Neuromuscular diseases week 6 Flashcards

1
Q

What are the differences btwn neuronopathy, axonopathy, and myelinopathy.

A

neuronopathy: pathology in cell body
axonopathy: pathology in axon
myelinopathy: pathology of myelin

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2
Q

Explain the differences in affects on strength and muscle atrophy when there is segmental demyelination vs axonal degeneration vs myopathy.

A

In segmental demyelination, there is no muscle atrophy because the muscles are still innervated, however, the person experiences weakness.

In axonal degeneration, there is muscle atrophy (due to deinnervation) that is regained with reinnervation (by regrowth of axon and/or nearby axons).

In myopathy, the pathology is in the muscle so there may be atrophy, inflammation, etc of the muscles.

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3
Q

In neuronopathy, what are the pathologic mechanisms?

What sensory ganglions may be affected?

What part of the axon degenerates first? What part of the axon degenerates following this?

A

Neuronopathy „

  • Pathologic mechanisms often not clear „
  • Multiple etiologies „
  • Sensory - Dorsal root and gasserian (aka trigeminal) ganglions vulnerable „
  • Degeneration of neuronal perikaryon (cell body)
  • Degeneration of axon follows „
  • Regeneration?
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4
Q

What is amyotrophic lateral sclerosis (ALS)?

What are the clinical features of ALS?

What is the percentage of sporadic and familial cases of ALS?

What sex is ALS more prevalent in?

What mutation is present in familial cases? What are possible causes in sporadic cases?

How is ALS diagnosed? What is the prognosis?

A

ALS: Degenerative disorder of the upper and lower motor neurons.

Upper Motor Neuron ‰signs

  • weakness ‰
  • spasticity ‰
  • hyperreflexia ‰
  • babinski sign, jaw jerk

„Lower Motor Neuron ‰signs

  • weakness ‰
  • fasciculations ‰
  • atrophy ‰
  • hypotonia

men ≥ women, 90% sporadic vs 10% familial

Time to diagnosis from clinical onset ( 70% limb, 30% bulbar) up to 18 months . Time from diagnosis to death 2-5 years with a range of 1.5- 20 years. Diagnosis by clinical and electrophysiological (El Escorial) criteria. There are no specific laboratory tests for ALS.

Causative agent presumed to be mutant SOD1 in familial cases of ALS with defined SOD1 mutations (Other mutations include TDP43, FUS, ALSIN). In sporadic cases cases multiple causes have been proposed include neuroinflammation, excitotoxicity.

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5
Q

What is spinal muscular atrophy?

What are the clinical signs?

What mutation is responsible?

What is the prognosis?

A

Spinal Muscular Atrophy „

  • Loss of alpha-motor neurons leads to lower motor neuron signs „
  • Hypotonia, symmetrical weakness, hypoventilation, swallowing difficulties (prevalence: 1/80 carrier state) „
  • Death by age 2 „
  • SMN protein required for assembly of snRNP splicing complexes. A silent nucleotide change in SMN2 results in skipping of exon 7 —> predominate production of an unstable protein. see attached pic
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6
Q

Generally, what may cause demyelination of peripheral nerves?

Generally, what may cause axonal damage to peripheral nerves?

A

Peripheral Neuropathy: Classification by pathologic process „

Demyelinating ‰

  • Immunologic damage to Schwann cells (GBS) ‰
  • Genetic defect in Schwann cells (HSMN-1) „

Axonal ‰

  • Metabolic failure of ganglion cells (DM) ‰
  • Ischemic damage to endoneurium (vasculitis) ‰
  • Toxic damage to endoneurium (amyloidosis)
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7
Q

What are examples of generalized symmetric, focal, and multifocal causes of peripheral neuropathy?

A

Peripheral Neuropathy: Classification by anatomic distribution „

Generalized symmetric ‰

  • Length-dependent (toxic,metabolic) : the longest axons are affected first and most severely. Remember that cell bodies must provide metabolic and other support to axons. For neurons in the extremities, the cell body may be far away from the tip of the axon. In this type of neuropathy, would see sx first in the feet, for example, that would move up to the hands.
  • Non-length dependent (immunologic) „

Focal ‰

  • Mononeuropathy (carpal tunnel sydrome) „

Multifocal ‰

  • Mononeuropathy multuplex (vasculitis)
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8
Q

What does symptoms does neuropathy cause?

A

Neuropathy causes weakness and atrophy of muscle, loss of sensation or altered sensation (pain, paresthesias), and reduced or absent tendon reflexes.

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9
Q

In distal axonopathy, in what part of the axon may the pathology be?

What is the cause of distal axonopathy?

What happens to distal muscles in this disorder?

A

Distal axonopathy „

  • Disturbance in cell body or throughout axon „
  • Failure of axonal transport „
  • Distal regions of axons most vulnerable „ “Length-dependent” „
  • Degeneration advances proximally „
  • Distal muscles undergo denervation atrophy
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10
Q

What are the common causes of distal axonopathy?

A

Distal axonopathy: Common Causes „

  • Toxic (alcohol) „
  • Metabolic (diabetes, uremia) „
  • Hereditary (HMSN type II) „
  • Malignancy associated
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11
Q

What is the diagnosis?

A

Acute inflammatory demyelination polyneuropathy (Guillan-Barre syndrome)

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12
Q

Explain the clinical presentation of Guillan-Barre syndrome.

What are the laboratory findings?

What is nerve conduction velocity like in this disease?

What is the most important criteria for diagnosis of AIDP?

When is maxium severity of symptoms observed in this disease?

A

Acute inflammatory demyelinating polyneuropathy (AIDP) „: Guillain-Barré Syndrome ‰

  • Clinical presentation: ascending paralysis, progressive (over hours to days) weakness of more than 2 limbs, areflexia, predominantly motor ‰
  • Laboratory findings - elevated CSF protein with relatively normal cell count, slowing of nerve conduction velocities/conduction block ‰
  • Respiratory involvement in ~25%
  • The most important criterion for AIDP/GBS is that the disease must have an acute onset.
  • Progression of symptoms is observed over several days to weeks, with maximum severity reached within 4 weeks of onset
  • Areflexia or hyporeflexia is observed within one week of symptom onset
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13
Q

What is myelinopathy?

Name causes for myelinopathy.

A

A disorder affecting the myelin of peripheral nerve fibers.

Myelinopathies: Causes „

  • Immunologic
    • AIDP
    • CIDP „ (chronic inflammatory demyelinating polyneuropathy)
  • Toxic (Diphtheria) „
  • Hereditary (Charcot-Marie-Tooth [CMT] type I) First Aid: AKA hereditary motor and sensory neuropathy (HMSN). group of progressive hereditary nerve disorders related to the defective production of proteisn involved in the strucutre and function of peripheral nerves or the myelin sheath
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14
Q

What is the diagnosis?

“Droopy Eyelids” „

  • A 28 year old previously healthy man „
  • Developed double vision 4 months ago „
  • “Droopy” eyelids toward the end of the day „
  • Mild increased fatigue in arms and legs ‰
    • “Hard to type for more than 20 minutes”
  • „Had previous episode of double vision that resolved „
  • No chronic medical issues „
  • Currently taking NO medications „
  • Family History ‰
    • Maternal aunt with “lupus”
A

Myasthenia gravis

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15
Q

What is myasthenia gravis?

What is the clinical presentation of someone with myasthenia gravis?

Explain the range in severity of symptoms in myasthenia gravis.

A

„Myasthenia gravis

  • Autoimmune disorder of neuromuscular transmission
    • Incidence: 1-2/100,000 ‰
    • Prevalence: 20-50/100,000 „
  • Weakness, fatigability „
  • Severity can range from mild ocular symptoms to severe limb weakness and respiratory failure

Clinical Presentation „

  • Fatigable weakness ‰
    • Extraocular muscles ‰
    • Facial/bulbar muscles ‰
    • Limb muscles ‰
    • Respiratory muscles „
  • Respiratory/bulbar weakness may be life threatening
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16
Q

Explain the immunophathogenesis of myasthenia gravis. What immune cell type is involved? What is affected?

A

Immunopathogenesis of MG ƒ

  • T cell-dependent autoantibody-mediated disorder ƒ
  • Pathogenic antibodies target muscle end-plate proteins ƒ
  • Fatigable muscle weakness ƒ
  • Target-specific pathogenic autoantibodies
    • AChR (85%)
    • MuSK (5-8%)
    • LRP4
17
Q

Note that the normal morphology of the end plate is disrupted in myasthenia gravis.

A

Note the decreased folding of the NMJ in the MG mouse cell on the right.

18
Q

What is the edrophronium test? What is it diagnostic of?

A

Edrophonium test: Administer Edrophonium Chloride

• Temporary inhibition of acetylcholinesterase

improvement of ptosis, other symptoms is diagnostic for MG

19
Q

What laboratory test may be used for diagnosis of MG?

How may electorphysiology be used to diagnose myasthenia gravis?

A

Serology

  • Anti-AChR antibodies: 85% of MG patients

Electrophysiology

  • record electrical activity of muscle fibers. note in picture on the right, the amplitude and duration of the AP is shorter
20
Q

Note that in picture B (myasthenia gravis) some neuromuscular transmission fails so the amplitude is not consistent.

A
21
Q

Pathology of what organ is a dominant feature of AChR MG?

A

Thymus pathology

attached is slide 225 of course notes

22
Q

What things can go wrong at the muscular level and cause disease?

A

Muscle: What can go wrong? „

  • Abnormalities causing muscle fiber necrosis ‰
    • Inflammatory/immune ‰
  • Dystrophic processes „
  • Abnormalities affecting the muscle membrane ‰
    • Hyperexcitability ‰
    • Reduced excitability „
  • Abnormalities affecting the muscle cytoskeleton „
  • Abnormalities with excitation-contraction coupling „
  • Metabolic/energy utilization problems
23
Q

What is the diagnosis?

“Wasted thighs and big, firm calves” „

  • 25 year old man „
  • Gradual onset of difficulty running and climbing stairs; “hollow back” since age 10 „
  • Calf pain with exercise „
  • Atrophy and weakness of quads and pectoral muscles
  • Gower’s sign: Use of arms and hands to “climb up the thighs” in assuming an erect posture; indicative of proximal muscle weakness.
  • Serum CK 6500 IU/L
  • „Muscle biopsy shows dystrophic changes and reduced dystrophin immunostaining „
  • Deletion of exons 48-49 in the dystrophin gene
  • „Echo shows EF 44%
A

Becker’s muscular dystrophy

24
Q

What are the features of Duchenne muscular dystrophy?

What is the prognosis?

A

Duchenne muscular dystrophy „

  • Most common lethal pediatric disorder ‰
  • Symptomatic by 5 yrs.; wheelchair bound by 10 yrs; death in 20s. ‰
  • Normal at birth ‰
  • Delayed walking, weakness in pelvic girdle and then shoulder girdle ‰
  • Pseudohypertrophy (hypertrophic fibers & later fat and fibrosis replace fibers) ‰
  • Arrhythmias/heart failure ‰
  • Cognitive impairment ‰
  • Death due to respiratory insufficiency
25
Q

What are the differences btwn Duchenne’s MD and Becker’s MD? (onset, symptoms)

A

Duchenne’s muscular dystrophy

  • Present at age 3-5
  • Waddling gait, Lordotic posture
  • Calf hypertrophy
  • Progressive weakness
  • Wheel chair by age 12

Becker’s muscular dystrophy

  • Onset of symptoms ~ age 12
  • Lose ability to walk at 25- 30 years (or later)
  • Cardiomyopathy
26
Q

What are the genetic differences btwn Duchenne’s and Becker’s muscular dystrophy?

In attached pic, note replacement of muscle fibers with connective tissue.

A

„Dystrophinopathies ‰

  • DMD – mutations that truncate the reading frame so that no dystrophin is produced
  • BMD – mutations that maintain an open reading frame. abnormal dystrophin protein is produced (so that there is still some dystrophin even though abnormal)

see slides 234-235 of course notes for dystrophin staining of muscle fibers in these diseases

27
Q

What gene correction strategies may be used for muscular dystrophy?

A

Gene correction strategies „

  • Nonsense suppression therapies ‰
    • Promote read-through „
      • Gentamicin „
      • Ataluren „
  • Exon-skipping ‰
    • Antisense oligomers to induce skipping of an exon flanking an out-offrame deletion (see pic)