Neuromuscular Disease Flashcards

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1
Q

What are the six different types of peripheral nerve disorders and what are they?

A

Sensory neuronopathies: loss of sensory neurons in dorsal root ganglion produces only sensory manifestations.

Motor neuronopathies: loss of motor neurons in the ventral horn causes motor manifestations.

Radiculopathies: loss of sensory and motor axons (nerve root) produces both sensory and motor symptoms.

Neuropathies: diseases of Schwann cells can cause demyelinating neuropathies.

Neuromuscular transmission disorders: Disease of presynaptic or postsynaptic cells produce disorders of neuromuscular junction.

Myopathies: diseaes of muscle cells produce myopathies.

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2
Q

What can cause sensory neuronopathies?

A

Loss of sensory neurons is rare but can be caused by:

  • Toxins (cis-Platin, to much B6/pyridoxine)
  • Anti-Hu antibodies (paraneoplastic syndrome)
  • Associated with Sjogren’s syndrome
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3
Q

Describe the regeneration process in motor neuron disease. What feature of motor neuron disease does this slide demonstrate? How will this muscle respond during an EMG?

A

Motor neurons that are lost do not regenerate but surrounding motor neurons generate new processes to innervate the old, denervated muscle fibers.

As the image shows, many cells have completely atrophied and a few have hypertrophied in order to compensate. The EMG will look abnormal because there will be fewer, but larger, motor units which are trying to innervate as much of the muscle as possible. The EMG will show significantly larger amplitudes than normal muscle and the motor unit potentials are greatly reduced.

Denervated muscle fibers show small spontaneous fibrillations that are much smaller than normal motor unit potentials.

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4
Q

What is Amyotrophic Lateral Sclerosis? Which neurons are affected? Is it genetic or sporadic?

A

Amyotrophic lateral sclerosis (Lou Gehrig’s disease) is a progressive motor neuron disease characterized by the degeneration of upper and lower motor neurons. Sensory neurons are not affected and the autonomic nervous system is usually spared. Incidence of the disease is very common and is usually sporadic, only about 10% is genetic.

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5
Q

What is spinal muscular atropy? What neurons are involved and what is the cause? What kinds of treatments are available?

A

Spinal muscular atropy is characterized by a progressive loss of motor neurons (sparing sensory) due to the loss of the SMN1 gene, which is replaced by SMN2. 100% of the SMN1 produced is fully functional while only 10% of the SMN2 produced is functional (90% is alternatively spliced so that it lacks exon 7 which makes it nonstable and truncated). The 20% SMN2 produced by two functional copies is not sufficient to prevent motor neuron death.

Current therapy involves using antisense oligonucleotides that bind to the intron between 7 and 8 to prevent the splicing out of exon 7.

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6
Q

What are examples of other motor neuron diseases?

A
  • Polio
  • Other kinds of enteroviruses
  • HIV
  • West Nile virus
  • Pompe disease (lack of alpha-glucosidase)
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7
Q

What are radiculopathies? What can cause them?

A

Radiculopathies involve a lesion to the spinal root. The sensory axons degenerate in the root and the motor axons degenerate distal to the lesion. Muscles that don’t have collateral innervation atrophy. Sprouting of intact motor neurons occurs in partially denervated muscles.

Radiculopathies are usually caused by compression of a nerve secondary to herniated disks or boney overgrowth (arthritis), most often at C7 and L5. Spinal stenosis can also cause radiculopathies in the lumbar region.

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8
Q

What are neuropathies and how do they often present? What can they be caused by?

A

Neuropathies are caused by many things and are usually length dependent–meaning the distal aspects of the longest axons die back, resulting in motor weakness, diminished reflexes, pain, and progressive sensory loss which is worst in the most distal extremities. Partially denervated muscles are maintained by sprouting to a degree.

Axonal neuropathies occur because PNS neurons are the longest cells in the body making them particularly vulnerable. Damage to any section of the axon results failure to transmit action potentials, therefore, demylination disorders or the inability to transport cargo to and from the cell body results in neuropathy. For example, deletion or duplication of PMP22 results in an insufficient amount of myelin or, conversely, its destabilization and destruction.

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9
Q

What is Charcot-Marie-Tooth disease?

A

Charcot-Marie-Tooth disease is a demyelinating disease caused by the presence of an extra copy of PMP22. Overexpression results in the destabilization of myelin and it’s destruction. It is characterized by distal muscle atrophy and sensory loss due to failed saltatory conduction. There is currently no treatment.

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10
Q

How does transmission at the neuromuscular junction occur?

A

An action potential causes the depolarization of voltage dependent calcium channels which open and allows calcium to promote the fusion of ACh vesicles with the presynaptic membrane. ACh binds receptors on the postsynaptic cell and is cleaved by acetylcholinesterase which is bound to the basal lamina at the NMJ.

ACh binding to its receptor induces an endplate potential by causing sodium influx which depolarizes the cell and propagates an action potential in the skeletal muscle. Vesicle release at the NMJ is sufficient to cause a postsynaptic action potential in the non-diseased state.

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11
Q

What are some causes of NMJ disorders?

A
  • Nerve gases: irreversibly bind ACh esterase
  • Botox: cleaves membrane fusion protein SNAP-25
  • Curarine: blocks ACh receptors
  • Tetrodotoxin: blocks postsynaptic sodium channels
  • Lambert-Eaton syndrome: caused by autoantibodies against presynaptic voltage dependent calcium channels
  • Myasthenia gravis: caused by autoantibodies against the ACh receptor or its associated proteins (Musk)
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12
Q

What is the safety factor and what is its relavence to NMJ disease? Give an example of a pre and post synaptic defect? How are they treated?

A

A single action potential in a motor neuron is sufficient to initiate an action potental in the postsynaptic muscle. When there is insufficient ACh reaching the receptor (presynaptic defect) or a reduced number of functional receptors (postsynaptic defect), transmission can fail and cause disease.

In Lambert-Eaton syndrome, repetitive stimulation results in intracellular increase in calcium levels, eventually permitting vesicle fusion so presynaptic defects show an increment in performance with repetitive stimulation.

In myasthenia gravis, repetitive stimulation results in depletion of the pool of immediately releasable synaptic vesicles, so eventually an insufficient amount of ACh is present to cause muscle activation.

Pre and postsynaptic disorders can be treated with ACh esterase inhibitors to increase the amount of ACh in the synaptic space.

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13
Q

What is a motor unit?

A

A motor neuron and all of the muscle fibers it innervates. One neuron innervates multiple muscle fibers, one muscle fiber is innervated by only a single neuron.

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14
Q

What is the purpose of empty vesicle transport?

A

Some neurotransmitters are synthesized in the cell body and transported down to the axon terminal. Other neurotransmitters are synthesized in the terminal, so empty vesicles with a low pH are transported to the terminal where they are loaded via an ACh-H+ exchanger. Its purpose is to provide empty vesicles for recycled neurotransmitters to be loaded into.

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15
Q

How many vesicles are present in the axon terminal and what proteins are responsible for docking and fusion? How much acetylcholine is in each?

A

Each vesicle contains 6000-10000 ACh molecules.

  • Immediate (primary) store: 1,000 vesicles
  • Mobilization (secondary) store: 10,000 vesicles
  • Reserve (tertiary) store: 100,000 vesicles

Synaptobrevin is a vesicle membrane protein which binds two neuronal cell membrane proteins, SNAP-25 and syntaxin, to dock primary vesicles at the terminal membrane. Loss of any of these proteins results in NMJ disorders.

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16
Q

How does depolarization cause vesicle fusion at the axon terminal? How many vesicles are released?

A

Depolarization causes calcium influx which binds synaptotagmin on the vesicle surface and mediates fusion. About 20% of primary vesicles are released by each action potential and the cell needs about 1 second to convert secondary vesicles into primary ones.

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17
Q

What proteins are relevant to the diffusion of acetylcholine in the synaptic cleft?

A

Acetylcholinesterase is responsible for the breakdown of ACh.

Nicotinic acetylcholine receptors are present on the postsynaptic membrane. These are transmembrane pentamer channels made up of four different subunits and bind two acetylcholine. This is a cation receptor that permits ions to flow in or out depending on the membrane potential and their electrochemical gradients.

18
Q

What type of ions affect resting membrane potential?

A

Those that cannot cross the membrane

19
Q

What is the relevance of the other proteins involved in the neuromuscular junction protein complex?

A

The complex contains a protein called muscle-specific tyrosine kinase (MuSK) which may be the target of autoantibodies.

20
Q

What ions is the acetylcholine receptor permeable to? Which ones meaningfully contribute to a change in membrane potential when the receptor is open?

A

The acetylcholine receptor is permeable to small monovalent and divalent cations:

  • Sodium
  • Potassium
  • Lithium
  • Calcium

Only sodium and potassium contribute significantly under physiologic conditions.

21
Q

What is the threshold of activation for skeletal muscles? What is the implication for those with NMJ diseases under circumstances of constant activation (when secondary vesicles cannot be mobilized)?

A

The threshold of activation is -50 mV and each normal vesicle increases the postsynaptic potential by about 0.4 mV. If 20% of primary vesicles are released by each action potential, then each wave will contain fewer vesicles if the secondary ones have not replenished the primary ones. While the end plate potentials will get smaller, they still exceed threshold in the normal neuromuscular junction, so action potentials still occur after repeated stimulation (safety factor). If the NMJ is impaired, not all end plate potentials will induce an action potential. As a result, fewer muscle cells are depolarized and contraction is weaker.

22
Q

What is a compound muscle action potential? What is its clinical relevance?

A

If all of the lower motor neurons innervating a muscle are directly stimulated, then all of the muscle fibers will generate action potentials if the NMJ is normal. The sum of the voltage of these muscle action potentials is the compound muscle action potential and remains constant after repeated simulation under normal physiologic conditions because the safety factor is sufficient to always induce an action potential. If the NMJ is impaired, not all end plate potentials stimulate an action potential and the CMAP vaires.

23
Q

What compounds impair the NMJ?

A
  • Botox
  • Organophosphorous gases
  • Succinylcholine for transient pharmacologic paralysis
  • Snake venom
24
Q

How is the neuromuscular junction impaired in Lambert-Eaton Myasthenic Syndrome?

A

Patients have antibodies directed against voltage gated calcium channels resulting in decreased calcium influx with depolarization. Patients have fluctuating, symmetric weakness in proximal limb muscles at rest which may improve during brief exercise because repeated stimulation allows calcium levels in the presynaptic terminal to rise.

25
Q

How is the neuromuscular junction impaired in botulism? Tetanus?

A

Clostridium botulinum, found in canned foods, secretes botulinum toxin (a proteinase) if ingested which interferes with the association of synaptobrevin and SNAP-25 or syntaxin at the presynaptic terminal. This can occur in infants and is characterized by descending weakness which can be fatal once it involves the respiratory muscles. It can also be injected directly into muscles to decrease wrinkles or spasticity. Infection is treated with infusion of Botulinum immunoglobulin.

Tetanus also interferes with synaptobrevin, but in the inhibitory interneurons of the spinal cord which produces spastic paralysis.

26
Q

How is the neuromuscular junction impaired by organophosphorous gases?

A

Organophosporous gases irreversibly modify acetylcholinesterase such that it can no longer break down ACh. ACh remains in the stynaptic cleft and continuously activates nicotinic receptors until the postsynaptic resting membrane potential increases to the point where no more action potentials can be stimulated. This causes death due to paralysis of the diaphragm.

27
Q

What drugs can be used to transiently inhibit acetylcholinesterase to treat impaired neuromuscular transmission, especially postsynaptic dysfunction?

A
  • Physostigmine
  • Neostigmine
  • Pyridostigmine
28
Q

What is autoimmune Myasthenia Gravis?

A

Autoimmune Myasthenia Gravis is a disease in which antibodies are directed against proteins in the postsynaptic membrane of the neuromuscular junction, most commonly the acetylcholine receptor (particularly the alpha subunit) and the MuSK protein.

Inflammation and destruction of the motor end plate results in a decreased number of acetylcholine receptors. This may prevent threshold from being reached which would result in a loss of generation of muscular action potentials.

Patients present with skeletal weakness that gets progressively worse with use, particularly ptosis, difficulty swallowing, proximal limb weakness, etc. Treatment involves acetylcholinesterase inhibitors (pyridostigmine) as well as immunosuppression (prednisone).

29
Q

How does succinylcholine, a paralytic used in anesthesia, work? Pancuronium?

A

Succinylcholine causes flaccid paralysis by depolarizing the neuromuscular junction and maintaining the channels open for a long time which results in the cell’s membrane potential being raised. The sodium channels enter the inactive state which prevents subsequent action potentials (similar to organophosphorous gases).

Pancuronium is used as a neuromuscular blockade in surgery which is a selective competitive antagonist to acetylcholine.

30
Q

What is the embryonic origin of muscles?

A

The somite, which is subdivided by signaling molecules to form the dermamyotome (medial portion forms epaxial muscles, lateral portion form hypaxial muscles). Muscles of the head (excluding the tongue) arise from pre-chordal mesoderm.

31
Q

Discuss the organization of muscle fibers.

A

Actin and myosin are organized into sarcomeres. Sarcomeres are lined up to form myofibrils which are bundled into a muscle fiber. Muscle fibers form fascicles and multiple fascicles make up a muscle.

All fibers are about the same size and almost all nuclei are located at the periphery of the fiber. There is little conective tissue between fibers.

32
Q

What is the sarcolemma? What important proteins associate with it?

A

The sarcolemma is the term for the unit of plasma membrane and basement membrane associated with the muscle. The sarcolemma has many membrane spanning proteins which associate with collagen externally and actin internally. Dystrophin is a large protein that is involved in linking actin to the plasma membrane.

33
Q

What is the difference between a myopathy and a dystrophy?

A

A myopathy is a disorder that is present at birth due to improperly built muscle which is intrinsically weak–there is no muscle tone. The muscle atrophies without degeneration. Myopathies are characterized by microscopic and ultrastructural features upon examination of a muscle biopsy. They can show clinical improvement or a relatively stable course. A dystrophy involves active breakdown and regeneration of muscle and get worse over time.

34
Q

What are the four classic congenital myopathies?

A
  • Nemaline myopathy
  • Centronuclear/myotubular myopathy
  • Central core disease
  • Multi/minicore myopathy

Nemaline myopathies show inclusions called nemaline rods under the electron microscope. It is genetically heterogeneous but all genes causing it code for components of thin filaments (ex: nebulin, actin, tropomyosin, troponin cofilin-2)

35
Q

What does the histology of a muscular dystrophy show?

A
  • Degeneration
  • Regeneration
  • Connective and fatty tissue infiltration
36
Q

Describe the inheritance, symptoms, progression, and complications of Duchenne muscular dystrophy.

A
  • X-linked, 1:3,500 boys
  • Onset 2-4 years, progression 7-8 years old, lifespan 3rd decade
  • Characterized by proximal progressive weakness, pseudohypertrophy, elevated creatine kinase
  • Signs: Gowers’ maneuver (proximal muscle weakness), Trendelenburg sign (hip abductor weakness)
  • Complications: cardiomyopathy, scoliosis, respiratory insufficiency
37
Q

Describe Becker muscular dystrophy.

A
  • X-linked, 1:30,000 males
  • Variable onset, wheelchair after 15 years, severity and lifespan variable
  • CK elevated
  • Complication: cardiomyopathy
38
Q

What mutations result in Duchenne and Becker muscular dystrophy? Can a carrier female present the disease?How does dystrophin staining appear in each?

A

Mutations in dystrophin produce both types of muscular dystrophy. Deletions, small mutations, duplications, and splice site mutations can all cause disease and 30% of mutations are de novo. The phenotype is determined by whether or not the reading frame is preserved–truncated proteins result in Duchenne while preservation results in Becker. Random X-inactivation can be skewed such that the disease can manifest in the female.

Patients with BMD have present but irregular dystrophin staining while those with DMD have a total absence except in revertant fibers in which a second somatic mutation restored the reading frame leading to some dystrophin expression.

39
Q

What are the treatment options for DMD?

A
  • Supportive/symptomatic
  • Mutation independent therapies: prednisone, myostatin blockade, growth factors
  • Gene delivery/correction: vector based, exon skipping for frame restoration (converting DMD into BMD using an oligo against exon 51))
  • Cell based: myoblasts, stem cells
  • A recombinant Adeno-associated virus for gene would be useful except the virus cannot accept a gene that large–smaller versions that still have functionality are being constructed
40
Q

What is facioscapulohumeral dystrophy (FSHD)?

A
  • Third most common dystrophy
  • Prevalence: 1-5:100,000
  • Dominant inheritance or de novo
  • Asymmetric weakness: face, scapula, biceps, distal leg (foot drop)
  • Caused by a loss of repeat elements on chromosome 4q–the larger the deletion, the earlier the onset and the more severe the disease
41
Q

What are sarcoglycanopathies?

A
  • Mutations in dystrophin associated proteins which mimics DMD and BMD
  • Autosomal recessive
  • Dystrophin is normal but the sarcoglycan complex is reduced
  • More common in females than DMD/BMD