S3: Neuromuscular Disease - Inherited and Acquired Flashcards

1
Q

Describe neuroanatomy of peripheral nerves

A
  • Thinking about the nerves individually, a receptor in the skin to a particular stimulus connects to an axon that goes into bundles of axons, that run in a peripheral nerve.
    This goes back up to the dorsal root ganglion and then into the spinal cord where they synapse onto an interneurone or (like in this diagram) back straight onto a motor neurone.
  • The motor neurone then exits via the anterior horn and out of the ventral nerve root. It then gets mixed up in a peripheral nerve with a lot of other axons and then comes out and innervates a muscle.
  • All motor neurones are myelinated because they need very fast conduction, myelination allows saltatory conduction which is why they are so quick!
  • Different sensory nerves are either myelinated or not myelinated, light touch vibration nerves tend to be large and myelinated, big pain receptor nerves tend to be unmyelinated and slower.
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

Describe structure of skeletal muscle

A
  • The muscle fibres (myofibres, these are the individual cells) are bundles into groups called fascicles. The fascicles are then also all bundles together and surrounded by epimysium to form the muscle.
  • Inside each myofibre. are packed long cylindrical structures called myofibrils, which consist of the two filaments, actin and myosin. This is what contracts.
  • Everything is in parallel which gives us the large level of strength (in our biceps for example).
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

How do we diagnose neuromuscular problems?

A
  • Taking a history.
  • Doing examinations.
  • We don’t do diagnosis on the molecular level because this would involve cutting bits out of the patient and looking at them under the microscope, which we do but not that often.
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

Describe taking a neuromuscular history

A

We ask questions and look for patterns. It is important that we remember that the autonomic system is also part of the peripheral nervous system so we may find problems with the heart, GI tract etc:

  • Defects in neurological function (motor problems, sensory, autonomic).
  • Anatomic distribution (legs vs arms, proximal vs distal, symmetric vs assymmetric, specific nerve or root distributions).
  • Temporal course (disease, age of onset, how it varies);.
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

What do we look for in a neuromuscular examination?

A
  • Tone (resting state of muscle contraction).
  • Power.
  • Coordination (how sensory nerves relay information back to where limbs are etc).
  • Reflexes (tell us about integrity of the spinal cord).
  • Sensation.
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

Describe muscle disease (myopathy)

A
  • Most muscles are concentrated around the hip and shoulder girdle so most myopathies cause weakness in these areas.
  • As there is damage to muscle, it leads to weakness but not necessarily wasting.
  • Reflexes in muscle diseases are normal because it’s just the muscle involved. The sensory nerve, spinal cord and motor nerve are all still working. Sensation is still normal.
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

How is myopathy diagnosed?

A
  • Creatinine kinase (CK) we use, and in patients with myopathy it is very high (as CK is released from damaged muscle).
  • EMG measures electrical activity in muscle.
  • History taken to determine if genetic or acquired. There are many possibilities e.g. family members may be affected but not manifesting symptoms or diagnosed, de novo mutations and low penetrance.
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

List some myopathies

A
  • Genetic: Duchenne, Beker, Myotonic, Fascioscapulohumoral

- Inflammatory: Oikymyorisi, Dermyositi, Inclusion body myotisis.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

Describe Duchenne Muscular Dystrophy (DMD)

A
  • DMD is the most common muscle disease, caused by an X-linked recessive mutation in the dystrophin gene (Xp21).
  • The dystrophin gene is one of the largest, the protein conencts the sarcolemma cytoskeleton to the extracellular matrix.
  • The frameshift mutation leads to a completely non-functioning protein, so they literally have none of this protein.
  • It is fatal, and onset is usually between age 3-5.
  • The children get proximal weakness and deteriorate over time. By the time they are in their teens they cannot walk.
  • They can get various other problems such as scoliosis (weak muscles around spine and abnormal forces), respiratory failure and cardiomyopathy.
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

What us a big sign if DMD in children?

A

A child with DMD, they have very weak spine muscles, so if they lie on the floor it is very difficult for them to stand up again. They use Gower’s manoeuvre to push themselves up using their hands to push themselves up their own body.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

Describe gene therapy for DMD

A
  • Ataluren. This is a small molecule that reads through stop codons so if there is an introduced stop codon in a patient with a frameshift, it will read through the stop codon and whole protein is translated.
  • Eteplirsen. This is an antisense oligonucleotide for a specific exon 21 mutation. Stop codon is spliced out so mRNA can continue to be translated resulting in a shortened but functional dystrophin produced.
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

Describe becker muscular dystrophy

A

In Becker muscular dystrophy, the mutation is a non-frameshift deletion mutation, which leads to a reduced function of the protein, but importantly it is still there and works to a degree! It is therefore a much milder phenotype DMD. So you have a child who does survive and less likely to die.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

Why is a frameshift mutation so severe?

A

A frameshift mutation completely changes the sequence, so if one or two bases are deleted, the whole codon sequence downstream will change.
If a codon is deleted, then it means that particular amino acid is left out, but the rest of the amino acids are still present and in the right order.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

Is genetic of acquired myopathies more common?

A

Acquired myopathies are much less common (this includes inflammatory myopathies).

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

Describe NMJ structure

A
  • We can see here the axon and the muscle fibre. The synaptic bouton meets at the myofibre at the neuromuscular junction. Ach is stored in vesicles that are released into the synaptic cleft.
  • The Ach binds to nicotinic Ach receptors which open up and Na+ flows in, causing an action potential, causing the muscle to contract.
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

Describe NMJ disorder

A
  • These occur because the NMJ structure and system is so complex.
  • Such conditions if inherited and are called congenital myasthenic syndromes, these are rare and are due to mutations in any of the components of the NMJ.
  • The acquired forms of these issues are much more common and the two very common are myasthenia gravis and botulism. Myasthenia gravis is an autoimmune disease (antibodies attack AchNic receptor and block it so Ach cannot bind). In botulism, the toxin stops Ach being released from the synaptic vesicle in the first place so no signals to muscle and person gets muscle weakness.
17
Q

What are the clinical features of NMJ disease

A
  • As it is a muscle disease, reflexes will still be normal and sensation normal.
  • CK will be normal because muscle isn’t damaged.
  • EMG shows an abnormal signal where there is decrement on receptive stimulation e.g. After repeated stimulation, the acetyl choline gets exhausted and amplitude of signal decreases.
  • However, fatigable weakness is present and usually proximal >distal.
18
Q

What is neuropathy?

A

Any problem from the NMJ to the spinal cord are called neuropathies.

19
Q

Clinical features of neuropathy

A
  • Weakness is usually distal e.g. motor neurone going to the big toe.
  • The axon requires a lot of energy because it’s so big (energy wasting) so problems with its energy metabolism etc. can cause it to break down.
  • It interferes with the reflex arc so reflexes will be reduced or absent.
  • Peripheral nerves also control sensation and autonomic function so there may be numbness, tingling, pain, bowel and bladder disturbances depending on the group of nerves it affects.
  • Neuropathy can be divided by the type of fibre affected e.g. motor, sensory, autonomic.
  • If you damage a nerve, the muscle downstream will begin to waste and be damaged so CK may be elevated but not massively.
  • The EMG also shows an abnormal signal.
20
Q

List different patterns of neuropathy

A
  • Type of fibre affected.
  • Pathological classification of neuropathy.
  • Mononeuropathy or polyneuropathy.
21
Q

What are the types of fibres affected in neuropathy?

A
  • Motor (large diameter axons which are heavily myelinated).
  • Sensory: there are large fibres (Aa, AB) for vibration which are myelinated and JPS. There are small fibres (Aδ, C) for pain and temperature sensation. Aδ are thinly myelinated and C fibres are not myelinated.
  • Autonomic: Small fibres.
22
Q

Describe pathological classification of neuropathy

A
  • Anaxal neuropathies where nerve is damaged because of problems with axon. This is the majority of causes. They tend to be due to toxic/endocrine causes or is acquired and usually irreversible.
  • Demyelinating neuropathies which affects myelination around the nerve. These are mostly inflammatory and autoimmune and there easier treated and reversed. Damage to the schwann cells means losing the saltory conduction and it slows transmission down and causing secondary damage to the nerve.
  • Mixed.
23
Q

Describe mononeuropathy and give examples

A

Mononeuropathy affects a single nerve. It can be due to truamatic injury like tearing or entrapment of a nerve.
- Examples include the median nerve in carpal tunnel syndrome, ulnar nerve in elbow or wrist handlebar neuropathy, radial nerve palsy or the common peroneal nerve in foot drop.

24
Q

Describe polyneuroapthy

A

When multiple nerves are affected typically in a length dependent pattern (affecting typically long nerves, because of their increased requirements etc.)
- There are lots of causes: Inflammation, endocrine, drugs, toxins (alcohol, lead), infectious (leprosy). All of acquired are toxic and they are critical cellular processes gone wrong that will affect the nerves.

25
Q

Describe Charcot-Marie-Tooth Disease

A
  • CMTD is the commonest genetic cause of neuropathy, the onset is usually in childhood or teens.
  • Distal wasting prominent - ‘champagne bottle legs’.
  • Divided into 80 separate genetic diseases.
26
Q

Describe plexopathy

A
  • Can have problems with peripheral nerves closer to spinal cord, such as the brachial plexus (a common one is Erb’s palsy) and lumbosacral plexus.
  • The causes are usually not toxic and due to trauma or autoimmune.
27
Q

Describe radiculopathy

A
  • Further up along the line we have the nerve root, this is almost always acquired and very rarely genetic.
  • Here we can see the spinal cord with its anterior and posterior horns. The anterior and posterior roots coming out.
  • Most common is IV herniation (prolapsed disc). We can see the intervertebral disc in the middle made up of the annulus and nucleus pulposus and the latter has herniated out and squashing the nerve roots (most commonly of mixed nerve root as it leaves the spine). So there will be affect motor function and sensation downstream of that.
  • So you will get pain depending on where the compression is e.g. radiculopathy.
28
Q

Describe motor neurone disease

A
  • In MND there is primary degeneration of the motor neurones in the central and peripheral nervous system! It affects motor neurones in both the anterior horn of the spinal cord and in the primary motor cortex (in brain).
  • It can be genetic or acquired.
  • It affects the control of ALL voluntary muscles except ocular and bladder and is a very serious disease with death usually occurring within 5 years.