B106 Muscular atrophy, dystrophies, and myositis

Question 1

Types/causes of muscular atrophy

Answer 1

Neurogenic Atrophy:

• Denervation injury causes a lack of trophic support and stimulation to the muscle.
• Normal skeletal muscle tissue has well mixed muscle fibers, innervated by different fiber types.
  
  • i. Slow twitch – type I – aerobic
    ii. Fast twitch – type II – anaerobic
  • Fiber types can be differentiated by an ATPase stain at pH 9.4. Type 1 aerobic, slow twitch fibers are lighter stained.
• After neuron injury surviving neurons send out sprouts and innervate large groups of adjacent neurons
• The neurons all then take on the type associated with that innervating neuron, resulting in fiber type grouping.
• Further damage causes clusters of fibers to atrophy.

Simple disuse atrophy

• type II anaerobic fibers are more affected
• causes random, dispersed atrophy of the myofibers.

Glucocorticoid atrophy, Endogenous or Exogenous

• ​Also affects type II fibers, specifically of the proximal muscles.
• dispersed distribution of atrophy.

Myopathy related atrophy

• Will have additional features,
• myofiber degeneration and regeneration and chronic remodelling
• inflammatory infiltration.

Question 2

How are inherited muscle disorders classically grouped?

Answer 2

Congenital Muscular dystrophies: inherited disorders whose symptoms are present at birth and progressively deteriorate.

Muscular dystrophies: stil inhereited disorders, but the symptoms take time to manifest and patients appear normal at birth, progressively get worse.

Congenital myopathies: inherited disorders, apparent at birth, but defects are static.

Question 3

Myopathy vs dystrophy

Answer 3

Dystrophies:

• Dystrophies are a subtype of myopathy
• Dystrophies involve muscle fiber degeneration and regeneration cycles
• Dystrophies are progressive diseases

Myopathies is a general term for any muscle disease, and are generally static, not progressing.

Question 4

List the muscular dystrophies

Answer 4

Duchenne and Becker muscular dystrophy

Limb Girdle muscular dystrophies

EMD, Emery-Dreifuss Dystrophy

Myotonic Dystrophy

Question 5

What causes Duchene and Becker muscular dystrophy,

Answer 5

Caused by deletions in the dystrophin gene on the X chromosome. Dystophyin is one of the largest genes in the human genome, target for mutaiton. Mutations are usually deletions, can be frameshift or point mutations. It is the most common type of muscular dystrophy

Familial cases are 2/3rds of DBMD, and 1/3 are sporadic.

Dystrophin links the muscle sarcomere to the cell membrane and to the extracellular matrix.

Defective dystrophin causes a failur of transferring the contraction forces to the ECM.

Duchene Dystrophy patients have virtually no dystrophin, and a very sever disease.

Becker dystrophy has low levels of dystrophin and a milder disease.

Question 6

Clinical features and presentation of Duchene and Becker muscualr dystrophy

Answer 6

Duchenne dystrophy:

• not apparent at birth
• first sign is delayed crawling/walking
• weakness first begins in the pelvic girdle, and next the shoulder girdle
• pseudohypertrophy of the calf is a major early finding by around age 5.
  
  • hypertrophy is due initially to myofiber hypertrophy
  • followed by degeneration and replacement by adipose tissue.
• Patients are wheelchair bound by early teens
• Inevitably die by young adulthood.
• Mortality is from:
  
  • Respiratory insufficiency,
    
    • Secondary pulmonary infections
  • Cardiac muscle degeneration and fibrosis
    
    • Fatal Arrythmias

Becker dystrophy

• Symptoms do not appear until late childhood/adolescence
• Progresses slowly and with more variability.
• Can live until late adulthood and have an almost normal lifespan.
• Cardiac problems usually dominate, atrophy and fibrosis predisposing to arrythmias late in life.

Question 7

Myotonic dystrophy, cause and pathogenesis

Answer 7

Autosomal dominant inheritance (or spontaneous acquisition) of CTG repeat expansion in the 3’ untranslated region of the DMPK protein kinase. Dystrophia Myotonica Protein Kinase (convenient). Expressed in the heart and skeletal muscle.

The severity of the disease is directly correlated to the degree of CTG expansion. But the exact mechanism of pathogenesis is unclear.

Exhibits anticipation phenomenon, where successive generations of affected individuals get worse symptoms.

Has characteristic long strings of centrally located nuclei (not peripherally) within the muscle fibers.

Question 8

Myotonic dystrophy, clincial presentation

Answer 8

Symptoms appear in late childhood. Involve the sustained, involuntary contraction of a muscle or group of muscles, that progresses to degeneration and weakness of those muscles.

Gait abnormalities, then problems with intrinsic hand muscles.

Inability to release their grip is a common first complaint.

Cardiac symptoms present as cardiac arrythmias.

Other symptoms:

• cataracts
• early balding
• testicular atrophy
• endocrinopathies

Question 9

Limb Girdle muscular dystrophies, cause and symptoms

Answer 9

Heterogenous genetic basis.

• other components of the dystrophin-gylcoprotein complex
• calveolin-3
• dysferlin, involved in vesicle transport and membrane repair.

Characterized by dystrophy that affects the proximal muscles of the trunk and limbs.

Question 10

Emery Dreifuss Muscular Dystrophy (EMD) cause and symptoms

Answer 10

Rare disorder. Heterogenous mutations that affect nuclear structural proteins such as Lamin

Can be X-linked or autosomal.

Theory is that the muscle cells are compromised because their nuclei are subjected to repetitive/chronic stress.

Causes progressive muscle weakness and muscle wasting.

Elbow and ankle contractures (muscle tightening causing limited motion)

Severe cardiac disease causing cardiomyopathy and fatal arrythmias in 40% of patients.

Question 11

Fascio-Scapulo-Humeral dystrophy

Answer 11

Autosomal dominant dystrophy.

Caused by deletions in chromosome 4q35. Unknown how this deletion causes the disease

At about age 20, the first sign is facial muscle and shoulder muscle weakness.

There is no cardiac involvement, and life expectancy is normal.

Question 12

What are the types and causes of myositis?

Answer 12

Polymyositis:

Autoimmune disorder increased MHC class 1 expression by myofibrils. Infiltration of cytotoxic CD8 Tc cells into the endomysium. myofibril necrosis and subsequent regeneration. Successfully treated with immune suppression.

Dermatomyositis:

Autoimmune basis with perivascular mononuclear cell infiltrates and myofibril damage and degeneration in a paraseptal and parafasicular pattern. Central fibers are more spared.

Spontaneous occurence in children, as the most common inflammatory myopathy.

Paraneoplastic syndrome in adults.

Inclusion body myositis

The most common inflammatory myopathy in the elderly. Unclear cause. Morphologic hallmark is rimmed vacuoles containing aggregates of neurodegenerative proteins: hyperphosphorylated tau. beta-amyloid precursor protein derivatives.

Myofibril degeneration, mononuclear cell infiltration, endomysial fibrosis, and fatty replacement.

Chroni, progressive disease that is not affected by immunosuppressive agents, sugggesting the inflammation is a consequence and not a cause.

Other primary immune disorders that can cause secondary myositis:

• SLE
• Sarcoidosis

Question 13

What are the ion channel myopathies

Answer 13

Familial disorders due to mutations in ion channels.

Relapsing episodes of myotonia and hypotonic paralysis, and respective hyper/hypokalemia.

Some are caused by mutations to the Sodium channel protein SCN4A

Rare symptom is malignant hyperthermia caused by mutations to the Ryanodine receptor releasing calcium into muscles.

Question 14

What are some characteristics of the mitochondrial myopathies?

Answer 14

Show maternal inheritance,

Proximal muscle weakness

Severe ocular muscle waeakness

neurologic symptoms

lactic acidosis

cardiomyopathy

Ragged Red fibers = aggregates of abnormal mitochondria.

Parking lot inclusions = crystalline inclusions.