in women,
- Effecting in older ages is more common in men.
This also varied based on the form with rarer MuSK and LRP4 targeted forms being more common in women.
Thymoma related froms are more common in men.
what are the core symptoms of MG?
MG can be defined by its fatiguable weakness, this being that weakness progressivel worsens over a day and when trying to use a muscle more.
-Limbs: There is weakness in the proximal limbs, arms and legs, importantly senstaion and reflexes are unaffected as MG is soleley a muscular issue.
- Ocular: patients often suffer from Ptosis-slacking of the eye over the day, and Opthalomoplegia- which is issues with oculomotor movement of the eye. (A KEY feature of MG is the daily+weakly varibility of the severity of these symptoms.)
- Important pupil dialtion is not effected as these ae served by muscharinic ACHRs. hence, asymmetic pupils is a sign of a different disease.
- brief improvement to Ptosis can be made by holding a icepack over the eye.
- Bulbar function- Commonly see symptoms immilar to bulbar palsy.
- dysphagia, issue swallowing.
- dysathria- slurring of words and speech.
- Respiratory- usually measured using Forced vital capacity (FVC) reduction as a sign.
- They also show a shorteness of breath.
- Dyspnoea- Hyperventilation during sleep.
-Thymus gland effects.- Commonly see hyperplasia, enlargement of the thymus gland in 80% of patients. This is related to an overlap with Thymomas (tumour), with 10% of thymoma patients developing MG and 30% of MGs haveing a thymoma,
How do we diagnose MG? discuss each one critcally
Basic methods involve the tensilon test:
- This involves the use of a anticholinesterase like edrophonium.
- This prevents ACH breakdown proloning action at the motor end plate, and thus briefly imporving NMJ function.
- We should see a ‘perking’ up of symptoms in MG patients.
- ve This is largerly not used not due the effects of the Ach flood in the blood leading to muscharinic actions like heart block(slowing of the heart rhyhm) or diarrhoea.
Now days electrical methods are mroe common measuring responses with the electromyography.
REPETITIVE NERVE STIMULATION
- This involves the directly stimulation the muscle fibre and recording the APs fired in response.
- normally the amplitude is maintained due to safety factor, this is that we have more receptors and channels than needed to fascilitate an AP SO THERES NEVER ISSUES.
- THE decline in ACHR in MG means this is LOST and thus we observe a decline in the firing.
-ve some myasthenic syndromes stem from pre-synaptic dysfunction and this is a measure of post-synaptic function.
Single fibre myography
- This is a more specific test to MG
- This inolves stimualting a single motor neurons and thus all the motor fibres it serves in the MOTOR UNIT.
- The firing of this collection of motor fibres has a distinctive Consistent firing pattern characterised in a WAVE.
- issues with NMJ function in MG means that the firing is not consistent and thus we observe varibaility or ‘JITTER’ in the wave.
Serology.
- A farily novel method which asseses the blood plasma for pathogenic antibodies.
- in MG antibodies for: ACHR, MuSK, LRP4 can be found.
- Also can see antibodies fro skeltal muscle like Titin or he rynaoidine receptor. These are NOT pathogenic but stem from muscle tissue damage.
- ve This can lead to a FALSE NEGATIVE in Seronegative cases. This is often seen in Ocular MG where there are no antibodies in the plasma.
basic methods like showing not pupil action, the ice pack test, variability in ocular symptoms is a way to differentiatie MG from other motor deficits.
why are the muscles supplying the pupils sparred in MG? Equally why are reflexes and sensation in limbs functional?
limb senstaion and reflexes are unaffected as MG is soleley a muscular issue.
pupil dialtion is not effected as these ae served by muscharinic ACHRs. hence, asymmetic pupils is a sign of a different disease.
What is ocular MG?
- Ocular MG occurs when only the ocualr deficits appear.
- This common asscoaited with absence of apthogenic anitbodies in serology study.
- This can spread to be more general, if not antiboides are seen in serology for 18 months then it is unlikely this will happen.
Discuss the relationshipo between the thymus gland and MG?
- Hyperplasia, enlargement, of the thymus gland can be seen in 80% of cases.
- In severe cases a thymoma forms.
- in individuals with thymoma 10% develop MG, in individuals with MG 30% have thymoma.
- It is thought dysfunction here leads to the rpoduction of skeletal muscle targetted antibodies which down stream results in the the autoimmune targeting of the NMJ.
- evidence is demonstarted in trail, Thymectomy allows withdrawal from treatement in 30% of patients.
- In more long term trials in which this was done alongside steroid treatment with prednisolone, The found that this was more effective than prednisilone alone, with patients MG scores improving and then requesting reduced dosage of steroid.
Discuss the variation in the condition see by the tragetting of MuSK or LRP4 over ACHR
Besides the core phenotype related to IgG1 targeting of ACHR there are froms tragetting MuSK and LRP4
The MuSK phenotype
- More resistant to first line treatement although MABs like Rituximab are effective.
- Skews towards more Bulbar and repiratory deficits
- More common in women.
- Does not tend to be ascoiated with thymoma and thus not improved by thymemctomy.
LRP4 phenotype.
- very rare with simmilar symptoms to the MuSK phenotype just MILDER.
- again more common in women.
Outline the human leukocyte antigen system and its relation to MG
The human leukocyte antigen (HLA) system is related to the regualtion of the immune system. They form the somponents of the Major Histocompatibiltiy complex (MHI).
- These cell surface complexes mediate the immune sytem intercations in humans.
Recently they have been related to allele specific predipostions to MG. showing infleunce on the age of onset.
- there are 2 classes 1 (B variants), 2(DR and DQ variants.
- HLA DR3, B8 have been associated with EOMG and thmus hyperplasia cases, more commonly seen in females.
- HLA DR2, B7 and DRB1 have been relates to LOMG, rayanodine antibodies and Thmymoma formation and are more common in males.
- MuSK MG has been linked to the risk allele HLA DQ5.
oultine drug induced and transient neonatal MG?
ransient neonatal MG
- seen in the offspring of MG mothers.
- results of ACHR antibodies crossing in placental transfer.
- This is only a transient deficit which is recovered following the babies av=bility to produce its own antibodies.
- Hence it is impornatnt doctors know the mothers condition so they can provide support to babies in the critical period.
Drug induced- This is related to iatrogenic cause of the disease
- Penicillamine can cause the production of pathogenic antibodies.
- Inteferon- alpha 2b is related to the inflamatory system.
- Bone marrow transplants- This can confer the trasnfer of pahtogenic antibodies.
