Neuromuscular Disease Flashcards
What are the six different types of peripheral nerve disorders and what are they?
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.
What can cause sensory neuronopathies?
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
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?
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.
What is Amyotrophic Lateral Sclerosis? Which neurons are affected? Is it genetic or sporadic?
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.
What is spinal muscular atropy? What neurons are involved and what is the cause? What kinds of treatments are available?
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.
What are examples of other motor neuron diseases?
- Polio
- Other kinds of enteroviruses
- HIV
- West Nile virus
- Pompe disease (lack of alpha-glucosidase)
What are radiculopathies? What can cause them?
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.
What are neuropathies and how do they often present? What can they be caused by?
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.
What is Charcot-Marie-Tooth disease?
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.
How does transmission at the neuromuscular junction occur?
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.
What are some causes of NMJ disorders?
- 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)
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 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.
What is a motor unit?
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.
What is the purpose of empty vesicle transport?
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.
How many vesicles are present in the axon terminal and what proteins are responsible for docking and fusion? How much acetylcholine is in each?
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.
How does depolarization cause vesicle fusion at the axon terminal? How many vesicles are released?
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.
What are the four classic congenital myopathies?
- 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)
What does the histology of a muscular dystrophy show?
- Degeneration
- Regeneration
- Connective and fatty tissue infiltration
What mutations result in Duchenne and Becker muscular dystrophy? Can a carrier female present the disease?How does dystrophin staining appear in each?
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.
