Case 3: David Beatty

Gross Motor Development Milestones: ≤ 1 Year

2 months:

• Raise head

4 months:

• Head control

• Prop up on forearms

6 months:

• Rolling

• Prop up on hands

9 months:

• Sit independently

12 months:

• Stand

• Cruising

Gross Motor Development Milestones: > 1 Year

18 months:

• Unassisted walking

2 years:

• Running

• Walk up stairs

2.5 years:

• Jumping

3 years:

• Dress independently

4 years:

• Catch big ball

5 years:

• Hop on 1 foot

Skeletal Muscle Cell

Elongated + multiple nuclei

Parts:

• Sarcolemma

• Sarcoplasm

• Sarcoplasmic reticulum (SR)

Skeletal Muscle Cell: Sarcolemma

Cell membrane

Invaginations = Transverse (T)-tubules

Transmit action potential (AP) to SR = Quick Ca2+ release = Muscle contraction

Skeletal Muscle Cell: Sarcoplasm

Cytoplasm

Skeletal Muscle Cell: Sarcoplasmic Reticulum (SR)

Store Ca2+

L-tubule network

• Terminal Cisternae: L-tubule ends

2 terminal cisternae on 1 T-tubule = Quick Ca2+ release

Skeletal Muscle: Myofilaments

Protein fibres in muscles

Contain:

• Actin

• Myosin

Skeletal Muscle: Actin Myofilament

Thin filaments

Regulatory Proteins:

• Tropomyosin: Block myosin-binding sites

• Troponin: Interact with Ca2+

Function: Foundation for myosin sliding during contraction

Skeletal Muscle: Myosin Myofilament

Thick filaments

2 heave + 2 light protein chains

Domains:

• Head: Actin + ATP binding sites

  • ATPase activity

• Neck: 2 light chains attached to heavy chain

  • Regulate head

• Tail: Heavy chains coil together

  • Heads on both sides

Function: Slide along actin filaments

Skeletal Muscle: Sarcomere

Functional unit

Parts:

• Z band

• M band

• I band

• A band

Sarcomere: Z Band

Separate sarcomeres (1 sarcomere length)

• Attached to actin filaments

Contraction = Decrease distance

Sarcomere: M Band

Attached to myosin filaments

H zone centre

Sarcomere: I Band

Actin filaments

Contraction = Actin slide over myosin = Decrease size

Sarcomere: A Band

3 segments

• H Zone:

  • Centre light segment

  • Myosin filaments

  • Contraction = Actin slide over myosin = Decrease size

• Dark Segments:

  • Between H zone + I bands

  • Overlapping actin + myosin filaments

Skeletal Muscle: Excitation-Contraction Coupling

At motor endplate (closest to motor neuron axon)

1. AP from LMN = Open presynaptic voltage-gated Ca2+ channels = Stimulate ACh release from vesicles into synaptic cleft

2. ACh bind postsynaptic cholinergic receptors = Muscle fibre depolarize = Stimulate Ca2+ release from SR into sarcoplasm (intracellular)

Skeletal Muscle: Crossbridge Cycle

Somatic control

1. Crossbridge Formation

2. Powerstroke

3. Crossbridge Loosening

4. Reorientation

5. Relaxation

Crossbridge Cycle 1: Crossbridge Formation

1. Intracellular Ca2+ bind troponin C = Conformation change

2. Tropomyosin uncover myosin binding site on actin = Myosin head (bound to ATP) bind actin at 90º

Crossbridge Cycle 2: Powerstroke

1. ATP hydrolysis = Myosin head release phosphate (Pi) = Myosin head tilts 45º = Pull myosin along actin

2. Muscle shortens (contracts) = Release ADP

Crossbridge Cycle 3: Crossbridge Loosening

New ATP bind myosin head = Myosin head detaches from actin

Crossbridge Cycle 4: Reorientation

1. ATPase on myosin head = ATP hydrolysis → ADP + Pi = Myosin head conformation change

2. Myosin return to original position = Ready for new actin attachment

Crossbridge Cycle 5: Relaxation

1. Ca2+ → SR = Decrease intracellular Ca2+

2. Tropomyosin cover myosin binding site on actin = Muscle relaxes

Myopathies: Types

Inflammatory myopathy (myositis)

Metabolic myopathy

Congenital structural myopathy

Dystrophy

Inflammatory Myopathy: Description

Acquired autoimmune disorders causing muscle inflammation

Inflammatory Myopathy: Onset

Adult

Dermatomyositis: Children

Inflammatory Myopathy: Progression

Subacute onset

Inflammatory Myopathy: Clinical Presentation

Subacute symmetric proximal muscle weakness

• Shoulder

• Hip

Skin rashes

Inflammatory Myopathy: Muscle Biopsy Findings

Mononuclear cell infiltration

Dermatomyositis: Perifascicular atrophy

Metabolic Myopathy: Description

Inherited energy metabolism disorders in muscles

Metabolic Myopathy: Onset

Variable (children + adults)

Metabolic Myopathy: Progression

Episodic

Metabolic Myopathy: Clinical Presentation

Exercise intolerance (rhabdomyolysis)

Muscle cramps

Myalgia

Metabolic Myopathy: Muscle Biopsy Findings

Glycogen accumulation

Lipid accumulation

Abnormal mitochondria

Congenital Structural Myopathy: Description

Inherited structural muscle disorders

Congenital Structural Myopathy: Onset

Congenital

Early childhood

Congenital Structural Myopathy: Progression

Static OR slow progression

Congenital Structural Myopathy: Clinical Presentation

Hypotonia + hyporeflexia

Facial weakness

Proximal muscle weakness

Low muscle bulk

Congenital Structural Myopathy: Muscle Biopsy Findings

Structural abnormalities without inflammation + necrosis

Dystrophy: Description

Inherited progressive degenerative muscle disorders

Dystrophy: Onset

Children

Dystrophy: Progression

Fast progression

Dystrophy: Clinical Presentation

Progressive proximal muscle weakness

Dystrophy: Muscle Biopsy Findings

Muscle fibre size variation

• Necrosis

• Regeneration

• Fibrosis

• Fat replacement

Protin deficiencies

Progressive Muscular Dystrophy: Description

Progressive degenerative disorders affecting MSK system

Types:

• Duchenne muscular dystrophy (DMD)

• Becker muscular dystrophy (BMD)

• Limb-girdle muscular dystrophy

• Facioscapulohumeral dystrophy

Progressive Muscular Dystrophy: Epidemiology

DMD: Affect males only

• 2-5 years

BMD: Affect males only

• > 15 years

Progressive Muscular Dystrophy: Etiology

X-linked recessive chromosomal mutations of dystrophin gene

DMD: Frameshift deletion or nonsense mutation = Short/absent protein

BMD: In-frame deletion = Dysfunctional protein

Progressive Muscular Dystrophy: Pathophysiology

1. Dystrophin gene mutation = Alter dystrophin protein structure = Impair protien function

• Dystrophin Protein: Connect striated muscle cytoskeleton actin filaments to membrane-bound a/b-dystroglycan = Anchor to ECM

2. Loss of muscle integrity + stability = Muscle cell necrosis = Replace with connective tissue + fatty tissue

3. Weak muscles + large appearance (pseudohypertrophy)

Progressive Muscular Dystrophy: Clinical Presentation

DMD:

• Progressive muscle paresis + atrophy

  • Start in proximal lower limbs (pelvic girdle)

  • Progress to upper body + distal limbs

• Weak reflexes

• Calf pseudohypertrophy

• Scoliosis or lumbar lordosis

• Difficulty walking + standing

  • Waddling gait

  • Trendelenburg sign

  • Gower sign: Support with hands on thighs + walk up body until standing

• Cardioresp:

  • Dilated cardiomyopathy

  • Arrhythmias

  • Resp insufficiency

BMD:

• Less severe than DMD

• Slower progression

Progressive Muscular Dystrophy: Investigations

Blood tests

DNA test

Muscle biopsy

Progressive Muscular Dystrophy Investigations: Blood Tests

Increased creatine kinase

• Normal: Greater in Black pts

  • Males: 200 U/L

  • Females: 150 U/L

• Increased aldolase (glycolysis enzyme)

  • Normal: 1-7.5 U'/L

Progressive Muscular Dystrophy Investigations: DNA Test

Confirm diagnosis

Dystrophin gene mutation

Progressive Muscular Dystrophy Investigations: Muscle Biopsy

Inconclusive genetic analysis

Muscle fibre diameter changes throughout disease course

Muscle necrosis + replacement with connective/adipose tissue

DMD: No dystrophin

BMD: Decreased dystrophin

Progressive Muscular Dystrophy: Treatment

Nonpharmacological

Pharmacological

Progressive Muscular Dystrophy Treatment: Nonpharmacological

Physiotherapy

Orthopedic assistive devices

Ventilation

Psychological support

Progressive Muscular Dystrophy Treatment: Pharmacological

DMD:

• Glucocorticoids (prednisone, deflazacort)

• Eteplirsen: Bind exon 51 in dystrophin RNA = Prevent splicing = Produce functional truncated protein

BMD: Glucocorticoids

Progressive Muscular Dystrophy: Complications

Cardiomyopathy

Respiratory failure

Progressive Muscular Dystrophy Complications: Cardiomyopathy

DMD: Usual cause of death (30 years)

BMD: Reduced life expectancy (40-50 years)

Pathophysiology: Commonly dilated

• Dystrophin protein dysfunction in cardiac muscle = Myocyte necrosis + replacement with connective/adipose tissue

• Ventricular dilation = Decreased contractility + ejection fraction

Progressive Muscular Dystrophy Complications: Respiratory Failure

DMD: Usual cause of death

Pathophysiology:

• Dystrophin protein dysfunction in diaphragm = Muscle remodelling + necrosis = Respiratory failure

  • Ineffective cough

  • Atelectasis