Neuromuscular Pathology

Question 1

What is spinal muscular atrophy SMA?

Answer 1

lower motor neuronal survival depends upon innervation of muscle, but MN death results in muscle atrophy, which is what happens in SMA

Question 2

What causes SMA?

Answer 2

Survival of motor neurons 1 is a protein that sits at the centre of the SMN complex, which is localized to both the nucleus and cytoplasm (left), and functions to regulate RNA metabolism, translation and the cytoskeleton. Smn undergone a human-specific gene duplication, producing SMN1 and SMN2. Their sequences are nearly identical, but SMN2 commonly has a mutation that causes splicing problems, meaning that exon 7 is spliced out 90% of the time, rendering 90% of the protein non-functional. So, patients commonly have only have 10% of SMN2 to fall back on. Both SMN genes are constituitively expressed, but given the massive metabolic and cytoskeletal demands of being a motor neuron, motor neurons underlie disease aetiology. Neurofilament L (light chain) levels in the blood are increased as a result, with levels being very high already at birth.

Question 3

What is the treatment for SMA?

Answer 3

Like in MD, an exonskipping approach can be employed using an anti -sense oligonucleotide, nursinersin (a). A small molecule approach, risdiplam (b), is efficacious, as is a gene therapy approach using an adeno -associated virus, Onasemnogene abeparvovec

Question 4

What is amyotrophic lateral sclerosis ALS?

Answer 4

Like SMA, ALS is a condition where MNs die, and this leads to muscle atrophy. Unlike SMA, it is a complex polygenic disease.

Question 5

What is cerebral palsy and what can it result in?

Answer 5

Non-progressive damage to the brain on account of antenatal, perinatal, or early postnatal insult. As such, it’s associated with prematurity. CP can result in:
• hypoplasia (a - left)
• polymicrogyria (a - right)
• periventricular leukomalacia (b)
• subcortical atrophy (c)

As a result of damage to neurological control of muscle, significant muscle pathology is typically observed. Laminin (muscle ECM).

Question 6

What causes clinical manifestations in CP?

Answer 6

Clinical manifestations can also be the result of the loss of UMN control of motor activity…
• impaired motor control
• weakness
…or the loss of LMN inhibition (eg. Babinksi):
• clonus
• spasticity

Question 7

What is myasthenia gravis?

Answer 7

Myasthenia gravis is a rareautoimmune disorderaffecting the neuromuscular junction

Question 8

What are the signs and symptoms of myasthenia gravis?

Answer 8

Question 9

What is the management of myasthenia gravis?

Answer 9

1. Anticholinesterases(e.g., pyridostigmine):inhibit the breakdown of acetylcholine(ACh)
2. Oral corticosteroidsare effective for achieving remission
3. ImmunosuppressantsSuppressingthe production of abnormal antibodies
4. Thymectomyin selected younger patients (can be curative) and for a malignant thymic mass
5. Acute management therapies
   – Plasmapheresis uses a machine toremove harmful antibodies in plasma
   – Intravenous immune globulin

Question 10

What lab tests would confirm myasthenia gravis?

Answer 10

1.Acetylcholine receptor antibody test (high)

2.MuSKantibody test

3.Repetitive nerve stimulation test

4.Electromyography

5.Edrophonium test

6.Ice pack test

7.Pulmonary function test

Question 11

What is guillain-baré syndrome?

Answer 11

Guillain-Barré syndrome is anacute rapidlyprogressive demyelinatingautoimmune disorderofperipheral nerve

Question 12

What are the risk factors and signs and symptoms of Guillain-Barré syndrome?

Answer 12

Risk factors-

•Gastrointestinal infection (Campylobacter jejuni)
•Upper respiratory tract infection (Influenza, CMV and EBV)
•HIV
•Influenza vaccine
•Surgery
•Trauma

Question 13

What is the diagnosis and treatment for Guillain-Barré syndrome?

Answer 13

Diagnosis:

• Nerve conduction velocity studies- Slow
• Lumbar puncture:Increase level of protein with normal WBC count

Treatment:

• Plasmapheresis
• Immunoglobulin (IV)
• Mechanical ventilator

Question 14

What is the aetiology underlying reflex absence and tongue fasciculations?

Answer 14

Reflexes are mediated by alpha motor neurons in the ventral horn of the spinal grey matter. These neurons die in SMA, leading to an absence of reflexes, a classic sign of a lower motor neuron lesion. Neuronal death is caused by the absence of SMN protein, which is involved in RNA splicing, mRNA transport and stability, cytoskeletal regulation, protein translation, and mitochondrial respiration .
Fasciculations are partial contractions of muscle where some muscle fibres contract and others do not. Muscle fibres that are no longer innervated do not contract, whereas those that retain innervation do. Fasciculations therefore represent a partially innervated muscle, and this progresses towards total loss of innervation and atrophy.

Question 15

Describe the treatment approach of onasemnogene abeparvovec

Answer 15

Onasemnogene abeparvovec is an adeno-associated virus treatment that contains a copy of an SMN coding sequence whose expression is driven by a strong promoter. Delivery of the gene into cells replaces the missing SMN1 protein in cells. The virus is taken up through infective endocytosis, and is transferred to the nucleus, where the viral gene is transcribed into functional SMN mRNA, which is then translated at the ribosome into functional SMN protein

Question 16

Describe the course of an EMG examination, and outline what conclusions can be drawn from it

Answer 16

• An EMG consists of a nerve conduction study, and muscle contraction study. The nerve conduction study involves the placement of electrodes at either end of a given nerve, followed by stimulation of one electrode, and recording through the other. The muscle contraction study involves the insertion of a fine needle electrode into a relaxed muscle, and then measurement of the electric current produced during voluntary contraction of the muscle.
• The nerve conduction test illustrates the speed of nervous conduction and the muscle contraction test provides information on the transmission of electric current within the muscle itself, and the recruitment of motor units.

Question 17

Describe and explain the basis for the differences between upper and lower motor lesions

Answer 17

UMN lesions refer to lesions within the brain or spinal cord of neurons or neuronal tracts that are concerned with the control of LMNs. UMNs include motor centres within the brain such as the primary motor cortex, the premotor cortices, the basal ganglia, the reticular system, the cerebellum, the cingulate motor cortex, the vestibular nuclei, and the tectum. Lesions can lead to a lack of activation of LMNs or a lack of inhibition of LMNs (indirectly through the action of GABAergic inhibitory interneurons), or a combination of both, yielding complex symptoms such as weakness and fasiculations but also hyperreflexia and spasticity.

LMNs comprise alpha motor neurons that innervate extrafusal fibres of body or cranial muscles through peripheral nerves. They drive vountary muscle contraction. Examples include ventral horn motor neurons of the spinal cord and cranial motor neurons whose cell bodies reside in cranial motor nuclei in the brain stem. Lesions of LMNs lead to weakness, fasciculations, and hypotrophy/atrophy of muscles.

In UMN lesions, you might observe increased muscle tone and exaggerated reflexes on EMG. In contrast, LMN lesions typically show decreased muscle tone and diminished reflexes. Additionally, UMN lesions often result in hyperactive or spastic muscle activity, while LMN lesions lead to denervation changes and fibrillation potentials on EMG.