Muscular Disease Flashcards
Types of defects
Myopathy = Defect in muscle
Mysathenia = Defect in neuromuscular junction
Neuropathy = Defect in nerve (neuron or schwann cell)
Cells involved in muscle contraction
Atrophy
Tissue gets smaller/ tissue wasting
fibres get smaller, very little, if any necrosis, regeneration and fibrosis
Dystrophy
A degenerative disorder
variable muscle fibre size, necrosis, regeneration and fibrosis
Spinal Muscular Atrophy (SMA)
- Lower motor neurons fail to function properly
- Skeletal muscles fail to contract normally
- Long term loss of innervation leads to muscle fibres atrophy
- Loss of muscles supporting respiration is lethal
SMA Types
Type 0:
- Symptoms present before birth.
- Extremely severe.
- Decreased foetal movement.
- Difficulty swallowing
- respiratory failure after birth
Life expectancy: 2months Prevalence: Very rare
Type 1: “Werdnig Hoffman Disease”
- Most common SMA (60%).
- Severe.
- Muscle weakness by 6months
Never sit independently.
- Difficulties sucking or swallowing.
- Normal intelligence.
Life expectancy: 2years respiratory failure. Prevalence 1:6000
Type 2: “Dubowitz Disease”
- Muscle weakness by 12 months
- Children can sit but not stand or walk
- Scoliosis
- Difficulties eating enough.
- Above average intelligence!
Life expectance: Adulthood with management. Prevalence: 1:70000
Type 3: “Kugelberg-Welander syndrome”
- Onset after 18 months
- Loss ambulation during adolescence
- Scoliosis
Life expectancy: Normal. Prevalence: 1:300000
Type 4:
- Apparent by 10 years
- Mild weakness and wasting in upper arms and legs
- Patients usually ambulatory with waddling gait
Life expectancy: Normal. Prevalence: 1:300000
SMA Skeletal Muscle Hisopathology
SMN1 Structure & Function
- Locus for SMA on long arm of human Chromsome 5
- Gene called ‘SMN1’ encode 9 exons mutated in SMA patients
- Mutation carrier frequency 1:60, highly dependent on ethnicity
- SMN1 ubiquitously expressed
Function: biogenesis of small nuclear ribonucleoproteins-snRNPs
components of spliceosome (converts pre-mRNA into mRNA)
No SMN1 = abnormal mRNA splicing
SMN2
- SMN2 located centromeric to SMN1
- SMN2 identical to SMN1 sequence except C→T in position 6 of exon 7
- C→ T causes a Exon Splice Enhancer (ESE) becoming an Exon Splice Silencer (ESS)
- ESS sites become binding sites for proteins (e.g. RNPA1) which prevent
access to normal splicing proteins - C→ T causes exon 7 not to be spliced into mRNA in 90% of transcripts. But 10% still contains Exon 7. mRNA lacking exon 7 unstable and degraded (90%)
- ## mRNA with exon 7 stable and forms working SNM protein
SMA Therapy: Viral Approach
Disadvantages of Viral Approach
Solution to Viral Approach
Antisense Oligonucloetide (AON) approach
Duchenne Muscular Distrophy
Becker Muscular Distrophy
History of Duchenne Muscular Distrophy
Dystrophin Gene
Dystrophin Gene Structure
Duchenne Mutations
Therapeutic Reagents: AON
Therapeutic Reagents: AAV
Immunogenicity problems with AAV Gene therapies
