Musculoskeletal 1a – Muscle Disease
Anil Chopra
1
Primary muscle diseases comprise:
- muscular dystrophies
- Congenital myopathies
2
Pathogenesis of muscle weakness - progressive muscle degeneration and fibroadipose tissue substitution in muscular dystrophy:
- Reduced force generated by muscle in congenital myopathies but little or no
change with time
3
Main group of proteins involved in muscular dystrophies
- the dystrophin-associated glycoprotein complex
- (laminin/ dystroglycan/ sarcoglycans/ dystrophin)
4
Main group of proteins involved in congenital myopathies
- Proteins of sarcomeres (actin, tropomyosin and nebulin)
5
Main clinical features of the muscular dystrophies:
- proximal weakness
- joint contractures
respiratory muscle involvement
Neuromuscular Disorders
 Many are inherited
 Various parts of the motor units affected
 A defect in a motor neuron or nerve is a neuropathy
 A defect at the neuromuscular junction is a myasthenia.
 A defect of muscle is a myopathy.
Myopathies
1. Congenital myopathies
2. muscular dystrophies
Congenital Myopathies
General Features
- non progressive
- weakness from birth or infancy
- generally, patients achieve the ability to walk independently
- serum creatine kinase are normal only mildly elevated, indicating low degree
of muscle damage.
- Characterised by generalised muscle thinning and muscle weakness.
- Respiratory muscle weakness can be out of proportion compared to limb
muscle weakness.
There are 4 types of congenital myopathies
- central core disease
o disturbance of excitation contraction coupling
- nemaline myopathy
o sarcomeric protein diseases
- myotubular myopathy
o problems in cell-cell signalling and energy metabolism
- minicore myopathy
o disturbance of excitation contraction coupling
Severity depends on the degree of disruption of the excitation/contraction coupling or
the degree of defect in the sarcomeric proteins.
Generally symptoms are mild:
 Proximal muscle weakness:
o difficulties in walking fast
o difficulties in running
o difficulties in getting up from the floor
 Axial weakness:
o scoliosis common
o respiratory muscle weakness common even in ambulant patients
Proteins Affected
 Nebulin
 Alpha-actin
 Beta tropomyosin (TPM2)
 Alpha tropomyosin 3 (TMP3)
 Troponin T1 (TNNT1)
Muscular Dystrophies
Histological Assessment
- Wide variations in fibre size
- Necrosis
- Fibrosis, fat
- Hypercontracted fibres
- Split fibres whorled fibres
- internal nuclei
- basophilic fibres
Muscular dystrophies can be congenital or onset during childhood, and rarely in adulthood.
They are characterised by:
- Often progressive weakness
- Variable severity: from congenital to adult onset depending on the subtype (many
subtypes recognised)
- Weakness
o usually proximal
o rarely distal
- Respiratory muscle weakness
- Limitation of joint movements often accompanies the weakness
- Muscle atrophy often with associated pseudohypertrophy in the same patient.
There are different muscle proteins involved with muscular dystrophies than with
myopathies. The ones affected in muscular dystrophy include:
1. Transarcolemma (Duchenne, sarcoglycanopathies, others)
2. Enzymes
3. Nuclear envelope
4. Extracellular matrix
5. Sarcomere
6. Others (cytoskeleton; ER proteins of unknown)
Deficiencies in extracellular proteins cause congenital muscular dystrophies. E.g.
merosin deficiency, collagen VI deficiency causes “Ulrich congenital muscular
dystrophy”. They are characterised by random contractures at birth – arthrogryposis.
Sarcoglycanopathies: deficiencies in sarcoglycans.
Duchenne Muscular Dystrophy
Caused by a deficiency in the dystrophin molecule.
 1 in 3500 male births
 symptomatic <1 year - 5 years
 loss of independent walking 6 -12 years
 death mid teens - early twenties
 30% significant learning difficulties
Molecular Basis
Duchenne is caused by abnomailities in chromosome 21 which codes for the
dystrophin protein. An “in frame” deletion causes fewer complications than an “out of
frame” deletion.
NH
CY
S
2
COOH
Full length protein
NH
Truncated and unstable protein
2
out of frame
deletion
Clinical Presentation:
 late walking - 50% >18 months
 toe walking
 unable to run or jump
 falls
CY
S
CO
OH






stairs and climbing hard
Gowers’ Manoeuvre – getting up by rolling onto their front and using their arms.
IQ shifted -1SD
30% IQ<70, mean IQ 85
verbal IQ < performance IQ
speech delay very common
Later Presentatons
 Progressive joint contractures
 Progressive scoliosis
 Dilated cardiomyopathy
 Weakness of the inspiratory and expiratory muscles: this is particularly dangerous
as it can lead to
o frequent respiratory infections
o nocturnal hypoventilation
o nocturnal hypoxia
o nocturnal hypercarbia (too much CO2)
o morning drowsiness, headaches, nausea, fatigue
o respiratory insufficiency and sudden death
Diagnosis – the diagnosis of Duchenne’s is difficult and is often untreatable.
• CK: 50 - 100x normal
• deletion in gene detectable in 70%
• muscle biopsy
– histology dystrophic
– immunocytochemistry shows absent dystrophin
Treatment
- using ACE inhibitors can slow the onset of dilated cardiomyopathy
- β- blockers are becoming increasingly used
Becker Muscular Dystrophy
Presentation
• Mean age of onset of symptoms is around 11 yrs
• Calf pains, slower than peers
• Variable progression
• Loss of walking ability – only in 18% (Mean age at loss of walking – 37 yrs)
• Scoliosis extremely uncommon
• Dilated cardiomyopathy however very common.
Molecular Basis
Generally only caused by “in frame” deletions leaving a partially functional protein.
NH
CYS
COOH
Full length protein
CY
S
COO
H
Shorter but partially functional
protein
2
N
H
2
in frame
deletion