W1: Neuromuscular pathologies Flashcards
Describe the structure of skeletal muscle
A sarcomere consists of myofilaments (actin and myosin).
These are arranged together in a myofibril.
Myofibrils are grouped together into a muscle fibre (muscle cell), withintin the cell there will be multiple peripheral nuclei, sarcolemma and a sarcooplasm.
Each muscle fibre is surrounded by endomysium.
Group together to form muscle fascicles which are surrounded by periymysium
Group together the form muscle surrounded by epimysium.
What is the process of action potential generation at a neuromuscular junction?
Action potential at nerve terminal causes release of ACh from nerve terminal
Binds to nicotinic receptors on the motor end plate, these are ligand gated Na+ channels that allow the influx of Na+ causing depolarisation of the membrane, when depolarisation is above threshold voltage-gated Na+ channels also open furthering depolarisation so action potential can be reached.
Depolarisation spread along the sarcolemma and transverse tubules.
T tubules contain dihydropyridine receptors (voltage-gated Ca2+ channels), the activation of these receptors causes a conformational change in themselves and ryanodine receptors in the close proximity sarcoplasmic reticulum, this allows Ca2+ to be released from the SR into the sarcoplasm and cause muscle contraction.
Hence Ca2+ provides the link in excitation-contraction coupling.
What is a motor unit?
All the muscle fibres innervated by the same motor neuron
What is a motor end plate?
Also referred to as a neuromuscular junction
Is a site of specialised chemical synpase between the terminal branches of an axon and a muscle fibre.
What protein is involed in limb girldel muscular dystrophy?
The sarcoglycan complex in the sarcolemma.
What are the clinical presentations of DMD?
Positive Gowers sign
Hypertrophy of the calf
Loss of motor development (regression or failure)
Loss of or late milestones
Waddling gait
Characterised by Proximal muscle weakness
Heel cord shortening
Blunted intellect
TYpically tend to be a male patient aged 3-6yrs
Progressive condition often wheelchari bound to adolescence and cardiac arrhythmias and respiratory problems in later stages.
What is the difference between Becker and Duchenne’s muscular dystrophy on a pathogenesis level?
Both are mutations in the same gene - dystrophen protein
Beckers - in frame mutation, typically mis-sense mutation. Some function of dystrophen protein remains, as the crucial ABD and CR,CT domains remain
Duchennes - out of frame mutation tends to be frameshift or non-sense mutation. Loss of function of protein. As the cystene binding domain tends to be absent.
What are the differences in the clinical presentations of Duchennes and Beckers Muscular Dystrophy?
Beckers - diagnosed from age 5 upwards, typically up to 15 years old but can be after this. life expectancy of 40-50yrs, often able to walk until teens and early adult life, often from cardiac effects before skeletal problems
Duchennes - diagnosed between 3-6 years, life expectancy around 20-30yrs, wheelchair-bound by early teenage years, muscular skeletal symptoms are obvious from early on.
Describe the role of dystrophin protein.
In skeletal muscle is part of a large complex of sarcolemma associated proteins that provides stability to the sarcolemma.
Protein consist of an N-terminal actin binding domain (ABD1) a central rod domain containing 4 hinge regions and 24 spectrin-like repeats, cystein rich domain for binding a beta dystroglycan and a C-terminus domain.
These carboxyl-terminal domains are important for anchoring to the sarcolemma via the dystrophin-glycoprotein complex, which then links to the endomysium by laminin.
This maintains the structural integrity os muscle fibre.
Has total of 79 exons
Explain the consequences of a malfunctional dystrophin protein that is seen in DMD.
Non functional protein leads to inability to anchor actin to sarcolemma then endomysium
Therefore intracellular contractile forces are not spread from the sarcolemma to the ECM
Can lead to small membrane tears and calcium ion influx, accumulates in nucleus (alter gene expression) and the mitochondria (holes in membrane release of cytochrome C triggering apoptosis pathway) that cause myofibre degeneration.
What are the morphological changes shown in muscle fibres in both DMD and BMD?
Variation in myofibre diameter
Increased numbers of internalized nuclei
Degeneration necrosis and phagocytosis of muscle fibres
Proliferative of endomysial connective tissue
late stage - muscle replaced by adipose tissue and water
What is the common presentation of limb-girdle muscular dystrophy?
Common onset in later childhood or early adulthood
Muscle weakness in hips and things - struggle standing up, back pain, difficulty climbing stairs
Muscle weakness in arms - struggle lifting heavy objects, struggle to lift arms above the head.
Loss of muscle mass in affected areas
What is the pathogenesis of limb-girdle muscular dystrophy?
Autosomal recessive condition fot type 2 or autosomal dominant for type 1.
Specific to LGMD 2F involves mutations in the δ-sarcoglycan gene, role in anchoring actin filaments to the sarcolemma
Weakness in the pelvic or shoulder girdle
Variable progression
Muscle fibre destruction and regeneration (milder than DMD)
Where is the dystrophin gene expressed?
How?
Dystrophin is expressed predominantly in smooth, skeletal and cardiac muscle as well as some brain neurons.
Has eight different promoters hence allows different functional proteins to be made from the same gene. These different proteins are all dystrophin isoforms.
What is meant by a hinge region in DNA?*
Region that in a functional protein will link to other functional units together
What is a spectrin repeat region in DNA?*
Codes for a a specifc protein shape - three alpha helical coiled coils
What promotor acts on the dystrophin gene to form the dystrophin gene relevant in skeletal muscle in DMD?
Dp427m.
