Diseases Of NMJ Flashcards
What is the motor unit?
• Alpha motor neuron plus all of the extrafusal fibers that it innervates
What are the neurogenic motor unit diseases?
– Diseases of the peripheral nerve – Lesions of: •Cell body •Axon •Neuromuscular junction •Schwann Cells
What are myogenic NMJ diseases?
– Diseases of the muscle (myopathies)
What NMJ diseasesimpact the soma?
Lou Gehrig’s disease (ALS)
Poliomyelitis
What diseases effect Schwann cells?
Guillain-Barre
Diphtheria
What are the diseases affecting the nerve endings of the NMJ?
Botulism
Alpha-Latrotoxin
Beta-Bungarotoxin
Curare
What NMJ diseases impact the end plate?
Myasthenia gravis
nACHR defects
What NMJ diseases impact the synaptic cleft?
Myasthenias
What NMJ diseases impact the muscle fiber?
Myotonias
Muscular dystrophy
What are the etiology of nerve (soma and/or axon)?
Etiology – Toxins – Drugs – Trauma – Idiopathic – Pathogens
Soma
- Lou Gehrig’s Disease (ALS)
- Poliomyelitis
What are the manifestations of lesions of nerve (doma and/of axom)?
Manifestations:
– Muscle atrophy and weakness
– Hyporeflexia
– Fasciculations and fibrillations
What is polymyelitis?
Polio - polios “grey”
Myelitis - myelos “marrow” + -itis “inflammation.“
Infection causing inflammation of the gray matter in the spinal cord leading to paralysis.
What us the etiology of poliomyelitis?
Etiology
• Small RNA viruses of the Enterovirus genus of the Picornaviridae family.
• Transmission is via fecal-oral route.
What are the clinical features of the poliomyelitis?
- Paralytic poliomyelitis: Profound asymmetrical muscle weakness and signs of LMN lesion
- Extensive paralysis of the trunk may occur
• Mid-cervical involvement (C3-4-5) can paralyze diaphragm,
necessitating ventilation
What is the diagnosis of poliomyelitis?
Clinical Features Polymerase chain reaction (PCR) for detection of poliovirus CSF - Elevated WBC - Mildly elevated protein - Glucose is normal
What is the impact of Schwann cell lesions?
Lesions of Schwann Cells cause demyelination
- Conduction slowing or block
Schwann Cells
1. Guillain-Barre 2. Diphtheria
What is the etiology of Schwann cell lesions?
Etiology:
– Autoimmune attack
– Toxins
What is the alpha laatrotoxin?
Alpha-Latrotoxin
• Toxin in venom of the black widow spider that
causes massive release of ACh by affecting presynaptic exocytotic proteins
What is Beta-Bungarotoxin?
Beta-Bungarotoxin
• Toxin in venom of snake initially provokes
ACh release followed by ACh depletion by acting on proteins in nerve terminals involved in exocytosis
What does the botulinum toxin do?
• BotulinumToxin
• Toxic anaerobic bacterial protease
that reduces ACh release by acting on presynaptic exocytotic proteins
What does Curare do?
- Curare(delta-tubocurarine)
* Blocks nAChRs
What is lambert Eaton syndrome?
This is a presynaptic disorder of neuromuscular transmission in which release of acetylcholine (ACh) is affected
Autoimmune disease
– antibodies attack presynaptic voltage- gated calcium channels
What does Lambert eaton syndrome affect?
Neuro-Muscular Junction
Lambert–Eaton Syndrome
What are the charscteristics of lambert eaton syndrome?
– Muscle weakness and ‘facilitating neuromuscular
block’
– Often found in patients with pulmonary small cell
cancers
– Cell cultures express voltage-gated calcium channels
• Antibodiesmanufacturedagainsttheseproteins
– Antibodies cross-link voltage-gated calcium channels in
motor nerve terminals
• ReducedAChrelease
What are the physiological changes at end plate in lambert eaton syndrome?
Physiological Changes at End Plate
– Amplitude of Mini EPP is unchanged
– Reduced amplitude of EPP
• Reduced quantal content
– Many EPPs do not attain threshold in muscle fibers
– Waxing response in EMG(relates to facilitating neuromuscular
block)
Describe therapy of lambert eaton syndrome
Therapy for Lambert-Eaton Syndrome
– Removal of underlying tumor and immunosuppressive drugs
– Plasma exchange
– Calcium gluconate to enhance calcium influx into nerve terminal
– 4-aminopyridine (potassium channel blocker) to prolong presynaptic action potential and improve transmitter release
What is congenital myasthenias?
- Many forms of congenital Myasthenia
* They usually present at birth and show signs and symptoms before the age of two years
What is congenital myasthenias?
- Many forms of congenital Myasthenia
* They usually present at birth and show signs and symptoms before the age of two years
What are the main forms of myasthenias?
- Deficiency of ACh-esterase in synaptic cleft at end plate
– EPP amplitude is larger and more prolonged than normal
– Motor nerve stimuli separated by long intervals cause single muscle twitches (indicating increased temporal summation)
– Motor nerve stimuli delivered in trains produce temporal summation of EPPs and cause depolarization block of muscle
2. Prolonged opening of channels • 'Slow Channel Syndrome' – Inherited rare condition presents at birth or early childhood • Muscle weakness • Rapid fatigue – Prolonged opening of the ACh channel – A resultant depolarization block
Other forms
– One form where the binding of ACh to nAChR is abnormal
– One form where the ACh-gated channels have very brief opening times
What is myasthenia gravis?
– Chronic autoimmune disease
• Antibodies to nAChRs develop and reduce transmission at the
NMJ
– Genetic susceptibility
What are the symptoms of myasthenia gravis?
Symptoms
– Weakness of somatic muscles
• Not associated with denervation
– Fatigability
– Temporary restoration of strength after rest
Describe antibody interactions
Interaction of Antibody and nAChR
– Antibodies bind to Alpha subunits of nAChR
– Antibodies do not compete with ACh for binding sites on subunits
– Antibodies cross-link neighboring nAChRs
Explain the dynamics of cross-linked nAChRs in end plate membrane
Dynamics of cross-linked nAChRs in end plate membrane
– Endocytosis of nAChRs in end plate membranes
– Lysosomal destruction
– Enhanced removal rate of nAChRs but no enhanced rate of insertion of nAChRs into end plate membrane
– Fall of density of nAChRs at end plate
What are the structural xhanges of the end plate?
Structional Changes at the End Plate – Fewer nAChRs
– Wider synaptic cleft
– Smaller junctional folds
What are the clinical. Features of myasthenua gravis?
Clinical features:
– incidence 1:10,000
– xx : xy = 2:1 (all races), xx age 20-30 , xy age 60-70
– Typical onset: 1st symptom is diplopia in the afternoon, disappears following morning
– Gradual increase in duration of diplopia, followed by ptosis
– Restriction of extraocular movements
– Ptosis compensated by backward tilting of the head and
wrinkling of frontalis muscle
How is Myasthenia Gravis diagnosed?
Diagnosis:
– Repeated clenching and unclenching of fist → rapid loss of strength
– Tensilon test (edrophonium): after injection of Tensilon (ACh- esterase inhibitor) muscular strength recovers temporarily
– Ice pack
– Anti- AChR antibody testing
– EMG
What are the therapies of myasthenia Gravis?
Therapies: – Thymectomy – Immunosuppressing medication: azathioprine, corticosteroids – Pyridostigmine (AChE inhibitor)
• Myasthenic crisis: medical emergency
– Causes: sudden onset of disease, patient becomes
refractory to drug
– ICU treatment, intubation and respirator therapy
Describe myotonia congenita
- Myotonia: delayed relaxation of muscle after voluntary contraction or percussion.
- Myotonia congenita is due to a mutation in the ClCN1 chloride channel.
- The chloride channel defect causes increased excitability
- Muscular hypertrophy can develop despite little physical activity in these patients.
What is myotonia congenita?
Smaller depolarization is required to evoke an action potential and may even cause a train of action potentials
Repetitive firing of the muscle fiber after motor nerve stimulation ceases
Delayed relaxation phase of the neuronal evoked muscular contraction
What is muscular dystrophy?
MuscularDystrophy
Group of disorders that characteristics of progressive muscular
weakness
Duchenne Muscular Dystrophy
Most common X-linked recessive disorder of muscles
Onset in early childhood
Muscle weakness develops progressively
Patients die from cardiovascular and respiratory insufficiency Cause: absence of muscle protein - Dystrophin
Describe the myopathy of muscular dystrophy
• Onset: 3–5 years of age
• Proximal muscle weakness and
calf hypertrophy is common
- difficulty in running or getting up from the ground, frequent falls, or toe-walking
- High serum marker levels of CK
What are the lower motor neuron syndrome?
Lower Motor Neurons (LMNS) - primary motor neurons of the spinal cord and brain stem that directly innervate skeletal muscles.
• Upper Motor Neurons
-neurons that originate in higher regions of the brain (cortex…) and synapse on lower motor neurons.
What are the signs of LMNS?
Signs of LMNS – Muscle weakness (paresis) – Flaccid paralysis – Loss of tendon reflexes – Fasciculations – Fibrillations – Developing muscle atrophy → death of muscle
What are fasciculations and fibrillations in an LMNS?
Fasciculations and fibrillations are signs that muscle fibers are undergoing de-nervation.
• Fasciculations:
– Fasciculationsareirregularspontaneouscontractionsofthemuscle fibers in motor units giving visible twitches at surface of body. Fasciculations by themselves are not always a sign of motor neuron damage
https://www.youtube.com/watch?v=u421daHAgpY
• Fibrillations (EMG!)
– arespontaneouscontractionsofsinglemusclefibers.
Describe the expression nAChRs in muscle
In embryonic muscle fiber the nAChRs are distributed across the entire surface
In adult muscle fiber the pattern of nerve stimulation leads to
aggregation of nAChRs under nerve endin
