Neuromuscular Problems ✅ Flashcards
What are neuromuscular disorders?
Condtions that lead to the impairment of muscle function
What are the sites of pathology to consider in neuromuscualr disorders?
- Anterior horn cells
- Peripheral nerves
- Neuromuscular junction
- Muscle
Where are nerve impulses generated?
Anterior horn cells
What does the generation of nerve impulses in the anterior horn cells lead to?
Activation of muscle fibres
What does anterior horn cell disease usually lead to?
Specific pattern of weakness
What does the specific pattern of weakness produced by anterior horn cell disease depend on?
The affected part
Why does the specific pattern of weakness produced by anterior horn cell disease depend on the affected part?
Because medial cells innervate proximal muscles, and lateral cells innervate more distal muscle groups
What are the clinical features of anterior horn cell disruption?
- Fasciculations
- Lost reflexes
- Fibrillation
What are fasciculations?
Muscle twitches
How does disruption of anterior horn cells produce fasciculations?
Disruption of anteior horn cells can lead to denervation, and the damaged alpha motor neurones produce spontaneous action potentials. These spikes cause the muscle fibres that are part of the neuron’s motor unit to fire, producing muscle twitches
How is fibrillation detected?
Electrophysiological testing
Why does disruption of anterior horn cells produce fibrillation?
As further generation occurs, only the remnants of the axon close to the muscle fibre remain. These individual axon fibres can generate spontaneous action potentials, whcih will only cause individual muscle fibres to contract, resulting in fibrillation
Give 2 conditions that cause disruption of anterior horn cells
- Spinal muscular atrophy
- Cervical cord damage
What is the inheritence of spinal muscular atrophy?
Autosomal recessive
What is the genetic abnormality in spinal muscular atrophy?
Defect in the SMN1 gene on chromosome 5
What does the SMN1 gene encode?
The SMN protein
What is the role of the SMN protein?
It is necessary for the survival of the motor neurons
What happens when there is a deficit of SMN protein?
Death of neuronal cells in the anterior horn of the spinal cord occurs
What muscles are most severely affected in SMA?
- Trunk
- Neck
- Hip muscles
Why are the trunk, neck, and hip muscles most severely affected in SMA?
Because they have the largest number of motor neurones, i.e. the biggest mass
How can a diagnosis of SMA be made?
Testing for SMN1 gene deletion
What is the most severe form of SMA?
Type 1
What is type 1 SMA also known as?
Werdnig-Hoffman disease
When does SMA type 1 present?
Infancy
How does type 1 SMA present?
- Tongue fasciculations
- Hypotonic
- Areflexia
- Early respiratory symptoms
What feature of type 1 SMA is almost pathognomic?
Tongue fasciculations
What is the prognosis of type 1 SMA?
Death within weeks or months
What is present at the same location as SMN1?
SMN2
What does SMN2 code for?
SMN protein
How many copies of SMN2 do most people have?
2
Why is SMN2 important in SMA?
In a child with SMA, the presence of normal copies of SMN2 can partially compensate for the absence of normal SMN1 function
What happens if a child with SMA has one or no copies of SMN2?
Their clincal course will be more severe
What investigation should be done if there is clinical suspicion of SMA?
Molecular genetic studies
What is the limitation of EMG and muscle biopsy in SMA?
Findings are non-specific
When does spinal muscular atrophy with respiratory distress (SMARD) present?
6 weeks - 6 months of life
What causes respiratory distress in SMARD?
Diaphragm weakness
What is the diagnostic test for SMARD?
Look for mutations in the IGHMBP2 gene
What is the inheritence pattern of SMARD?
Autosomal recessive
What radiological finding tends to be associated with SMARD?
Diaphragm eventration
Give 2 causes of cervical cord damage in neonates
- Congential malformation of cervical cord
- Injury during intrapartum period
What can cervical cord damage be difficult to differentiate from in the neonatal period?
Neonatal encephalopathy
What can be useful in distinguishing cervical cord damage from neonatal encephalopathy?
MRI of cervical cord and nerve routes
What is a key feature of disorders of the peripheral nerve?
Distal involvement, especially at the onset
Do peripheral nerve problems produce motor or sensory features?
May be both
Give an example of a peripheral nerve problem that produces motor and sensory features
Hereditary motor and sensory neuropathy (HMSN) type 1a
What is hereditary motor and sensory neuropathy (HMSN) type 1a also known as?
Charcot-Marie-Tooth syndrome
What causes Charcot-Marie-Tooth syndrome?
Gene mutations that cause defects in neuronal proteins
What do the defects in neuronal proteins affect in Charcot-Marie-Tooth syndrome?
Myelination of peripheral nerves
What is found on nerve conduction studies in Charcot-Marie-Tooth syndrome?
Reduced nerve conduction velocity
Give an example of a purely demyelinating disorder
Guillian-Barre syndrome
Which kind of neurones does Guillian-Barre syndrome affect most severely?
Motor fibres
Does Guillian-Barre syndrome affect pain and temperature sensation?
Little or no effect
Why does Guillian-Barre syndrome affect motor fibres much more than sensory?
Type I and II nerve fibres are myelinated, and have reasonably fast conduction velocity. Type III and IV fibres (responsible for pain and temperature) are lightly myelinated and unmyelinated respectively
What happens when a nerve impulse reaches the neuromuscualr junction?
It activates calcium channels
What is the result of activation of calcium channels at the neuromuscular junction?
Leads to regulation of acetylcholine
What does the regulation of acetylcholine at the neuromuscular junction lead to?
Muscle contraction via further post-synaptic action
What clinical features are present when acetylcholine is depeleted or it’s regulation is affected?
- Fatigability
- Diurnal variation
Give 2 conditions that affect the neuromuscular junction
- Congential myasthetic syndromes
- Myasthenia gravis
What can congenital myasthetic syndrome be divided into?
- Pre-synaptic
- Synaptic
- Post-synaptic
What is the genetic abnormality in most children with congenital myasthetic syndrome?
Gene mutations in one of the several genes encoding the acetylcholine receptors
What does a mutation in genes encoding the acetylcholine receptor lead to?
Deficiency at the endplate
What is the inheritence pattern of most genes causing congenital myathenic syndrome?
Autosomal recessive
What kind of mutation are most those causing congenital myasthetic syndrome?
Loss of function
What symptoms should prompt you to think of congenital myasthetic syndrome as a differential?
Infant presenting with;
- Stridor
- Respiratory difficulties, including apnoeas
- Feeding difficulties
- General hypotonia
How can congenital myasthetic syndrome be diagnosed?
- IV edrophonium (Tensilon) testing
- Trial of pyridostigmine or neostigmine prior to a feed
- Genetic testing
- Stimulation single-fibre electromyography (StimSFEMG)
What is the limitation of IV edrophonium testing to diagnose myasthenia?
It can be difficult to interpret
How is a trial of pyridostigmine/neostigmine useful in diagnosing congenital myasthenic syndrome?
Can assess response
What needs to be assessed in the mother of a child with congenital myasthenic syndrome?
Evidence of maternal myasthenia
Where does genetic testing for congenital myasthenic syndrome need to be done?
A national myasthenia reference laboratory
How can StimSFEMG be helpful in diagnosing congenital myasthenic syndrome?
Can detect a decremental response following repetitive nerve stimualtion
Give 2 examples of neuromuscular disorders where the site of pathology is the muscle
- Congenital myotonic dystrophy
- Duchenne muscular dystrophy
What are the types of congenital myotonic dystrophy?
- Type 1
- Type 2
What is type 1 congenital myotonic dystrophy also known as?
Steinert disease
How does type 1 congenital myotonic dystrophy differ from type 2?
Type 1 tends to present earlier and affected children can show signs from birth.
Type 2 tends to be detected later and is a less severe form
What is the inheritence pattern of congenital myotonic dystrophy?
Autosomal dominant
What kind of genetic disorder is congenital myotonic dystrophy?
Trinucleotide repeat disorder
Where is the gene for myotonic dystrophy type 1?
Long arm of chromosome 19
What does the myotonic dystrophy type 1 gene mutation cause?
Expansion of the cytosine-thymine-guanine (CTG) triplet repeat in the DMPK gene
What does the DMPK gene code for?
Myotonic dystrophy protein kinase
How does the number of trinucleotide repeats affect the phenotype in myotonic dystrophy>?
The greater the number of trinucleotide repeats, the more severely affected the child will be
What should be done when a diagnosis of congenital myotonic dystrophy is suspected?
- Maternal examination
- Electromyogram
- Molecular genetic analysis for trinucleotide repeats
What is the most common muscular dystrophy?
Duchenne muscular dystrophy
When should DMD be suspected?
Any boy with delayed motor milestones
What can DMD be associated with?
- Learning difficulties
- Disorders speech
- Features of autistic spectrum disorder
What is a common examination finding in DMD?
Pseudohypertrophy of the calves
What is DMD caused by?
Mutation of the dystrophin gene
What is dystrophin?
An important structural protein within skeletal and cardiac muscle
Where is the dystrophin gene?
At locus Xp21
What is the inheritence of DMD?
X-linked recessive
Can girls be affected by DMD?
Yes, rarely
What shape is dystrophin?
Rod shaped
What is dystrophin bound to?
- One end to sarcolemma
- Other end bound to outermost actin filaments of the myofibril
What is the structural role of dystrophin?
Provides a cytoskeleton for the muscle fibre
What effect does the absence of dystrophin have on the muscle?
Allows excess calcium to penetrate the muscle cell membrane
What does penetration of calcium through the muscle cell membrane in DMD cause?
Alteration of signalling, leading to muscle degeneration and death
What is the first line investigation for DMD?
Blood creatinine kinase
What should be done if blood CK is raised in suspected DMD?
Genetic testing to identify specific exon mutation
How many exons is the muscle-specific form of the dystrophin gene formed of?
79
Is analysis able to identify the specific type of mutation in DMD?
Usually
What should be done if genetic testing is unable to find a mutation in suspected DMD?
Muscle biopsy
How can a muscle biopsy confirm a diagnosis of DMD?
Absence of dystrophin on staining
What other muscular dystrophy is caused by dystrophin gene mutations?
Becker muscular dystrophy
How does Becker muscular dystrophy compared to DMD?
It is milder
