S3: Neuromuscular Disease - Inherited and Acquired Flashcards
Describe neuroanatomy of peripheral nerves
- 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.
Describe structure of skeletal muscle
- 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 do we diagnose neuromuscular problems?
- 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.
Describe taking a neuromuscular history
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);.
What do we look for in a neuromuscular examination?
- 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.
Describe muscle disease (myopathy)
- 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 is myopathy diagnosed?
- 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.
List some myopathies
- Genetic: Duchenne, Beker, Myotonic, Fascioscapulohumoral
- Inflammatory: Oikymyorisi, Dermyositi, Inclusion body myotisis.
Describe Duchenne Muscular Dystrophy (DMD)
- 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.
What us a big sign if DMD in children?
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.
Describe gene therapy for DMD
- 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.
Describe becker muscular dystrophy
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.
Why is a frameshift mutation so severe?
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.
Is genetic of acquired myopathies more common?
Acquired myopathies are much less common (this includes inflammatory myopathies).
Describe NMJ structure
- 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.
